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Just listened to Matt's presentation at the Bloom Burton conference from today and it explains the bump/reversal today. Finally some very frank open talk about interest from Pharma, multiple deals being worked on both global and regional and a confidence that is refreshing to hear. Somebody pinch me.
Looks like giving up the Japan market may be the best way to make the first registration pathway happen without little dilution. The burn rate was $1 mil /Month as almost all clinical programs have been halted to focus on regulatory and business deals.
Very impressive clinical results and an ASCO presentation coming up that seems to suggest that Reolysin can potentiate the effects of the best-selling cancer drugs today. Manufacturing needs a bump in scale but that is great to hear that at the 100 Liter scale 30 batches would be needed per year to service the breast cancer market if I heard him right. Matt led the bump in scale last time and I feel he is the right person to lead the company in the near term until a partner (or partners) are named.
Given all the stock I own and having been an owner for more than 10 years, I never thought I'd be thinking of buying more but I find it hard to resist lowering my current underwater holding basis at this point.
Any thoughts from people that have been here a while?
onco_investor
Good to see this company finally making some progress.
More Anecdotal Evidence - UK
http://www.thestar.co.uk/news/health/local-health/healthy-living-1-5465469
12 years ago John was told he had terminal cancer, but he’s still Living the Dream
Nothing could have prepared John Price for the heartbreaking prospect of not living to see his two children grow up - the bleak future he faced when doctors delivered the devastating news that he was suffering from terminal cancer.
But 12 years on, John, aged 59, is still living life to the full and looking forward to building precious family memories that once seemed an impossible dream.
His survival is thanks to a ground-breaking drugs trial at Sheffield’s Weston Park Hospital - and after 10 years of being clear from cancer, John is hoping to fund further pioneering research by raising a record amount of money for the hospital, while at the same time raising awareness of prostate cancer.
John, from Sandygate, holds an annual golf day in aid of Weston Park, and hopes to reach a total of £120,000 with this year’s event, which will be followed by a Blues Brothers night the following evening, involving family, friends, businesses and sponsors.
“Put very simply, the research study at Weston Park Hospital saved my life and meant that I was able to see my children grow up,” he said.
“I will be forever grateful to Weston Park Hospital and will gladly continue to support and fund the groundbreaking research and treatment that happens there every single day. I would urge anyone, if worried, to visit the doctors and get checked out.”
John was initially diagnosed with kidney cancer in 1998. Although he made a good recovery, in 2001 he was given the devastating news that he had developed secondary cancers and this time the diagnosis was terminal.
At the same time, Weston Park was conducting a research study into the use of a new form of cancer treatment called ‘magic bullets’.
John was able to participate in the trial, which resulted in the four tumours that had developed significantly decreasing in size and eventually disappearing entirely.
The experiment involved using the drug Reolysin, which contains particles of a harmless virus which normally causes stomach upsets.
The common virus is injected into patients and boosts their immune systems, blasting away tumours. Used alongside radiotherapy, it creates a potent combination that makes the disease more treatable.
Clinical oncologist Professor Barry Hancock, who treated John, said: “Eleven years ago John came to the clinical trials centre when his kidney cancer had started to spread.
“He enthusiastically agreed to take part in a Medical Research Council international clinical trial involving new biological therapies and in which Sheffield was one of the lead investigators. It was wonderful to see the cancer clear completely on this treatment and we are delighted that John remains in complete remission to this day.”
John said he later developed further issues which he feared were the first signs of prostate cancer.
“I experienced urological problems and my initial thoughts were that it could be prostate cancer, but luckily this was not the case,” he said.
John - whose wife, Anne, works as an administrator for the cancer charity - has since gone on to see both of his sons marry, as well as becoming a grandfather for the first time.
Seeing his father’s fight against cancer and the care also inspired John’s eldest son, James, to become a doctor.
This year’s golf day is happening at the Hallamshire Golf Club on Friday July 12, involving 55 teams making their way around the course dressed as characters from the film The Blues Brothers.
Last year’s event raised more than £26,000 for the teenage cancer unit at Weston Park, and John is eager to raise more this year with support from local firms such as the Special Steel Group and Westfield Health.
The day, already a sell-out, will be rounded off with an auction and raffle.
* Visit www.wphcancercharity.co.uk for more information on how to support Weston Park Hospital or call 0114 226 5370.
Enrollment Completed in NCI Randomized Pancreatic Trial
http://www.oncolyticsbiotech.com/news/press-release-details/2014/Oncolytics-Biotech-Inc-Announces-Completion-of-Patient-Enrollment-in-US-Randomized-Phase-II-Pancreatic-Cancer-Study/default.aspx
Oncolytics Biotech® Inc. Announces Completion of Patient Enrollment in U.S. Randomized Phase II Pancreatic Cancer Study
CALGARY, July 8, 2014 /CNW/ - Oncolytics Biotech Inc. ("Oncolytics") (TSX:ONC, NASDAQ:ONCY) today announced completion of patient enrollment in a two-arm randomized phase II study of carboplatin, paclitaxel plus REOLYSIN® versus carboplatin and paclitaxel alone in the first line treatment of patients with recurrent or metastatic pancreatic cancer (OSU-10045). The principal investigator is Tanios Bekaii-Saab, MD, associate professor and gastrointestinal oncology section chief at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James). The trial is sponsored by the U.S. National Cancer Institute (NCI) through a clinical trials agreement between the Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis and Oncolytics. Oncolytics is providing clinical supplies of REOLYSIN for the study.
"This is the second randomized study utilizing REOLYSIN to complete enrollment," said Dr. Brad Thompson, President and CEO of Oncolytics. "This is an important study given the relatively limited treatment options and generally poor prognosis for pancreatic cancer patients, who are often not diagnosed until the more advanced stages of the disease."
The study is an open-label, multi-institution, two-arm phase II randomized study of patients with metastatic pancreatic cancer. Patients were randomized to receive either carboplatin, paclitaxel plus REOLYSIN (Arm A) or carboplatin and paclitaxel alone (Arm B). Patients in both arms received treatment every three weeks (21-day cycles) and standard intravenous doses of paclitaxel and carboplatin on day one only. In Arm A, patients also received intravenous REOLYSIN at a dose of 3x1010 TCID50 on days one through five. Tumor response assessment was done by computed tomography (CT) scan and conducted every eight weeks. Patients who progressed on carboplatin and paclitaxel (Arm B) had REOLYSIN added. If patients experienced significant toxicity related to carboplatin and/or paclitaxel, they could continue with single agent REOLYSIN.
The primary objective of the trial is to assess improvement in progression-free survival with REOLYSIN, carboplatin and paclitaxel relative to carboplatin and paclitaxel alone in patients with metastatic pancreatic cancer. The primary endpoint is progression free survival in both arms. Secondary endpoints include overall response rate and overall survival. The study enrolled 70 evaluable patients at test centers across the United States.
As the sponsor of the study, the NCI is responsible for following patients and collecting and collating all patient data. Once complete, the data will be analyzed and provided to Oncolytics.
Bekaii-Saab, principal investigator of the clinical study, has no financial interests in Oncolytics, manufacturer of the investigational drug REOLYSIN.
About Pancreatic Cancer
The American Cancer Society estimates that 46,420 Americans will be diagnosed with pancreatic cancer and an estimated 39,590 Americans are expected to die from the disease in 2014. The prognosis for patients diagnosed with pancreatic cancer, regardless of stage, is generally poor; the relative five-year survival rate for all stages combined is approximately six percent.
About The OSUCCC - James
The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 228-bed adult patient-care component, The James is a "Top Hospital" in the nation as ranked by U.S.News & World Report.
About Oncolytics Biotech Inc.
Oncolytics is a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of later-stage, randomized human trials in various indications using REOLYSIN®, its proprietary formulation of the human reovirus. For further information about Oncolytics, please visit: www.oncolyticsbiotech.com.
Enrollment completed for NCI Randomized Ovarian Trial
http://www.oncolyticsbiotech.com/news/press-release-details/2014/Oncolytics-Biotech-Inc-Announces-Completion-of-Patient-Enrollment-in-US-Randomized-Phase-2-Ovarian-Cancer-Study/default.aspx
Oncolytics Biotech® Inc. Announces Completion of Patient Enrollment in U.S. Randomized Phase 2 Ovarian Cancer Study
09/03/2014
CALGARY, Sept. 3, 2014 /CNW/ - Oncolytics Biotech Inc. ("Oncolytics") (TSX:ONC, NASDAQ:ONCY) today announced that patient enrollment has been completed in a randomized Phase 2 study of paclitaxel plus REOLYSIN® versus paclitaxel alone in patients with persistent or recurrent ovarian, fallopian tube or primary peritoneal cancer (GOG186H). The study chair is David E. Cohn, MD, gynecologic oncology division director at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). This is a legacy study done by the Gynecologic Oncology Group, now incorporated into NRG Oncology. The trial is sponsored by the U.S. National Cancer Institute (NCI) through a Clinical Trials Agreement between the Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, NCI and Oncolytics. Oncolytics is providing clinical supplies of REOLYSIN.
"Our randomized clinical program continues to gather momentum as this is the second randomized study sponsored by the NCI that has completed enrollment in the last quarter," said Dr. Brad Thompson, President and CEO of Oncolytics. "Ovarian cancer is often diagnosed at a very late stage, requiring more aggressive interventions and resulting in relatively low five-year survival rates."
The current study is a randomized Phase 2 trial of weekly paclitaxel versus weekly paclitaxel with REOLYSIN in patients with persistent or recurrent ovarian, fallopian tube or primary peritoneal cancer. Patients were randomized to receive either paclitaxel alone or paclitaxel plus REOLYSIN. Patients in both arms received treatment with paclitaxel, with the second arm also receiving intravenous REOLYSIN. Patients received standard doses of paclitaxel on days one, eight, and 15 every 28 days. In the second arm, patients received, on days one through five of each 28-day cycle, intravenous REOLYSIN at a dose of 3x1010 TCID50.
The primary objectives of the trial are to estimate the progression-free survival hazard ratio of the combination of weekly paclitaxel with REOLYSIN to weekly paclitaxel alone in patients with persistent or recurrent ovarian, fallopian tube, or primary peritoneal cancer and to determine the frequency and severity of adverse events associated with treatment with weekly paclitaxel alone and weekly paclitaxel with REOLYSIN as assessed by Common Terminology Criteria for Adverse Events (CTCAE). The secondary objectives are to estimate the progression-free survival and overall survival of patients treated with weekly paclitaxel alone and weekly paclitaxel with REOLYSIN; to estimate (and compare) the proportion of patients who respond to the regimen on each arm of the study (according to RECIST 1.1 with measurable patients and by CA-125 for those patients with detectible disease only); and to characterize and compare progression-free survival and overall survival in patients with measurable disease (RECIST 1.1 criteria) and patients with detectable (nonmeasurable) disease. The study enrolled approximately 150 patients.
NRG Oncology is responsible for following patients and collecting and collating all patient data. Once complete, the data will be analyzed and provided to NCI and Oncolytics.
About Ovarian Cancer
The American Cancer Society estimates that 21,980 American women will be diagnosed with ovarian cancer and an estimated 14,270 will die from the disease in 2014. Ovarian cancer accounts for about 5% of all cancer deaths among women. The prognosis for patients diagnosed with ovarian cancer at the localized stage is good with a five-year survival rate of 92%; however, only about 15% of cases are diagnosed at this stage. The relative 10-year survival rate for all stages combined is approximately 35%.
About The OSUCCC – James
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 228-bed adult patient-care component, The James is a "Top Hospital" in the nation as ranked by U.S. News & World Report. In December 2014, Ohio State will open a new 1.1 million square foot, 21-floor James Cancer Hospital and Solove Research Institute. The freestanding hospital will feature the nation's first fully integrated cancer emergency department and above-ground radiation therapy center as well as a precision cancer medicine clinic and distinct subspecialty care floors with integrated translational research labs.
Updated Investor's Prseentation - Aug 17th
http://www.oncolyticsbiotech.com/files/doc_presentations/Investor-Presentation-August-17-2014.pdf
Dr Patrick Lee Reovirus in Cancer Therapy -Research
http://www.dovepress.com/reovirus-in-cancer-therapy-an-evidence--based-review-peer-reviewed-article-OV
Reovirus in cancer therapy: an evidence-based review
Authors: Clements D, Helson E, Gujar SA, Lee PWK
Published Date July 2014 Volume 2014:3 Pages 69 - 82
DOI: http://dx.doi.org/10.2147/OV.S51321
Received: 05 April 2014 Accepted:29 April 2014
Published:09 July 2014
Derek Clements,1,* Erin Helson,2,* Shashi A Gujar,2,3 Patrick WK Lee1,2
1Department of Pathology, 2Department of Microbiology and Immunology, Dalhousie University, 3Strategy and Organizational Performance, IWK Health Center, Halifax, Nova Scotia, Canada
*These authors contributed equally to this work, and are joint first authors
Abstract: Reovirus, a double-stranded ribonucleic acid virus and benign human pathogen, preferentially infects and kills cancer cells in its unmodified form, and is one of the leading oncolytic viruses currently undergoing clinical trials internationally.
With 32 clinical trials completed or ongoing thus far, reovirus has demonstrated clinical therapeutic applicability against a multitude of cancers, including but not limited to breast cancer, prostate cancer, pancreatic cancer, malignant gliomas, advanced head and neck cancers, and metastatic ovarian cancers. Phase I trials have demonstrated that reovirus is safe to use via both intralesional/intratumoral and systemic routes of administration, with the most common adverse reactions being grade I/II toxicities, such as flu-like illness (fatigue, nausea, vomiting, headache, fever/chills, dizziness), diarrhea, and lymphopenia. In subsequent Phase II trials, reovirus administration was demonstrated to successfully decrease tumor size and promote tumor necrosis, thereby complementing compelling preclinical evidence of tumor destruction by the virus.
Importantly, reovirus has been shown to be effective as a monotherapy, as well as in combination with other anticancer options, including radiation and chemotherapeutic agents, such as gemcitabine, docetaxel, paclitaxel, and carboplatin. Of note, the first Phase III clinical trial using reovirus in combination with paclitaxel and carboplatin for the treatment of head and neck cancers is under way.
Based on the evidence from clinical trials, we comprehensively review the use of reovirus as an anticancer agent, acknowledge key obstacles, and suggest future directions to ultimately potentiate the efficacy of reovirus oncotherapy.
FDA Grants Fast Track for Oncolytic Virotherapy Glio
http://www.marketwatch.com/story/fda-grants-fast-track-status-to-dnatrix-drug-dnx-2401-for-recurrent-glioblastoma-2014-06-17
For those keeping score Frank Tufaro is on Oncolytics Advisory Board
http://investing.businessweek.com/research/stocks/people/board.asp?ticker=ONCY
The company is privately held and is only in Phase 1 trials and has treated 35 patients. FDA endorsement of a genetically modified OV is positive for all OV researchers.
http://www.dnatrix.com/science-and-technology/
DNAtrix founders Drs. Juan Fueyo and David Curiel designed and patented DNX-2401, a novel adenovirus that fulfilled the dual requirements of higher potency with excellent safety. To do this, the scientists engineered two stable genetic changes in the adenovirus dsDNA genome that cause it to (1) replicate selectively in retinoblastoma (Rb)-pathway deficient cells and (2) infect cells that express certain RGD-binding integrins more efficiently. Because virtually all tumor cells, including GB, are defective in Rb function and already in the cell cycle, DNX-2401 replicates in and kills these tumor cells selectively and efficiently. DNX-2401 is vastly superior to wild type adenovirus with respect to killing rapidly growing tumor cells, an unprecedented property for an oncolytic virus.
While DNX-2401 should be effective against multiple tumor types, we are initially focused on high-grade gliomas for three reasons: (1) these tumors remain confined to the brain, so patient assessment is not complicated by the presence of metastatic disease, (2) tumor responses can be accurately documented and presented to the FDA to support product approval, and (3), the path to regulatory approval has already been established for high-grade gliomas.
Insider buys 15000 ONCY shares on open market
http://canadianinsider.com/node/7?ticker=onc
Going viral with Cancer Immunotherapy
http://www.nature.com/nrc/journal/vaop/ncurrent/full/nrc3770.html
Going viral with cancer immunotherapy
Brian D. Lichty, Caroline J. Breitbach, David F. Stojdl & John C. Bell
Nature Reviews Cancer (2014) doi:10.1038/nrc3770
Published online 03 July 2014
Abstract• References• Author information
Recent clinical data have emphatically shown the capacity of our immune systems to eradicate even advanced cancers. Although oncolytic viruses (OVs) were originally designed to function as tumour-lysing therapeutics, they have now been clinically shown to initiate systemic antitumour immune responses. Cell signalling pathways that are activated and promote the growth of tumour cells also favour the growth and replication of viruses within the cancer. The ability to engineer OVs that express immune-stimulating 'cargo', the induction of immunogenic tumour cell death by OVs and the selective targeting of OVs to tumour beds suggests that they are the ideal reagents to enhance antitumour immune responses. Coupling of OV therapy with tumour antigen vaccination, immune checkpoint inhibitors and adoptive cell therapy seems to be ready to converge towards a new generation of multimodal therapeutics to improve outcomes for cancer patients.
NCI completes enrollment in Reolysin Pancreatic Cancer study
http://finance.yahoo.com/news/oncolytics-biotech-inc-announces-completion-103000550.html
Completion of Patient Enrollment in U.S. Randomized Phase II Pancreatic Cancer Study
PR Newswire Oncolytics Biotech Inc.
CALGARY, July 8, 2014 /PRNewswire/ - Oncolytics Biotech Inc. ("Oncolytics") (TSX:ONC, NASDAQ:ONCY) today announced completion of patient enrollment in a two-arm randomized phase II study of carboplatin, paclitaxel plus REOLYSIN® versus carboplatin and paclitaxel alone in the first line treatment of patients with recurrent or metastatic pancreatic cancer (OSU-10045). The principal investigator is Tanios Bekaii-Saab, MD, associate professor and gastrointestinal oncology section chief at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James). The trial is sponsored by the U.S. National Cancer Institute (NCI) through a clinical trials agreement between the Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis and Oncolytics. Oncolytics is providing clinical supplies of REOLYSIN for the study.
"This is the second randomized study utilizing REOLYSIN to complete enrollment," said Dr. Brad Thompson, President and CEO of Oncolytics. "This is an important study given the relatively limited treatment options and generally poor prognosis for pancreatic cancer patients, who are often not diagnosed until the more advanced stages of the disease."
The study is an open-label, multi-institution, two-arm phase II randomized study of patients with metastatic pancreatic cancer. Patients were randomized to receive either carboplatin, paclitaxel plus REOLYSIN (Arm A) or carboplatin and paclitaxel alone (Arm B). Patients in both arms received treatment every three weeks (21-day cycles) and standard intravenous doses of paclitaxel and carboplatin on day one only. In Arm A, patients also received intravenous REOLYSIN at a dose of 3x1010 TCID50 on days one through five. Tumor response assessment was done by computed tomography (CT) scan and conducted every eight weeks. Patients who progressed on carboplatin and paclitaxel (Arm B) had REOLYSIN added. If patients experienced significant toxicity related to carboplatin and/or paclitaxel, they could continue with single agent REOLYSIN.
The primary objective of the trial is to assess improvement in progression-free survival with REOLYSIN, carboplatin and paclitaxel relative to carboplatin and paclitaxel alone in patients with metastatic pancreatic cancer. The primary endpoint is progression free survival in both arms. Secondary endpoints include overall response rate and overall survival. The study enrolled 70 evaluable patients at test centers across the United States.
As the sponsor of the study, the NCI is responsible for following patients and collecting and collating all patient data. Once complete, the data will be analyzed and provided to Oncolytics.
Bekaii-Saab, principal investigator of the clinical study, has no financial interests in Oncolytics, manufacturer of the investigational drug REOLYSIN.
About Pancreatic Cancer
The American Cancer Society estimates that 46,420 Americans will be diagnosed with pancreatic cancer and an estimated 39,590 Americans are expected to die from the disease in 2014. The prognosis for patients diagnosed with pancreatic cancer, regardless of stage, is generally poor; the relative five-year survival rate for all stages combined is approximately six percent.
About The OSUCCC - James
The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 228-bed adult patient-care component, The James is a "Top Hospital" in the nation as ranked by U.S.News & World Report.
About Oncolytics Biotech Inc.
Oncolytics is a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of later-stage, randomized human trials in various indications using REOLYSIN®, its proprietary formulation of the human reovirus. For further information about Oncolytics, please visit: www.oncolyticsbiotech.com.
New Clinical Trial Announced Multiple Myeloma
http://clinicaltrials.gov/ct2/show/NCT02101944?term=reolysin&rank=16
New trial Sponsored by the US NCI - posted March 28, 2014
Principal Investigator: Craig Hofmeister Ohio State University
Purpose
This pilot clinical trial studies viral protein production after dexamethasone, wild-type reovirus, and carfilzomib in treating patients with multiple myeloma. Drugs used in chemotherapy, such as dexamethasone and carfilzomib, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. A virus called wild-type reovirus may be able to kill cancer cells without damaging normal cells and seems to work best when given with chemotherapy. Giving wild-type reovirus with chemotherapy may kill more cancer cells and be an effective treatment for multiple myeloma.
Further study details as provided by National Cancer Institute (NCI):
Primary Outcome Measures:
Reovirus replication as measured by reovirus capsid protein production [ Time Frame: Days 1 and 9 of first course ] [ Designated as safety issue: No ]
Adverse events based on Common Terminology Criteria for Adverse Events (CTCAE) criteria [ Time Frame: Up to 4 weeks post treatment ] [ Designated as safety issue: Yes ]
Tolerability (number and severity of toxicity incidents) of combination carfilzomib and wild-type reovirus assessed by CTCAE version 4 [ Time Frame: Up to 4 weeks post treatment ] [ Designated as safety issue: Yes ]
Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.
Number of patients who required dose modifications and/or dose delays in subsequent cycles [ Time Frame: Up to 4 weeks post treatment ] [ Designated as safety issue: Yes ]
Proportion of patients who go off treatment due to adverse reactions or refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial [ Time Frame: Up to 4 weeks post treatment ] [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
Number and percentage of subjects experiencing objective response [ Time Frame: Up to 4 weeks post treatment ] [ Designated as safety issue: No ]
Summary statistics will be computed for baseline biomarkers. The absolute and percent change from baseline will be calculated for each subsequent measurement. Summary statistics will be computed for each collection time point. The objective response rate will be analyzed by using a 95% confidence interval for the proportion responding at trial closure in the treated population.
Clinical benefit endpoint described as that portion of patients experiencing complete response (CR), very good partial response (VGPR), or partial response (PR) [ Time Frame: Up to 4 weeks post treatment ] [ Designated as safety issue: No ]
The objective response rate will be analyzed by using a 95% confidence interval for the proportion responding at trial closure in the treated population.
Duration of response [ Time Frame: Duration from first observation of partial response to the time of disease progression, up to 4 weeks post treatment ] [ Designated as safety issue: No ]
This time-to-event distribution will be evaluated using the methods of Kaplan and Meier, with a focus on graphical evaluation as well as early timepoint and median estimates of survival distributions.
Progression free survival [ Time Frame: Duration from start of treatment to disease progression or death, regardless of cause of death, whichever comes first, up to 6 months ] [ Designated as safety issue: No ]
This time-to-event distribution will be evaluated using the methods of Kaplan and Meier, with a focus on graphical evaluation as well as early timepoint and median estimates of survival distributions.
Time to progression [ Time Frame: Time from the start of the treatment until the criteria for disease progression are met, up to 4 weeks post treatment ] [ Designated as safety issue: No ]
This time-to-event distribution will be evaluated using the methods of Kaplan and Meier, with a focus on graphical evaluation as well as early timepoint and median estimates of survival distributions.
Other Outcome Measures:
Immunologic correlative markers [ Time Frame: Up to day 28 ] [ Designated as safety issue: No ]
Will descriptively summarize the continuous markers quantitatively. Patterns of change in the longitudinal data on these markers will be evaluated in this manner for each of the correlative outcomes of interest. Appropriate transformations of the various correlative markers will be used in the presence of skewed data distributions. Multiple comparison corrections will not be used for these secondary correlative analyses.
Estimated Enrollment: 12
Study Start Date: March 2014
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure
PRIMARY OBJECTIVES:
I. Determine safety and tolerability of reolysin (wild-type reovirus), carfilzomib and dexamethasone in patients with relapsed multiple myeloma.
II. Obtain evidence of reovirus protein production by immunohistochemical localization of reoviral capsid protein in myeloma cells from bone marrow biopsies obtained on cycle 1 day 9.
SECONDARY OBJECTIVES:
I. Obtain preliminary data on response as determined by International Myeloma Working Group criteria after protocol therapy.
II. Obtain pilot overall and progression free survival data for all treated patients.
III. Assess cytokine arrays of peripheral blood obtained on days 1, 2 and 9 to obtain exploratory data regarding inflammatory cytokine concentrations and their correlation with response.
IV. Cryopreserve marrow aspirates obtained cycle 1 day 1 and all subsequent marrow aspirates while on trial for future studies of genetic and epigenetic changes focused in part on endoplasmic reticulum (ER) stress, autophagy and reovirus resistance studies.
OUTLINE:
Patients receive dexamethasone intravenously (IV), carfilzomib IV over 10 minutes, and wild-type reovirus IV over 60 minutes on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 4 weeks and then every 6 months.
Amgen on Oncolytic Immunotherapy - Effects on ONCY?
What is Oncolytic Immuntherapy?
http://www.oncolyticimmunotherapy.com/
http://www.oncolyticimmunotherapy.com/stages/index.html
Engineer
Lyse
Alert
Find
Fight
Why is Amgen studying Oncolytic Immunotherapy for cancer?
Harnesing a virus by gene modification - What is Amgen doing?
"The virus is modified through the insertion, deletion, and/or inactivation of various genes designed to achieve desired effects, including tumor-cell selectivity, antigen presentation, and cytokine expression"
My comments to this... I see this website appearing now as Amgen's start of the education campaign needed to explain Oncolytic Immunotherapy to potential patients in clinical and eventual commercial acceptance with the intention of moving forward into this space with their BioVex purchase several years ago now and continuing clinical program using a modified Herpes Virus. Funny how the timeline of significant events exclude the discovery of Reovirus' potential in the 90s by Patrick Lee and Matt Coffey at Univ of Calgary.
Now what if the virus did not have to be "engineered" or start with a Herpes virus to fight but a natural unmodified Dearing 3 Reovirus being studied by the pioneers in the field, Oncolytics Biotech which was awarded the rights to try to commercialize the Patrick Lee discoveries.
Reovirus is naturally occurring not modified like the virus being studied by Amgen. It is my opinion that Amgen faces additional regulatory hurdles using a genetically modified virus rather than one that is naturally occurring like Reolysin. It may turn out that you can enhance the effects of Oncolytic Immunotherapy by genetically modifying the virus but if your are using a naturally occurring virus like Reolysin you might just be able to do combos of proven adjuncts like some that have been recently reported so the race is on to figure out what works best and what can get approved in the shortest timeframe both short term and planning for long term competitiveness.
Also Oncolytics claims significant patent positions for broad rights in using Oncolytic virus' for the treatment of cancer and specific manufacturing cell growth and purification methods for viruses. See this link. This IP is valuable IMO.
It sure would make sense to me that ONCY may be a purchase target by Amgen and maybe others who want a piece of what could be new Immunotherapy options for cancer with minor flu-like side effects that you really want if you are using it because if you don't get flu-like symptoms it probably is not working for that specific type of cancer! This field looks very exciting but still is unproven to meet FDA approval but is getting closer everyday.
Here is a link to the current Oncolytics Clinical Trial program.
http://www.oncolyticsbiotech.com/clinical-trials/default.aspx
Also a link to Reolysin clinical trials on clinicaltrials.gov is here. - Search Reolysin
Cheers.
onco_investor - All comments are my opinion only. If you are considering learning more please visit the iBox above or for official company information visit www.oncolyticsBiotech.com
Updated Investors Presentation Feb 2014
http://www.oncolyticsbiotech.com/files/doc_presentations/slideshows_posters/Corporate%20Presentation%20(February%202014).pdf
Over 1000 treated to date
Bone Marrow Transplantation- Dr.Morris Reolysin and Multiple Myeloma
http://www.nature.com/bmt/journal/v49/n1/full/bmt2013130a.html?WT.ec_id=BMT-201401
PreClinical Study by Dr.Morris' Lab
p49, 80-86 (January 2014)
Reovirus as a successful ex vivo purging modality for multiple myeloma
C M Thirukkumaran, Z Q Shi, J Luider, K Kopciuk, N Bahlis, P Neri, M Pho, D Stewart, A Mansoor and D G Morris
Abstract
Autologous stem cell rescue (ASCT) following high-dose myeloablative chemotherapy is considered to be a therapeutic option for many multiple myeloma (MM) patients; however relapse post ASCT presents a major challenge.
The oncolytic potential of reovirus has been previously demonstrated and is currently undergoing phase I monotherapy clinical trials for MM and phase II/III clinical trials for solid tumors.
Here we tested the hypothesis that reovirus can successfully purge MM in a murine model that partially recapitulates human MM.
RPMI 8226, MM1S, H929 and U266 human myeloma cell lines were exposed to reovirus and oncolysis was assessed. Apheresis product admixed with MM cells was purged with live reovirus (LV) or dead virus (DV) and purging efficacy was monitored via flow cytometry, reverse transcribed–PCR (RT–PCR) and disease relapse in non obese diabetic/severe combined immune deficient (NOD/SCID) mice.
Significant LV purging was seen with MM1S, H929 and U266 and the complete ex vivo purging achieved with RPMI 8226 was confirmed by flow cytometry, RT–PCR and absence of disease relapse in vivo.
Mice that received LV-purged autografts exhibited 100% survival in comparison to mice that received DV-purged controls.
Reovirus’s unique ability to kill MM while sparing hematopoietic stem cells places it as an attractive purging agent for MM during ASCT.
Dr.Saab OSU Pancreatic Reolysin Study not DrKolb eom
Fox News Picks up Dr.Kolb-OSU Pancreatic Cancer Story
Dr.Lee British Journal of Cancer Nov 26
http://www.nature.com/bjc/journal/vaop/ncurrent/full/bjc2013695a.html
Another published paper by Dr Lee's Dalhouse University Lab with Dr Gujar suggesting "anti-tumour immunological mechanisms" Kudos to Dr. Lee for continuing his research with Reovirus.
Gemcitabine enhances the efficacy of reovirus-based oncotherapy through anti-tumour immunological mechanisms
S A Gujar, D Clements, R Dielschneider, E Helson, P Marcato and P W K Lee
Abstract
Background:
Reovirus preferentially infects and kills cancer cells and is currently undergoing clinical trials internationally. While oncolysis is the primary mode of tumour elimination, increasing evidence illustrates that reovirus additionally stimulates anti-tumour immunity with a capacity to target existing and possibly relapsing cancer cells. These virus-induced anti-tumour immune activities largely determine the efficacy of oncotherapy. On the other hand, anti-viral immune responses can negatively affect oncotherapy. Hence, the strategic management of anti-tumour and anti-viral immune responses through complementary therapeutics is crucial to achieve the maximum anti-cancer benefits of oncotherapy.
Methods:
Intra-peritoneal injection of mouse ovarian surface epithelial cells (ID8 cells) into wild-type C57BL/6 mice was treated with a therapeutic regimen of reovirus and/or gemcitabine and then analysed for prolonged survival, disease pathology, and various immunological parameters. Furthermore, in vitro analyses were conducted to assess apoptosis, viral spread, and viral production during reovirus and/or gemcitabine treatment.
Results:
We demonstrate that reovirus and gemcitabine combination treatment postpones peritoneal carcinomatosis development and prolongs the survival of cancer-bearing hosts. Importantly, these anti-cancer benefits are generated through various immunological mechanisms, including: (1) inhibition of myeloid-derived suppressor cells recruitment to the tumour microenvironment, (2) downmodulation of pro-MDSC factors, and (3) accelerated development of anti-tumour T-cell responses.
Conclusion:
The complementation of reovirus with gemcitabine further potentiates virus-initiated anti-cancer immunity and enhances the efficacy of oncotherapy. In the context of ongoing clinical trials, our findings represent clinically relevant information capable of enhancing cancer outcomes.
NBC News Reolysin Pancreatic Cancer Trial Update
http://www.nbc4i.com/story/24037701/trial-uses-common-cold-to-fight-pancreatic-cancer
Although the title incorrectly says this is the common cold virus the video clip is about the randomized PH II Pancreatic cancer trial being conducted at Ohio State University and many other locations sponsored by the NCI.
Clinical Trials.gov link is at
http://clinicaltrials.gov/ct2/show/NCT01280058?term=reolysin&rank=19
COLUMBUS, Ohio -
A breakthrough in cancer treatment is unfolding in Central Ohio, targeting pancreatic cancer by using the common cold virus.
Pancreatic cancer has a high mortality rate. 94 percent of pancreatic cancer patients die within five years. But a new trial is using the common cold to kill cancer.
The cold virus is part of a new trial at The Ohio State University's Wexner Medical Center.
"This virus is likely to be the next standard of care in pancreas cancer," said Dr. Tanios Bekaii-Saab.
Saab is leading the charge in the first-of-its-kind trial on reolysin in pancreatic cancer.
Reolysin is the virus that causes the common cold.
"When it gets in the cancer sell, it acts in a completely different way. It's very harmful to the cancer cell, which is exactly what we want it to do," Sabb said.
Saab said the results have been amazing so far, both slowing cancer growth and reducing the size of the tumor.
It leaves healthy cells in the body alone.
It sounds too good to be true, but it's the future, and is just the beginning of virus cancer treatments unfolding currently.
"This is an oncologist's dream where you find an agent that has minimal toxicity, but when it gets to the cancer, it induces absolute harm to the cancer," Saab said.
Patients are also given chemotherapy treatment, but have fewer side effects, and are living longer with the new treatment.
Positive Top-Line Data from REO 018
Company decides to wait no longer to unblind half of the trial, move forward with design of the second portion and wait until the predetermined threshold mortality rate is reached in the mets only arm. (n=49)
CEO confirms a significant number of mets only patient are still alive after 1 year and counting and the company is still blinded in this arm. The critical path to approval is through the next trial so the company feels it has the data now to make that decision without waiting for mets only data. This is a smart move IMO.
Data released today IMO is very good considering the bias involved. Company chose to rightly exclude patients that went on to other treatment to eliminate any bias this presents. New issue however is the role fever is playing in dropouts, especially patients that most likely are responders. Not sure how many mets patients this affects either yet. If you listen to the conference call you will learn much more than this press release and learn the PIs have discussed the results. Preliminary target size for part 2 of this trial will be 250 patients and most likely will be proposed as a single blind study instead of double blind to deal with the fever treatment dilemma. Not yet approved by regulators but discussed among the PI team which includes Dr. Vermorken, the company indicates they see a clear path forward in trial design to maximize chances of success.
http://finance.yahoo.com/news/oncolytics-biotech-inc-announces-positive-110000877.html
Oncolytics Biotech® Inc. Announces Positive Top-Line Data from REO 018 Randomized Study of REOLYSIN® in Head and Neck Cancers
CNW Group Oncolytics Biotech Inc.
November 21, 2013 6:00 AM
--Company Intends to Proceed Into Follow-On Registration Study in This Indication--
TORONTO , Nov. 21, 2013 /CNW/ - Oncolytics Biotech Inc. ("Oncolytics" or the "Company") (TSX:ONC, NASDAQ:ONCY) today announced positive top-line data for the endpoints in its double blinded, randomized clinical study examining REOLYSIN in combination with carboplatin and paclitaxel in patients with second-line platinum-refractory, taxane-naïve head and neck cancers (REO 018).
Summary of Trial Results
Efficacy
An analysis was performed on an intent-to-treat basis of the 118 patients with loco-regional head and neck cancer, with or without metastases. Patients in the control arm were treated with carboplatin and paclitaxel, while patients in the test arm were treated with carboplatin, paclitaxel and REOLYSIN;
The analysis showed a median progression free survival (PFS) of 94 days (13.4 weeks) in the test arm (n=62), versus 50 days (7.1 weeks) in the control arm (n=56). The test arm maintained a PFS benefit over the control arm through five cycles of therapy;
Eighty-eight loco-regional patients did not receive additional therapy following discontinuation of study treatment. An analysis of these patients showed a median overall survival (OS) of 150 days (21.4 weeks) in the test arm (n=50), versus 115 days (16.4 weeks) in the control arm (n=38), and;
As of the time of reporting, there have not been a sufficient number of events (i.e. patient deaths) to conduct a survival analysis of patients in the metastatic-only group (i.e. those patients with no loco-regional recurrence).
Safety
REOLYSIN was safe and well-tolerated by patients;
The side effects experienced by patients in the test arm of the study were consistent with expectations based on outcomes of earlier clinical studies using REOLYSIN. Patients on the test arm of the study experienced a higher incidence of flu-like symptoms consistent with treatment with a virus, most commonly mild fever, chills, nausea and diarrhea, on both a per-patient and a per-cycle basis; and
Fewer patients required dose reductions of paclitaxel due to neuropathy or neurotoxicity on the test arm than the control arm (zero in the test arm versus six in the control arm; p=0.028). On this basis, the Company intends to explore the potential chemoprotective and neuroprotective properties of REOLYSIN in future clinical studies.
"The overall goal of this clinical trial was to determine the specific parameters for the use of REOLYSIN in a registration study in head and neck cancers," said Dr. Brad Thompson , President and CEO of Oncolytics. "We are excited to move forward with our head and neck program, and intend to discuss the design and execution of a follow-on registration study with regulators in the near future."
Implications of the Results
As disclosed in the press release dated September 12, 2012 , Oncolytics intends to treat this expanded first stage of the REO 018 clinical trial as a separate supportive study to a planned registration study that will be similar to, and take the place of, the original second stage of the REO 018 clinical trial. Based on these data, the Company intends to discuss the design and execution of a randomized, follow-on Phase III registration study in patients with loco-regional head and neck cancer with regulators in multiple jurisdictions.
Detailed Efficacy Data
The REO 018 study enrolled 167 patients. The efficacy analysis was performed on an intent-to-treat basis of the 118 patients with loco-regional head and neck cancer with or without metastatic disease. In the intent-to-treat patient population, PFS, progression at first post-treatment scan, cycles of therapy received, and tumour shrinkage at first post-treatment scan were analyzed.
The analysis showed a median PFS of 94 days (13.4 weeks) in the test arm (n=62), versus 50 days (7.1 weeks) in the control arm (n=56). The test arm maintained a PFS benefit over the control arm through five cycles of therapy.
A number of patients on study received additional treatments with other agents following discontinuation of study treatment in accordance with the clinical practices of individual enrolling centres. Thirty of the 118 patients in the loco-regional group received at least one therapy with other agents after study therapy was discontinued. A greater number of patients in the control arm received post-discontinuation therapy versus the test arm. This imbalance created a "confounding," or distorting, effect on OS (Pazdur; The Oncologist 2008, 13:19-21), as such additional therapy can extend the patients' lifespan beyond that expected from receiving the study therapy. Eighty-eight loco-regional patients did not receive additional therapy and an analysis of these patients showed a median OS of 150 days (21.4 weeks) in the test arm (n=50) versus 115 days (16.4 weeks) in the control arm (n=38).
Patients were evaluated for progression at the first scheduled post-treatment scan (performed at six weeks, post-cycle two of therapy). Of 62 patients on the test arm, 32.3% had progressed, compared with 51.8% of the 56 patients on the control arm (p=0.04). The patients were also evaluated for the total cycles of therapy received. The patients on the test arm had received a median of four cycles of therapy, versus a median of two cycles on the control arm. The same proportion of patients from each arm remained on study at five cycles.
Of 86 patients with measurable disease at the first post-treatment scan, the test arm (n=48) had a statistically significant increase in tumour shrinkage over the control arm (n= 38; p=0.049).
As of the time of reporting, there have not been a sufficient number of events (i.e. patient deaths) to conduct a survival analysis of patients in the metastatic-only group.
Detailed Safety Data
Overall, the treatment combination was found to be safe and well tolerated by patients. The adverse events (AEs) experienced by patients in the test arm of this, the first double blinded, randomized clinical study of REOLYSIN, were consistent with expectations based on the outcomes of earlier single arm clinical studies of REOLYSIN, both as a monotherapy and in combination with chemotherapeutic agents.
Investigators reported a statistically significant increase in the number of patients on the test arm experiencing mild fever, chills, nausea, and diarrhea. These adverse events were generally mild, with three patients on the test arm experiencing Grade 3 diarrhea; one patient on the control arm and two on the test arm experiencing Grade 3 nausea; and no reports, on either arm, of Grade 3 fever or chills (in the absence of infection). There was an increase in the percentage of patients at each cycle with fever in the test arm (mean=27.2%, median=25.9%), versus the control arm (mean=5.3%, median=4.8%). There was also an increase in the percentage of patients at each cycle of therapy exhibiting flu-like symptoms in the test arm (mean=87.9%, median=81.7%) versus the control arm (mean=47.3%, median=45%).
Hematological data showed no statistical or clinical differences in hemoglobin, lymphocytes, or platelet counts. Twenty patients with decreased white blood cell counts (WBC) (Grade 3 and 4) were noted in the test arm versus 10 in the control arm (p=0.068). There were 21 patients in the test arm with decreased absolute neutrophil counts (ANC) (Grade 3 and 4) versus 15 in the control arm. There were nine patients on each arm who had Serious Adverse Events (SAE's) with hospitalization that were related to a low ANC, with or without demonstrated infection.
There were no clinical or statistical differences in terms of hepatic or renal evaluations.
There were 19 SAEs not related to flu-like illness that were judged by the investigators to be at least possibly related to treatment in the control arm and 24 in the test arm. There was no pattern in the nature of SAEs observed between arms, except for flu-like signs and symptoms.
Fewer patients on the test arm required dose reductions of paclitaxel due to neuropathy or neurotoxicity than the control arm. There were no dose reductions for neuropathy in the test arm versus six in the control arm (p=0.028). On the basis of these data, the Company intends to further investigate the possibility that REOLYSIN may have a neuroprotective and/or chemoprotective effect.
"These data demonstrate that REOLYSIN can be safely added to this chemotherapeutic combination," said George M. Gill , MD, Senior Vice President, Regulatory Affairs, and Chief Safety Officer of Oncolytics. "This controlled comparison supports our belief that the addition of REOLYSIN to other regimens will not increase the frequency or severity of adverse events caused by the chemotherapeutic agents with which it is combined."
REO 018 Study Design and Analytical Considerations
REO 018 is a randomized, double blinded, two arm, multi-centre trial assessing the intravenous administration of REOLYSIN with the chemotherapy combination of paclitaxel and carboplatin versus the chemotherapy alone in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who have progressed on or after prior platinum-based chemotherapy. The trial is examining 167 patients segregated into two patient groups: patients with local recurrent disease, with or without distal metastases, and those with only distal metastases. The Company is treating REO 018 as a separate supportive study to an intended subsequent registration study.
All patients received treatment every three weeks (21-day cycles) with paclitaxel and carboplatin and also received, on a blinded basis, either intravenous placebo or intravenous REOLYSIN. All dosing took place in the first five days of each cycle with all patients receiving standard intravenous doses of paclitaxel and carboplatin on day one only, and either intravenous placebo or intravenous REOLYSIN at a dose of 3x1010 TCID50 on days one to five. Patients could continue to receive the trial combination therapy for up to eight cycles and, thereafter, blinded placebo or blinded REOLYSIN until the patient had progressive disease or met other criteria for discontinuation from the trial.
On December 13, 2012 , the Company announced positive data on an endpoint examining initial percentage tumour changes between the pre-treatment and first post-treatment scans (typically performed at six weeks post-first treatment) of all patients enrolled in the study. The analysis was designed to assess early differences in response between loco-regional tumours and metastatic tumours, as classified and observed by the investigators.
Conference Call Details
Dr. Brad Thompson , President and CEO of Oncolytics, will host a conference call and webcast on Thursday, November 21, 2013 at 6:00 a.m. MT (8:00 a.m. ET) to discuss in more depth the data from the Company's REO 018 trial in head and neck cancers. To access the conference call by telephone, dial 1-647-427-7450 or 1-888-231-8191. A live audio webcast will also be available at the following link: http://www.newswire.ca/en/webcast/detail/1265023/1394835 or through the Company's website at www.oncolyticsbiotech.com/presentations. Please connect at least 10 minutes prior to the webcast to ensure adequate time for any software to download. A replay of the webcast will be available at www.oncolyticsbiotech.com/presentations and will also be available by telephone through November 28, 2013 . To access the telephone replay, dial 1-416-849-0833 or 1-855-859-2056 and enter reservation number 15177323 followed by the number sign. The Company also intends to post the prepared remarks from the call to its corporate website following the call.
About Oncolytics Biotech Inc.
Oncolytics is a Calgary -based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of human trials including a Phase III trial in head and neck cancers, and six randomized Phase II studies in prostate, colorectal, breast, lung, pancreatic and ovarian cancer using REOLYSIN®, its proprietary formulation of the human reovirus. For further information about Oncolytics, please visit: www.oncolyticsbiotech.com.
This press release contains forward-looking statements within the meaning of the U.S. Securities Act of 1933, as amended, and U.S. Securities Exchange Act of 1934, as amended, and forward-looking information within the meaning of Canadian securities laws. Statements, other than statements of historical facts, included in this press release that address activities, events or developments that Oncolytics expects or anticipates will or may occur in the future, including such things as, the Company's expectations related to the REO 018 head and neck cancers trial of REOLYSIN in combination with carboplatin and paclitaxel, and the Company's belief as to the potential of REOLYSIN as a cancer therapeutic, and other such matters are forward-looking statements and forward-looking information and involve known and unknown risks and uncertainties, which could cause the Company's actual results to differ materially from those in the forward-looking statements and forward-looking information. Such risks and uncertainties include, among others, risks related to the statistical sufficiency of patient enrollment numbers in separate patient groups, the availability of funds and resources to pursue research and development projects, the efficacy of REOLYSIN as a cancer treatment, the tolerability of REOLYSIN outside a controlled test, the success and timely completion of clinical studies and trials, the Company's ability to successfully commercialize REOLYSIN, uncertainties related to the research and development of pharmaceuticals and uncertainties related to the regulatory process. Investors should consult the Company's quarterly and annual filings with the Canadian and U.S. securities commissions for additional information on risks and uncertainties relating to the forward-looking statement and forward-looking information. Investors are cautioned against placing undue reliance on forward-looking statements and forward-looking information. The Company does not undertake to update these forward-looking statements and forward-looking information, except as required by applicable laws.
SOURCE Oncolytics Biotech Inc.
Contact:
The Equicom Group
Nick Hurst
300 5th Ave. SW, 10th Floor
Calgary, Alberta T2P 3C4
Tel: 403.218.2835
Fax: 403.218.2830
nhurst@tmxequicom.com
Dian Griesel, Inc.
Susan Forman
335 West 38th Street, 3rd Floor
New York, NY 10018
Tel: 212.825.3210
Fax: 212.825.3229
sforman@dgicomm.com
Q3 Results Reported - Burn Rate Down 30%
http://finance.yahoo.com/news/oncolytics-biotech-inc-announces-third-113000784.html
CALGARY, Nov. 7, 2013 /PRNewswire/ - Oncolytics Biotech Inc. (TSX:ONC, NASDAQ:ONCY) ("Oncolytics" or the "Company") today announced its financial results and operational highlights for the quarter ended September 30, 2013.
"In recent months we have reported positive data in our squamous cell and non-squamous cell lung clinical trials both in terms of tumour response and survival," said Dr. Brad Thompson, President and CEO of Oncolytics. "On the strength of this reported data, we intend to conduct randomized clinical studies in these indications that will further expand our lung cancer program."
Selected Highlights
Since June 30, 2013, the Company has made a number of announcements including:
Clinical Trial Results
Reporting positive final results from a U.S. Phase 2 study examining the use of REOLYSIN® in combination with carboplatin and paclitaxel in patients with stage IV non-small cell lung cancer (NSCLC) with Kras or EGFR-activated tumors (REO 016). Response evaluation for 36 evaluable patients showed 11 partial responses (PR) (30%) (EGFR amplified, five; BRAF two; Kras, three; EGFR mutated, one), 21 stable disease (SD), and four progressive disease (PD). The data also correlated a number of molecular abnormalities with best response, progression free survival (PFS) and one-year survival. Current data in these patients demonstrates that 20 of 36 evaluable patients (56%) survived a year or more. There were 13 patients with only EGFR mutations or amplifications, of whom nine (69.2%) survived a year or longer. Four of four (100%) patients with BRAF and EGFR amplification survived a year or longer; and
Reporting final tumour response and progression free survival ("PFS") data from a U.S. Phase 2 clinical trial in patients with squamous cell carcinoma of the lung (SCCLC) using intravenous administration of REOLYSIN® in combination with carboplatin and paclitaxel (REO 021). Of the 25 evaluable patients who had more than one cycle of therapy, 23 (92%) exhibited overall tumour shrinkage. When evaluated for best response, which is the best percentage response recorded on study compared to baseline, 10 patients (40%) had partial responses (PRs), while a further 14 (56%) showed stable disease (SD), and one (4%), had progressive disease (PD). Using RECIST criteria to evaluate best overall response, 10 patients (40%) had partial responses (PRs), 12 (48%) showed stable disease (SD) and three (12%), had progressive disease (PD). 31.8% of patients with sufficient follow up had a PFS greater than six months.
Updated Investors Presentation - ONCY
http://oncolytics.s3.amazonaws.com/presentations/60/original.pdf?1383068724
EORTC - Poster and PFS Data SCCN Lung Cancer
http://finance.yahoo.com/news/oncolytics-biotech-inc-announces-progression-103000522.html
This is an update to REO 21 SCCLC only. More details next week on the NSCLC trial REO 16.
CALGARY , Oct. 22, 2013 /CNW/ - Oncolytics Biotech Inc. ("Oncolytics") (ONC.TO) (ONCY) today announced that a poster presentation covering progression free survival (PFS) and final tumour response data from its U.S. Phase 2 single arm clinical trial in patients with squamous cell carcinoma of the lung (SCCLC) using intravenous administration of REOLYSIN in combination with carboplatin and paclitaxel (REO 021), is being made today at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. The conference is being held in Boston, MA from October 19-23 .
The investigators reported that there were 25 evaluable patients, each of whom had received between two and 12 cycles of therapy. Of the evaluable patients who had more than one cycle of therapy, 23 (92%) exhibited overall tumour shrinkage. When evaluated for best response, which is the best percentage response recorded on study compared to baseline, 10 patients (40%) had partial responses (PRs), while a further 14 (56%) showed stable disease (SD), and one (4%), had progressive disease (PD). Using RECIST criteria to evaluate best overall response, 10 patients (40%) had partial responses (PRs), 12 (48%) showed stable disease (SD) and three (12%), had progressive disease (PD). 31.8% of patients with sufficient follow up had a PFS greater than six months. A copy of the poster presentation, which includes a waterfall graph showing individual patient data, will be available on the Company's website at http://www.oncolyticsbiotech.com/presentations.
About Lung Cancer
The American Cancer Society estimates that in 2013, approximately 228,190 new cases of lung cancer will be diagnosed. Between 85% and 90% of all lung cancers are classified as non-small cell lung cancer (NSCLC); squamous cell carcinomas account for 25-30% of all lung cancers. Lung cancer is by far the leading cause of cancer death among both men and women. There will be an estimated 159,480 deaths from lung cancer in the United States in 2013, accounting for around 27% of all cancer deaths. Lung cancer is the leading cause of cancer death, with more people dying each year of lung cancer than from colon, breast, and prostate cancers combined. For more information about lung cancer, please go to www.cancer.org.
About Oncolytics Biotech Inc.
Oncolytics is a Calgary -based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of human trials including a Phase III trial in head and neck cancers using REOLYSIN®, its proprietary formulation of the human reovirus. For further information about Oncolytics, please visit: www.oncolyticsbiotech.com.
Ovarian Cancer Reovirus Research in Molecular Therapy
Pre-Clinical research of the Reovirus in Dr. Patrick Lee's lab along with Dr. Gujar
http://www.nature.com/mt/journal/v21/n2/abs/mt2012228a.html
Original Article
Subject Category: Vector Toxicology, Immunogenicity and Safety
Molecular Therapy (2013); 21 2, 338–347. doi:10.1038/mt.2012.228
Multifaceted Therapeutic Targeting of Ovarian Peritoneal Carcinomatosis Through Virus-induced Immunomodulation
Shashi Gujar1, Rebecca Dielschneider1,2, Derek Clements3, Erin Helson1, Maya Shmulevitz4, Paola Marcato3, Da Pan1, Lu-zhe Pan1, Dae-Gyun Ahn1, Abdulaziz Alawadhi1 and Patrick WK Lee1,3
1Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
2Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
3Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
4Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
Correspondence: Patrick WK Lee, Professor and Cameron Chair in Basic Cancer Research, Dalhousie University, Department of Microbiology and Immunology, 7P, Charles Tupper Building, 5850 College Street, Halifax, Nova Scotia B3H 1X5, Canada. E-mail: patrick.lee@dal.ca
Received 4 August 2012; Accepted 7 October 2012
Advance online publication 13 November 2012
Abstract
Immunosuppression associated with ovarian cancer (OC) and resultant peritoneal carcinomatosis (PC) hampers the efficacy of many promising treatment options, including immunotherapies. It is hypothesized that oncolytic virus-based therapies can simultaneously kill OC and mitigate immunosuppression. Currently, reovirus-based anticancer therapy is undergoing phase I/II clinical trials for the treatment of OC. Hence, this study was focused on characterizing the effects of reovirus therapy on OC and associated immune microenvironment. Our data shows that reovirus efficiently killed OC cells and induced higher expression of the molecules involved in antigen presentation including major histocompatibility complex (MHC) class I, ß2-microglobulin (ß2M), TAP-1, and TAP-2. In addition, in the presence of reovirus, dendritic cells (DCs) overcame the OC-mediated phenotypic suppression and successfully stimulated tumor-specific CD8+ T cells. In animal studies, reovirus targeted local and distal OC, alleviated the severity of PC and significantly prolonged survival. These therapeutic effects were accompanied by decreased frequency of suppressive cells, e.g., Gr1.1+, CD11b+ myeloid derived suppressor cells (MDSCs), and CD4+, CD25+, FOXP3+ Tregs, tumor-infiltration of CD3+ cells and higher expression of Th1 cytokines. Finally, reovirus therapy during early stages of OC also resulted in the postponement of PC development. This report elucidates timely information on a therapeutic approach that can target OC through clinically desired multifaceted mechanisms to better the outcomes.
Dr.Patrick Lee Dr.Shashi Gujar Reovirus and Immunology
http://www.dmrf.ca/en/home/mollyappeal/aboutus/facesofmolly/dalresearchers/cancerresearchers/drpatrickleeanddrshashigujar.aspx
Keeping cancer from coming back
Dr. Patrick Lee and Dr. Shashi Gujar
see reovirus as a powerful way to stop cancer recurrence
Dr. Patrick Lee, a virologist who is world famous for finding that viruses can infect and kill cancer cells without harming healthy cells, is taking this groundbreaking discovery to a new level with help from immunologist Dr. Shashi Gujar. These Dalhousie Medical School researchers are pursuing a strategy that could turn the common and harmless human reovirus into a potent means of preventing cancer from coming back after treatment.
"We've found from our studies that when you treat a cancer with reovirus, cancer is prevented from coming back," says Dr. Lee, noting that recurrence is one of cancer's most difficult to solve problems - especially since recurrent cancers tend to resist treatment.
This protective effect is due to a change in the body's immune response against cancer cells after they've been infected by reovirus. "After the initial wave of cancer-killing infection, we've found that the remaining cancer cells suddenly become visible to the immune system," explains Dr. Lee, a professor in the department of Pathology and Microbiology & Immunology. "Cancer cells are usually able to hide from the immune system, but the virus forces them to give up their shields so now the immune system can see and destroy them. As a result, no cancer cells remain to seed a future cancer of that type,"
Dr. Gujar's expertise in immunology is helping make reovirus treatment even more effective. "The problem with using a virus to treat cancer is that the immune system wil try to stop the virus before it has a chance to infect the cancer," says Dr.Gujar, a postdoctoral fellow in Dr. Lee's lab. "But we have isolated the particular immune cells that attack reovirus and programmed them to self-destruct as soon as they recognize the reovirus - so the reovirus can attack and kill cancer cells unhindered."
These researchers hope reovirus will become a standard treatment to use in conjunction with chemotherapy. Calgary-based Oncolytics Biotech is currently conducting phase three clinical trials on reovirus-chemotherapy combinations, so this treatment option may soon be available.
Additional Details - Thanks matdu
The first publication below details the finding in the article described by Drs. Lee and Gujar. The second publication (you can access the entire paper via the link) demonstrates interesting relationship between p53 and cancer cell susceptibility, also authored by the Lee's group.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054006
(1) Reovirus Virotherapy Overrides Tumor Antigen Presentation Evasion and Promotes Protective Antitumor Immunity
Shashi A. Gujar, Paola Marcato, Da Pan and Patrick W.K. Lee
+ Author Affiliations
Authors' Affiliation: Department of Pathology and Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
Corresponding Author:
Patrick W.K. Lee, Department of Pathology and Microbiology and Immunology, Dalhousie University, Room 7-P, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5. Phone: 902-494-8048; Fax: 902-494-5125. E-mail: patrick.lee@dal.ca
Abstract
Tumor-associated immunosuppressive strategies, such as lack of tumor antigen recognition and failure of lymphocyte activation and homing, resist the development of tumor-specific immunity and hamper the immune response–mediated elimination of cancerous cells. In this report, we show that reovirus virotherapy overrides such a tumor immune evasion and establishes clinically meaningful antitumor immunity capable of protecting against subsequent tumor challenge. Reovirus-mediated destruction of tumor cells facilitates the recognition of tumor antigens by promoting the display of otherwise inaccessible tumor-specific immunogenic peptides on the surface of dendritic cells (DC). Furthermore, on exposure to reovirus, DCs produce IL-1á, IL-1â, IL-6, IL-12p40/70, IL-17, CD30L, eotaxin, GM-CSF, KC, MCP-1, MCP-5, M-CSF, MIG, MIP-1á, RANTES, TNF-á, VCAM-1, VSGF, CXCL-16, AXL, and MCP-2; undergo maturation; and migrate into the tumor microenvironment along with CD8 T cells. These reovirus-activated DCs also acquire the capacity to prime tumor antigen–specific transgenic T cells in vitro and intrinsic antitumor T-cell response in vivo. Further, reovirus virotherapy augments the efficacy of DC- or T cell–based anticancer immunotherapies and synergistically enhances the survival in tumor-bearing mice. Most importantly, antitumor cellular immune responses initiated during reovirus oncotherapy protect the host against subsequent tumor challenge in a reovirus-independent but antigen-dependent manner. These reovirus oncotherapy–initiated antitumor immune responses represent an anticancer therapeutic entity that can maintain a long-term cancer-free health even after discontinuation of therapy. Mol Cancer Ther; 9(11); 2924–33. ©2010 AACR.
(2) Activation of p53 by Chemotherapeutic Agents Enhances Reovirus Oncolysis
Da Pan, Paola Marcato, Dae-Gyun Ahn, Shashi Gujar, Lu-Zhe Pan, Maya Shmulevitz, Patrick W. K. Lee
Abstract
Mammalian reovirus is a benign virus that possesses the natural ability to preferentially infect and kill cancer cells (reovirus oncolysis). Reovirus exploits aberrant Ras signalling in many human cancers to promote its own replication and spread. In vitro and in vivo studies using reovirus either singly or in combination with anti-cancer drugs have shown very encouraging results. Presently, a number of reovirus combination therapies are undergoing clinical trials for a variety of cancers. Previously we showed that accumulation of the tumor suppressor protein p53 by Nutlin-3a (a specific p53 stabilizer) enhanced reovirus-induced apoptosis, and resulted in significantly higher levels of reovirus dissemination. In this study, we examined the role of p53 in combination therapies involving reovirus and chemotherapeutic drugs. We showed that sub-lethal concentrations of traditional chemotherapy drugs actinomycin D or etoposide, but not doxorubicin, enhanced reovirus-induced apoptosis in a p53-dependent manner. Furthermore, NF-êB activation and expression of p53-target genes (p21 and bax) were important for the p53-dependent enhancement of cell death. Our results show that p53 status affects the efficacy of combination therapy involving reovirus. Choosing the right combination partner for reovirus and a low dosage of the drug may help to both enhance reovirus-induced cancer elimination and reduce drug toxicity.
15th World Conference on Lung Cancer Oct27th
Looks like there will be additional details released at the Annual World Conference on Lung Cancer. It has been noted that most patients in these studies were Stage IV
10/01/2013 13:15:00
Oncolytics Biotech Inc. Collaborators to Present Positive Clinical Trial Data at the 15th Annual World Conference on Lung Cancer
CALGARY, Oct. 1, 2013 /CNW/ - Oncolytics Biotech Inc. ("Oncolytics") (TSX:ONC) (NASDAQ:ONCY) today announced that abstracts detailing results from two Phase II studies examining the use of REOLYSIN® in combination with carboplatin and paclitaxel in patients with non-small cell lung cancer (NSCLC) with Kras or EGFR-activated tumors (REO 016) and in patients with squamous cell carcinoma of the lung (REO 021), are now available on the International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer website at http://wclc.iaslc.org. The conference is being held from October 27th to 30th, 2013 in Sydney, Australia.
The first abstract, titled "Final Results of a Phase 2 Trial of the Oncolytic Virus REOLYSIN in Metastatic NSCLC Patients with a Ras-activated Pathway," indicated that patients received reovirus (3 x 1010 TCID50) intravenously daily on days one to five, in combination with paclitaxel at initial doses of paclitaxel 175 mg/m2 and carboplatin AUC 5, on day one of each 21-day cycle. Overall, 37 patients received 209 cycles (per patient median four, range one to 18). Grade 3-4 toxicities included febrile neutropenia (two patients), grade 3 diarrhea (two patients), grade 3 anemia (seven patients), fatigue in 6 patients (five grade 3, one grade 4), nausea/vomiting (two patients), electrolyte abnormalities, and single grade 3 episodes of arthralgia and thrombocytopenia. Molecular tumor demographics included: 20 Kras, 3 EGFR and 4 BRAF mutations, and 10 with EGFR amplifications only. Response evaluation for 36 evaluable patients showed 11 partial responses (PR) (30%) (EGFR amplified, five; BRAF two; Kras, three; EGFR mutated, one), 21 stable disease (SD), and four progressive disease (PD). Of the 36 evaluable patients with sufficient follow up to date, progression free survival (PFS) at six months is 36% and one-year survival, 53%.
"The response and clinical benefit rates reported are consistent with the interim data our collaborators reported in late 2012," said Dr. Brad Thompson , President and CEO of Oncolytics. "The six-month progression-free survival and one-year survival data is very encouraging. In the literature, it has been reported that treatment with various chemotherapy combinations alone averaged one-year survival rates of 33% in patients with advanced non-small cell lung cancer1. Stage IV patients similar to the ones we treated in this study see overall one-year survival rates of approximately 16%."
The second abstract, titled "A Phase 2 Study of Intravenous Administration of REOLYSIN (Reovirus Type 3 Dearing) in Combination with Paclitaxel (P) and Carboplatin (C) in Patients with Squamous Cell Carcinoma of the Lung," reflects information submitted to the IASLC conference in June 2013, prior to the Company's subsequent announcement of updated data from the REO 021 study in the press release dated September 9, 2013.
About Lung Cancer
The American Cancer Society estimates that in 2013, approximately 228,190 new cases of lung cancer will be diagnosed. Between 85% and 90% of all lung cancers are classified as non-small cell lung cancer (NSCLC); squamous cell carcinomas account for 25-30% of all lung cancers. Lung cancer is by far the leading cause of cancer death among both men and women. There will be an estimated 159,480 deaths from lung cancer in the United States in 2013, accounting for around 27% of all cancer deaths. Lung cancer is the leading cause of cancer death, with more people dying each year of lung cancer than from colon, breast, and prostate cancers combined. For more information about SCC lung cancer, please go to www.cancer.org.
References
1 As reported in The New England Journal of Medicine (N Engl J Med, Vol. 346, No. 2, January 10, 2002) by Schiller, et al, a total of 1,207 patients with advanced non-small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. The response rate for all 1,155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent).
2 As reported in Clinical Epidemiology (2011:3 139-148), Cetin, et al, using data from the Surveillance, Epidemiology and End Results (SEER) Program, stratified 51,749 incident stage IV NSCLC patients (1988-2003 with follow-up through 2006) by major histologic subtype. Overall one-year survival (95% confidence interval) in stage IV non-small cell lung cancer patients who survived at least 31 days (n=44,172) was 15.9%.
About Oncolytics Biotech Inc.
Oncolytics is a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of human trials including a Phase III trial in head and neck cancers using REOLYSIN®, its proprietary formulation of the human reovirus. For further information about Oncolytics, please visit: www.oncolyticsbiotech.com.
This press release contains forward-looking statements, within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements, including the Company's expectations related to the U.S. Phase II non-small cell lung cancer trial, the U.S. Phase II squamous cell carcinoma lung cancer trial, future trials in these indications, and the Company's belief as to the potential of REOLYSIN as a cancer therapeutic, involve known and unknown risks and uncertainties, which could cause the Company's actual results to differ materially from those in the forward-looking statements. Such risks and uncertainties include, among others, the availability of funds and resources to pursue research and development projects, the efficacy of REOLYSIN as a cancer treatment, the tolerability of REOLYSIN outside a controlled test, the success and timely completion of clinical studies and trials, the Company's ability to successfully commercialize REOLYSIN, uncertainties related to the research, development and manufacturing of pharmaceuticals, changes in technology, general changes to the economic environment and uncertainties related to the regulatory process. Investors should consult the Company's quarterly and annual filings with the Canadian and U.S. securities commissions for additional information on risks and uncertainties relating to the forward-looking statements. Investors should consider statements that include the words "believes", "expects", "anticipates", "intends", "estimates", "plans", "projects", "should", or other expressions that are predictions of or indicate future events or trends, to be uncertain and forward-looking. Investors are cautioned against placing undue reliance on forward-looking statements. The Company does not undertake to update these forward-looking statements, except as required by applicable laws.
SOURCE Oncolytics Biotech Inc.
Abstracts from the Conference Website
P1.11-026 | Final Results of a Phase 2 Trial of the Oncolytic Virus Reovirus Serotype 3-Dearing Strain (REOLYSIN®) in Metastatic NSCLC Patients with a Ras-activated Pathway.
Authors: Miguel Villalona-Calero1, Elaine Lam1, Weiqiang Zhao1, Gregory Otterson1, Deepa Subramaniam2, Bo Chao1, Matthew Timmons1, Larry Schaaf1, George M Gill3, Matt Coffey3
1The Ohio State University, Columbus, OH/UNITED STATES OF AMERICA, 2Georgetown University, Washington/UNITED STATES OF AMERICA, 3Oncolytics Biotech INC, Alberta/CANADA
Background:
Reovirus is a naturally occurring virus which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. In preclinical studies, reovirus induces cell cycle arrest, acting synergistically with standard cytotoxic agents. We have hypothesized that patients with EGFR-mutated, EGFR-amplified, BRAF or Kras-mutated NSCLC should all have a common downstream activated Ras pathway and should be susceptible to treatment with reovirus.
Methods:
We conducted a Fleming, single-arm, phase II study to evaluate safety and the objective response rate (primary end-points), as well as 6-month progression-free and 1 year survival (secondary end-points) of metastatic NSCLC patients treated with reovirus in combination with paclitaxel/carboplatin (P/C). Eligible patients had ECOG PS 0-2, adequate organ function, no prior chemotherapy for metastatic disease, and tumors with the specified above genotype, as per CLIA certified laboratory testing. Prior adjuvant chemotherapy, or erlotinib/gefitinib for pts with EGFR-mutant tumors was permitted.
Patients received Reovirus (3 x 1010 TCID50) intravenously daily on days 1-5, in combination with P/C at initial doses of P 200 mg/m2 and C AUC 6, on day 1 of each 21-day cycle. Due to exacerbation of prior colitis and febrile neutropenia (1 each) in the first two pts, doses were subsequently reduced to P 175 mg/m m2 and C AUC 5.
Results:
Overall, 37 patients received 209 cycles (per pt median 4, range 1 to 18). Grade 3-4 toxicity included febrile neutropenia (3 pts), G3 diarrhea (2 pts), G3 anemia (8 pts), fatigue in 6 pts (5 G3, 1 G4), nausea/vomiting and thrombocytopenia (2 pts each), electrolyte abnormalities, and single G3 episodes of arthralgia and transaminitis.
Molecular tumor demographics included: 20 Kras (2 G12A, 9 G12C, 1 G12D, 1 G12R, 1 G12S, 3 G12V, 1 G13C, 1 G13R, 1 G12C/V double mutant), 3 EGFR exon 19, 4 BRAF V600E mutations, and 10 EGFR amplified only.
Response evaluation showed 11 RECIST partial responses (30%) (EGFR amp 5, BRAF 2, Kras 3, EGFR mut 1), 21 SD, and 4 PD. PFS (by CT and PET) at 6 months for 36 patients with enough follow up to date is 36%, with PET results influencing switching to second line therapy in several patients with SD by CT. Sixteen patients received 6 or more cycles. One year survival was 53%.
Conclusion:
Reovirus can be administered safely in combination with P/C and patient selection by Ras-activated pathway is feasible in the clinical setting. Overall clinical efficacy is encouraging.
Randomized evaluation is planned.
P1.11-048 | A Phase 2 Study of Intravenous Administration of REOLYSIN® (Reovirus Type 3 Dearing) in Combination with Paclitaxel (P) and Carboplatin (C) in Patients with Squamous Cell Carcinoma of the Lung
Authors: Alain C. Mita1, Athanassios Argiris2, Matt Coffey3, George M. Gill3, Monica Mita1
1Cedars-Sinai Medical Center, Los Angeles, CA/UNITED STATES OF AMERICA, 2University of Texas Health Science Center at San Antonio, San Antonio, TX/UNITED STATES OF AMERICA, 3Oncolytics Biotech Inc., Calgary/CANADA
Background:
Squamous Cell Carcinoma of the lung (SCCLung) has long been recognized as very difficult to treat, with few agents showing effectiveness. Because the combination of P/C and REOLYSIN was shown to be active in 2 trials in SCC of the head and neck, we elected to test this regimen in this Phase 2 trial in SCCLung.
Methods:
We conducted a single-arm, open-label phase II study to determine (primary) the Objective Response Rate (ORR) and(secondary) the 6-month Progression-free Survival (PFS) and the Overall Survival (OS) of patients with metastatic or recurrent squamous cell carcinoma of the lung, treated with REOLYSIN in combination with P/C.
The study had a two-stage design, with 19 patients in the first stage. The trial would be terminated if 3/19 or fewer patients obtained an objective response. If the trial continued to the second stage, a total of up to 36 patients would be studied. The primary endpoint would be met if patients in both stages had an ORR of at least 35%.
Eligible patients had ECOG PS 0–2, adequate organ function, and no prior systemic chemotherapy for their metastatic or recurrent disease. Prior adjuvant chemotherapy or chemo-XRT for treatment of primary disease was allowed, provided it had been = 6 months since the last chemotherapy. Treatment dosages were: paclitaxel 200 mg/m2 IV over 3 hours; carboplatin at a dose of AUC 6 mg/mL minute calculated using standard formula(s)and REOLYSIN 3x1010 TCID50IV over 1 hour daily for 5 days.
Results:
32 patients entered the study and received at least one dose of study drug. The patient population included 20 males and 12 females, median age was 62 years (range: 37 to 80 years) and all were Caucasian including one Hispanic patient.
Of the 32 entered, 25 patients received more than one Cycle of therapy and a total of 125 cycles were administered in that group (per patient mean=5, median=6, range 2-12). The 7 non-evaluable patients received 1 cycle or less.
Of the 25 evaluable patients who received more than one cycle, 12 (48%) had a PR, 10(40%) had stable disease (SD), and 3 (12%) had progressive disease (PD) for overall disease control (CR + PR + SD) in 22/25 (88%). Of 21 patients with >6 months follow-up, 7 (33.3%) have PFS of at least 6 months.
The most common adverse events (AEs) seen were those expected with P/C---neutropenia 17 (9=Gr 3-4) and thrombocytopenia 15 (5=Gr 3-4) and those expected with REOLYSIN---fever 6 (1=Gr 3) and fatigue 11 (4=Gr 3). The AE profile of P/C therapy did not appear to be significantly altered by the addition of REOLYSIN.
The only serious adverse event reported as unexpected and related to study therapy was reversible Gr 2 elevation of creatinine (and increased BUN) which occurred 3 weeks after Cycle 8 in a 65-year-old woman.
Conclusion:
Combination therapy with paclitaxel/carboplatin/REOLYSIN was well-tolerated in patients with recurrent/metastatic SCClung and the response results justify further studies.
Dr.David Cohn, PI for Ph2 Ovarian Monotherapy Study
One of the few Reolysin Monotherapy studies, it is interesting to listen to the PI talk very candidly about the promise of viral therapy and side effects that are described by patients as "much less" than chemo.
INNOVATIONS IN SCIENCE
Virus Therapy
by David Cohn, MD
No cancer diagnosis is good news, but ovarian cancer can be particularly unsettling since more than eighty percent of patients are diagnosed with the disease after it has already spread. Despite several effective treatments for this type of cancer, most women whose cancer has spread to distant locations in their bodies, or whose tumors return after treatment, find themselves in a tough battle for survival.
In my eight years as a practicing gynecologic oncologist, I have been continually frustrated that recurrent ovarian cancer remains incurable.
It’s difficult to deliver bad news to these patients, particularly after they undergo a failed regimen of chemotherapy and all its side effects. “Isn’t there anything else we can try?” is a question I hear all the time.
Each year nearly 22,000 American women are diagnosed with ovarian cancer. Despite all the progress we’ve made in treating ovarian and other cancers, close to 16,000 women die from ovarian cancer every year.
My practice at the James Cancer Hospital at The Ohio State University is currently testing a new treatment for women whose ovarian cancer has recurred or progressed either during or shortly after chemotherapy treatment. The treatment, Reolysin, is an entirely new agent in the war on ovarian cancer or, for that matter, on any type of cancer: Reolysin happens to be a live, infectious virus.
But before getting into the specifics of how we came to use a virus to treat cancer, it would be useful to provide a bit of background on ovarian cancer and its treatment.
Conventional Treatments
Most women with suspected ovarian cancers undergo surgery to remove the main tumor and to confirm that it originated in the ovaries. Once ovarian cancer is confirmed by examining a slice of the tumor under a microscope, the surgeon typically removes the woman’s ovaries, uterus, fallopian tubes, and sometimes other nearby tissues. Depending on the stage of the cancer, some women will subsequently receive chemotherapy.
First-line chemotherapy for ovarian cancer is comprised of platinum-based drugs (carboplatin or cisplatin), often in combination with a taxane (paclitaxel). New combinations of drugs are helping women live cancer-free longer than at any time in the past. Most women respond well to these drugs, which is good news. Unfortunately, in many patients the cancer returns.
If the patient had responded initially to a chemotherapy regimen, most physicians (including me) will try the same drug or combination of drugs again. If it worked once, it is most likely to work again. But once the tumor returns it is not considered curable.
If the treatment used initially fails to shrink the tumor during the second round of therapy, an oncologist may try any of the half-dozen other chemotherapy agents approved specifically for ovarian cancer, or even prescribe drugs normally used for other cancers. The goal of therapy for recurrent ovarian cancer thus shifts from curing the disease to improving quality of life by slowing or stopping tumor growth. I have many patients who are still in remission after many years of being treated in this way.
Hope Out of Despair
For women whose tumors fail to respond at this stage, one potential and interesting treatment option may be a clinical trial.
A clinical trial is a specialized human study of an experimental drug performed under carefully controlled conditions. Pharmaceutical companies, hospitals, and government institutions use clinical trials to evaluate new treatments and to investigate the optimal use of already-approved drugs.
Participation in a clinical trial can be fulfilling and beneficial to patients in many ways. Participants in clinical trials receive the best evaluation and care available, usually from highly trained physician-researchers. While no study will promise a long-term remission or even prolonged survival, those outcomes do occur in patients treated in clinical trials.
In addition to direct benefits, study patients can take satisfaction in the knowledge that they are advancing medical science, and in so doing may help not only themselves, but other patients with their disease.
Virtually every important medicine on the market today, including all cancer drugs, was tested extensively in clinical trials. Taxane chemotherapy agents, which are part of the standard of care for first-line ovarian cancer treatment, were first tested during the 1980s and 1990s and have greatly extended the lives of millions of cancer patients, including those with ovarian cancer.
The Reolysin Study
Our clinic is currently testing one of the most interesting, and potentially promising, cancer therapies to emerge in many years. The treatment, Reolysin, consists of a virus that attacks tumor cells while leaving normal cells unscathed. The treatment is being developed by Oncolytics Biotech, a Canadian biotechnology company.
Virus therapy works by exploiting a genetic mutation inside cancer cells that does not exist in normal cells. The mutation allows the virus to enter tumor cells and produce thousands of copies of itself.
Eventually, the cancer cells bursts, releasing the virus particles, which in turn will infect other cancer cells. To date, 270 patients with various forms of cancer have been treated with Reolysin in various trials in Canada, the U.S. and the U.K.
Side effects of oncolytic virus treatment are extremely mild compared with those of chemotherapy or radiation. Some patients report a combination of mild, flu-like symptoms, low-grade fever, and a feeling of fullness in the abdomen (more on that in a minute). Side effects usually resolve rapidly. Several of my patients have commented that the side effects of Reolysin therapy have been much less severe than those of chemotherapy. In our clinic, no patient has had to drop out of a Reolysin study due to side effects.
Women in the Reolysin study receive the virus intravenously for five consecutive days. On two of those days patients also receive an infusion of Reolysin into their abdomens (hence the feeling of fullness mentioned above). The treatment cycle is repeated every 28 days as long as the patient continues without undue side effects.
Several ovarian cancer studies suggest greater effectiveness with chemotherapy agents when the drugs are administered into the abdomen as well as intravenously. Researchers believe this effect is due to the drug being in closer contact with the cancer. Based on these findings, the National Cancer Institute, under whose auspices we are conducting this study, was interested in testing if abdominal administration could improve outcomes with virus therapy as well.
Reolysin is currently under investigation in ten U.S. and U.K clinical trials for a variety of cancers, including tumors of the lung, head and neck, bone or soft tissue, colon, skin, and ovaries. In some trials, as in the ovarian cancer trial, Reolysin is administered alone; in others patients receive it along with chemotherapy. So far, reported results have been extremely encouraging, with many patients seeing their cancers stabilize or shrink significantly.
The appeal of Reolysin is that unlike chemotherapy, which affects many different cells, the oncolytic virus kills only cancer cells. Normal cells, such as hair follicles and intestinal cells, are undisturbed, so patients do not lose their hair or appetite. Compared with conventional chemotherapy and radiation, this alone is a huge step forward.
Experience has shown that oncolytic viruses are not only well tolerated, but offer hope for cancer patients who otherwise have limited options. Oncolytic viral therapy is a welcome addition to the fight against ovarian cancer.
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Women with cancers of the fallopian tube, ovaries, or the abdominal cavity who are interested in entering the ovarian cancer study at the James Cancer Hospital at The Ohio State University should call (614) 293-3873 or visit their website, www.jamesline.com.
***************
David Cohn, MD specializes in gynecologic oncology at The Ohio State University Medical Center in Columbus, OH. His research areas include genetics of gynecologic oncology, prevention of gynecologic cancer, and vaccine therapy for ovarian cancer.
Journal Royal Society of Medicine -Sept 2013
Live viruses to treat cancer
Oliver Donnelly1
Kevin Harrington2
Alan Melcher1
Hardev Pandha3?
1Targeted and Biological Therapies Group, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James’s University Hospital, Leeds LS9 7TF
2Targeted Therapy Team, The Institute for Cancer Research, Division of Cancer Biology, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB
3Department of Oncology, Faculty of Health and Medical Sciences, Leggett Building, University of Surrey, Guildford, Surrey GU2 7WG
Corresponding author:
Hardev Pandha. Email: hpandha@surrey.ac.uk
Abstract
Viruses that selectively replicate in cancer cells, leading to the death of the cell, are being studied for their potential as cancer therapies. Some of these viruses are naturally occurring but cause little if any illness in humans; others have been engineered to make them specifically able to kill cancer cells while sparing normal cells. These oncolytic viruses may be selective for cancer cells because viral receptors are over-expressed on the surface of cancer cells or because antiviral pathways are distorted in cancer cells. Additionally, when oncolytic viruses kill cancer cells, it can stimulate an antitumour immune response from the host that can enhance efficacy. Numerous early phase trials of at least six oncolytic viruses have been reported with no evidence of concerning toxicity either as single agents or in combination with chemotherapies and radiotherapy. Three oncolytic viruses have reached randomized testing in cancer patients; reolysin in head and neck cancer and JX594 in hepatocellular cancers, while results from the first-phase III trial of T-vec in metastatic melanoma are expected shortly.
Introduction
Remarkably, cancer-killing or ‘oncolytic’ viruses (OV) have appeared in the medical literature repeatedly over the last 100 years. Despite their undoubted antitumour effects, OV have been regarded as medical curiosities rather than credible cancer therapies. However, our improved understanding of both the molecular pathology of common malignancies, as well as basic viral biology, has renewed interest over the last decade.1 The true measure of relevance of any medical innovation is progression to a randomized phase III trial platform and, thereby, potential registration. There are currently two OV that have reached this stage: a modified herpes virus for the treatment of malignant melanoma (talimogene laherperepvec [T-Vec] NCT00769704) and a naturally occurring reovirus for the treatment of head and neck cancer (pelareorep NCT01166542, www.Clinicaltrials.gov). This review will give an overview of the advantages and disadvantages of oncolytic viruses as treatments for cancer including a review of clinical trials to date.
Methods
This review is intended to serve as an overview of the field for fellow clinicians, with particular attention to the clinical data. Medline, PubMed, ClinicalTrials.gov and the authors’ collective familiarity with the literature were used to retrieve the relevant references.
What are oncolytic viruses and how are they suited for cancer therapy?
It is a perverse irony that pathogens responsible for untold human suffering and mortality may hold the key to a new generation of cancer therapeutics. Viruses capable of killing cancer cells, or OV, may be naturally occurring, but can also be genetically engineered for attenuation or to encode additional genes to deliver a ‘therapeutic payload’. Both types of agent specifically replicate in cancer cells leading to their death, while sparing normal cells. In cancer cells, OV usurp cellular machinery for their own reproduction, such that the cell dies as the virus replicates, and daughter virions are released to spread and infect neighbouring cells (Figure 1).2 The basis for OV selectivity against malignant cells centres around three main key concepts: first, cancer cells are unable to generate an antiviral interferon response on infection by OV whereas normal cells can; second, genetic dysregulation in cancer cells (e.g. in the Ras oncogene pathway) supports viral replication; and finally targeting of cancer cells generates an antitumour immune response – in other words, OV-mediated tumour cell death generates a therapeutic vaccine in situ. 3,4
http://jrs.sagepub.com/content/106/8/310/F1.large.jpg
Figure 1.
One mechanism by which oncolytic viruses may replicate selectively in cancer cells. The normal response to viral infection is the triggering of specific molecules inside the cell leading to the production of type 1 interferons. These cytokines have a direct antiviral effect and switch off viral replication. In cancer cells, genetic mutations result in the loss of this interferon inhibition.
Advantages of oncolytic viruses over conventional therapeutics
Theoretically, OV have a number of positive attributes as cancer therapies: the replication of viruses selectively in cancer cells potentially provides a high-therapeutic index; upon systemic delivery, viruses can efficiently traffic to tumour tissue using specific or ubiquitous cell receptors to gain entry; viruses have tropism for cancer-associated blood vessels and distinct mechanisms of tumour cell-killing reduce the likelihood of cross-resistance to other anticancer modalities.2 All these mechanisms have been exploited in a burgeoning number of preclinical models as oncolytic virotherapy has developed. However, these studies have also highlighted a number of limitations, particularly related to the body’s highly evolved capacity to deal with viral infections. Hence, OV may be rapidly cleared by antibodies and complement or become trapped in the liver or spleen, before they can reach their intended tumour targets. Even after OV reach a tumour deposit, particular features of the tumour stroma and microenvironment may limit access to, and spread between, tumour cells.5 To address these problems and improve responses, a range of preclinical strategies has been employed in mouse models, including combining OV with other agents, such as immunomodulators and drugs to enhance viral penetration and spread within solid tumours.
Testing oncolytic viruses in humans – clinical trials
Twenty viruses have been or are currently under preclinical evaluation. A dozen or so viruses have been used in clinical trials over the last century. In the current era, there are seven viruses in clinical trial, including three in randomized studies. The prototype OV were adenoviruses, but despite elegant genetic engineering to increase tumour selectivity, they have been problematic due to inadequate infection of cancer cells, lack of specificity and the vigorous antiadenoviral antibody immune response. ONYX 015 was the first live-engineered OV evaluated in humans and, although responses were disappointing, a similar agent has now been licensed in China for the treatment of head and neck cancer in combination with chemotherapy.
In the UK, the largest clinical programmes of systemic and local delivery have involved reovirus (Respiratory Enteric Orphan Virus) and herpes simplex virus (HSV). Reoviruses are naturally occurring and ubiquitous non-pathogenic viruses. Malignant cells harbouring mutations or activation of the Ras oncogene (a defect in around half of all cancer) are susceptible to reovirus replication and killing. This is because Ras-activated cancer cells, unlike normal cells, are unable to activate protein kinase R, an intracellular protein present in all cells, which senses the presence of viral RNA and shuts down viral replication. Clinical evaluation of intravenous reovirus is the largest OV programme currently ongoing worldwide, and the manufacturers estimate that over 2000 viral doses have been delivered to patients as part of over 30 trials (http://www.oncolyticsbiotech.com/). Evidence of antitumour activity has been documented radiologically and histologically in tumour biopsies taken following therapy. Importantly, replicating virus has recently been isolated from tumour sites days after intravenous infusion.6 There were concerns that the potential of reovirus and other systemically delivered OV would be seriously limited by the generation of existing or induced neutralizing antibody (NAB) responses, as had been shown in animal models. However, we recently showed that after systemic delivery, even in the presence of pre-existing NAB, reovirus can ‘hitch hike’ on white blood cells and platelets, evade humoural immunity and efficiently access tumour sites with cytotoxic effect (Figure 2).7 Following a phase I/II study that demonstrated an encouraging response rate, reovirus is currently in a phase III randomized trial in combination with paclitaxel and carboplatin chemotherapy for patients with refractory head and neck cancers.8
http://jrs.sagepub.com/content/106/8/310/F2.large.jpg
Figure 2.
Reovirus ‘hitch hikes’ onto white blood cells where it is protected from neutralizing antibodies and delivered to the tumour.
Although four strains of engineered HSV type 1 (HSV-1) have progressed to clinical trial, the most advanced programme is using T-Vec (talimogene laherparepvec). To enhance the safety of this virus, the gene responsible for neurovirulence has been replaced with a gene encoding the cytokine GM-CSF (granulocyte macrophage colony stimulating factor), intended to boost the immune response against the tumour in conjunction with virus-induced tumour destruction. Repeated intratumoural injection of single-agent T-Vec in melanoma metastases has been shown to result in local tumour kill, but also generation of systemic antitumour immune responses, with radiological evidence of tumour shrinkage in distant, uninjected metastases; complete response evaluation criteria in solid tumours (RECIST) responses were seen in eight of the 50 patients treated in a phase II trial and partial responses in a further five patients.9 These results led to a randomized phase III study in patients with metastatic melanoma, which has recently completed and is expected to report this year.
The third OV to have progressed to randomized testing in patients with hepatocellular cancer is a Wyeth strain of vaccinia, JX-594. The virus has been genetically modified by the deletion of viral thymidine kinase gene (to switch off phosphorylation of nucleotides and prevent viral replication in normal cells) and incorporation again of immunostimulatory GM-CSF similar to T-Vec. In addition to direct and immune-mediated killing of tumour cells, a human study of JX-594 demonstrated an additional potential mechanism of OV anticancer effect, namely the selective targeting of tumour vasculature shutting down tumour perfusion.10
Challenges facing oncolytic virotherapy
Based on findings from phase I and phase II studies, the clinical data to date for OV have been promising enough for progression to randomized trials and significant investment from the pharmaceutical industry.11 Importantly, virotherapy has been remarkably well tolerated with no serious safety or toxicity issues reported to date in treated patients, their families or attending medical staff. The most common adverse effects of OV therapy have been transient flu-like symptoms, as might be expected from a viral infection. These do not overlap with the toxicities of chemotherapy and/or radiotherapy, so that the further development of combination strategies is unlikely to be limited by toxicity. On the negative side, there are a number of factors that still challenge the development of OV therapy. The UK’s robust regulatory framework presents several practical hurdles for widespread routine use in all cancer centres. Handling genetically modified agents raises concerns within the NHS clinical infrastructure but is certainly feasible. There is no evidence to date of virus shedding by patients after treatment that poses a risk to other patients, medical staff or their families. There may be a necessity for the adaptation of current pharmacy facilities, but many centres already have experience handling biological agents. In our experience, defining where, in the hospital, the agents will be administered and how they must be contained, has been an initial, albeit surmountable challenge. Other issues centre around appropriate radiological evaluation of response, since conventional imaging modalities and interpretation of response have been defined in the context of radiotherapy and chemotherapy, while OV result in local tumour destruction with immune-mediated effects. Both these features may be slow to develop and may be highly significant but without shrinkage in tumour size by imaging. OV-specific refinement of radiological RECIST may therefore be required in a similar way to recent adaptations to response definition in cancer immunotherapy.
Producing virus to the high concentrations and purity required for virotherapy is also challenging, and it remains to be seen what the cost of these agents will be if they do prove to be effective therapies.12
The future for OV therapy – next steps
As with many anticancer agents, OV are likely to work better in combination with other treatment modalities rather than as single agents. Several synergistic mechanisms have been identified such as the enhancement of apoptotic pathways when chemotherapy and OV are combined or increased viral replication in irradiated cells.13,14 Preclinical and clinical data already support combinatorial strategies, and it is reassuring that there is no evidence that co-administration of OV with chemotherapy or radiotherapy damages the virus or significantly increases toxicity.15,16 With the expanding portfolio of both new OV agents and novel targeted drugs entering the clinical arena, the number of potential combinations is huge, making rational clinical development a challenge. If, as seems likely, an OV is soon shown to be effective in a phase III setting, there will be a need to carefully prioritize the next tranche of studies to address how best to exploit specific biological features of the tumour (e.g. induction of new cancer-associated vasculature and angiogenesis), the OV (e.g. JX-594 noted for its vascular tropism) and the combination agent (e.g. tyrosine kinase inhibitors with antiangiogeneic properties). It should, ultimately, be possible to define optimal combinations, disease targets, dose and response assessment. Both preclinical models and clinical trials accompanied by meticulous translational scientific analysis will inform us how best to move forward via iterative ‘bench to bedside and back again’ research. In this way, OV may truly become an established and familiar part of the anticancer armamentarium.
Previous Section
Next Section
Declarations
Competing interests
All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). Hardev Pandha, Hevin Harrington and Alan Melcher have projects funded by Oncolytics Biotech, but declare no conflict of interest. Oliver Donnelly declares no conflicts.
Contributorship
HP conceived the article and along with OD developed the first draft. AM, KH, HP and OD then made a series of revisions to produce the finalized article. KH obtained the patient’s story, along with consent for it to be used for publication. OD and AM prepared Figure 2 and HP prepared Figure 1.
Acknowledgements
OD gratefully acknowledges that he was a recipient of the Ellison-Cliffe Travelling Fellowship from the Royal Society of Medicine (London).
Provenance
Submitted; peer-reviewed by Ketan Shah and John Bell.
Previous Section
References
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? Senzer NN, Kaufman HL, Amatruda T, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol 2009; 27: 5763–71. Abstract/FREE Full Text
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? Touchefeu Y, Vassaux G, Harrington KJ. Oncolytic viruses in radiation oncology. Radiother Oncol 2011; 99: 262–70. CrossRefMedlineOrder article via Infotrieve
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Published online before print July 3, 2013, doi: 10.1177/0141076813494196
J R Soc Med August 2013 vol. 106 no. 8 310-314
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Summary of Recent Analyst Comments
Thanks Taltell
Chad Messer, Needham (9/13/13) "Valuation is "compelling. Oncolytics is developing Reolysin, a naturally occurring virus that is safe to humans but kills cancer cells. The company will report pivotal data in head and neck cancer this September or October, which could lead to EU approval and, along with a confirmatory study, support a US filing. We expect positive data based on an earlier interim analysis. Trading at an enterprise value of <$350 million, we find ONCY shares compelling given the potential near-term upside"
Douglas Loe, Euro Pacific Capital (9/9/13) "We maintain our Speculative Buy rating for Oncolytics Biotech Inc. The company reported final tumor response data from its 55-patient, phase 2 open-label trial of Reolysin's effect on squamous cell carcinoma (SCC). . .the positive tumor response signal in SCC is consistent with prior interim analyses and our valuation. We are highly encouraged to see Reolysin perform well by one key measure in this cancer form."
Neil Maruoka, Canaccord Genuity (9/9/13) "Oncolytics Biotech Inc. reported positive response rate data from its phase 2 study of Reolysin in squamous cell carcinoma of the lung. Results showed that 92% of patients demonstrated disease control (stable disease or better). . .we see key randomized data on the horizon and we continue to recommend risk-tolerant investors accumulate the stock ahead of these potential near-term catalysts. . .the company has adequate cash on hand. . .ending the quarter with cash and cash equivalents of $38.2M, which represents approximately 19 months of cash at projected burn."
The Life Sciences Report Interview with Jim Letourneau (8/15/13) "A good firm in the oncolytic virus space is called Oncolytics Biotech Inc. The company is based in Alberta and has been around for a very long time. Oncolytics makes a human reovirus, called Reolysin, that it can inject into tumors to kill cancerous cells. Oncolytics has had some good results with head-and-neck tumors, and is conducting ongoing phase 2 clinical trials with partial results released. The criticism is the company is a bit selective in what trial results it chooses to release. But regardless, it has raised a lot of money." More >
Andy Batts, Seeking Alpha (8/9/13) "The strongest argument in favor of the Oncolytics Biotech Inc. investment thesis is that Reolysin is expected to work on some of the most prevalent forms of the disease, including lung, colorectal, prostate, ovarian, breast and pancreatic cancers. . .the company looks sound with sufficient cash on balance sheet for daily operating activities as well as funding clinical trial programs until the end of 2014 or early 2015. . .Oncolytics is very late in the development stage of its manufacturing process, which I feel is a major strength."
The Life Sciences Report Interview with Greg Wade (8/8/13) "There are quite a few catalysts in H2/13 for Oncolytics Biotech Inc. The phase 3 head-and-neck cancer data are going to read out in Q3/13. The company has a pancreatic cancer study going on, and we might see some early data in that before the end of the year. With each of these studies we're going to start to see the first randomized data that will help us to get a view on how Reolysin is really doing. . .I think a lot of investors have taken a disciplined approach with this stock, preferring to wait to see randomized data prior to embracing the reovirus approach. That, combined with peers doing well, has led investors to sell the one that's not going up and buy the others. With these upcoming data, which we expect will be positive, Oncolytics will have the opportunity to work for investors. . .the head-and-neck cancer study—the larger randomized trial—is the most powerful [catalyst]. Positive data there would be very well received. But the pancreatic cancer study is also randomized. Both could be meaningful."
Needham Initiated Coverage Today - Target $8.00
http://www.streetinsider.com/Analyst+Comments/UPDATE%3A+Needham+%26+Company+Starts+Oncolytics+Biotech+(ONCY)+at+Buy,+$8+PT/8684682.html
(Updated - September 12, 2013 4:39 PM EDT)
Needham & Company initiated coverage on Oncolytics Biotech (NASDAQ: ONCY) with a Buy rating and a price target of $8.00. Analyst Chad Messer thinks valuation is "compelling."
"Oncolytics is developing Reolysin, a naturally occurring virus that is safe to humans but kills cancer cells. The company will report pivotal data in head and neck cancer this September or October, which could lead to EU approval and, along with a confirmatory study, support a US filing. We expect positive data based on an earlier interim analysis. Trading at an enterprise value of <$350 million, we find ONCY shares compelling given the potential near-term upside," said Messer.
For an analyst ratings summary and ratings history on Oncolytics Biotech click here. For more ratings news on Oncolytics Biotech click here.
Shares of Oncolytics Biotech closed at $2.82 yesterday, with a 52 week range of $1.60-$4.93.
2nd Quarter Results Posted -
http://finance.yahoo.com/news/oncolytics-biotech-r-inc-announces-103000358.html
08/01/2013 06:30:00
Oncolytics Biotech(R) Inc. Announces Second Quarter 2013 Results
CALGARY, Aug. 1, 2013 /CNW/ - Oncolytics Biotech Inc. (TSX:ONC) (NASDAQ:ONCY) ("Oncolytics" or the "Company") today announced its financial results and operational highlights for the quarter ended June 30, 2013.
"We are pleased to continue to demonstrate positive clinical results with the recent announcement of a disease control rate of 71.5% in our metastatic melanoma study," said Dr. Brad Thompson, President and CEO of Oncolytics. "We are ready to commence the data analysis of stage 1 of our head and neck trial as soon as we can and we continue to enroll patients in our six other randomized trials."
Selected Highlights
Clinical Trial Results
Reached the stage 1 endpoint in stage 1 of the U.S. Phase 2 clinical trial in patients with metastatic melanoma (REO 020) after only 14 patients were enrolled. The primary objective of this Phase 2 trial was to assess the antitumour effect of the treatment regimen in the study population in terms of objective response rates. The secondary objectives were to assess progression-free survival and overall survival for the treatment regimen; the disease control rate (complete response (CR) plus partial response (PR) plus stable disease (SD)) and duration, and to assess the safety and tolerability of the treatment regimen in the study population. Three of the 14 patients exhibited a PR, and an additional seven patients had SD for a disease control rate of 71.5%.
Clinical Trial Program
Preparing to commence the data analysis of stage 1 of the randomized head and neck clinical study (REO 018) once sufficient patient events have occurred; and
Financial
Exited the second quarter with over $36.1 million of cash, cash equivalents and short-term investments.
Clarification on Phase III H&N trial
Investor Question to CEO
Dear Dr. Thompson,
Just a quick question:
Suppose that
1. The existing Head & Neck phase III returns p=.06 for mets and p=.07 for local regional.
2. A somewhat larger stage 2 trial is run in mets only, returning p=.049 for that trial.
Would the FDA require yet another trial? (IE. would the first trial count towards the required two randomized trials if it didn't return p=.05 or better?)
____________________
He responded as follows:
------------
The original study design was to enrol a first stage (80 patients), and then perform a predictive probability of success for a second stage which was very likely to be necessary. The probability of success for this analysis was 0.7 or greater which loosely translates into a p of 0.15 to 0.20. If we had equalled or
surpassed the 0.7 then we would have proceeded to the second stage. The only way we would not have proceeded, on success, to the second stage ( for the US) was to have a probability of success of .98 or .99, which gives a very low p value.
We doubled up on patient numbers last year to account for the two groups (loco regional and mets only) and will do an analysis of p value for each group. If the p value is 0.15 to 0.2 or better for each or either group, we will proceed to a second stage as before. The size of the second stage will be about the same as before, about 150 to 200 per patient group. If the p value is extra low ( unlikely with such small patient numbers ) as before we will potentially file with the single stage data.
Please post this if you choose,
Thanks,
Brad
Sent from AOL Mobile Mail
Post-AGM Discussion with Management Comments from Attendees
rjc
> I missed most of the AGM, but did arrive for the end of the Q&A, and participated in the talks with Brad and Matt after the more formal presentation.
> After the meeting, Matt was clear that it was two suitably structured randomized Trials that the FDA require, rather than two Phase III Trials. On this basis, all 6 of our current randomized Phase II Trials, plus our 167 patient randomized Phase III H&N Trial can function as the first of two required Trials across the covered indications. Matt also said that the second randomized Trial in a given indication might not be required in Europe for a conditional approval.
> Matt recently received additional information on this, and it was recommended that Matt get over to Europe to speak with the regulators there to get things moving, based on the randomized results that Oncolytics now has, or will soon have. Because of this, Matt will be in Europe next week.
> From what Matt and Brad said separately, and in combination, I think it might be possible that the Big Pharmas that are taking an interest in Oncolytics could influence the choice that is made as to which of the current 7 randomized Trials will be the basis of the selected next (follow-up) randomized Trial.
> rjc
------------------------
Dr Coffey will be in Europe to build relationships and make sure all European requirements for provisional registration are understood and complied with.
Europe requires ONE well-designed, well-controlled, randomized trial with good results for provisional approval and the start of Reolysin sales there. FDA requires TWO independent, randomized, well-controlled trials, each with good results for approval in the US. Phase II trials count if they meet all the criteria above.
Matt wants Oncolytics to be ready to file in Europe WHEN the results of any of our seven randomized trials are complete, un-blinded, and analyzed for statistical significance. Knowing the European regulators and their processes are important too, so they know you when you walk in with trial results, asking for provisional registration.
In after-AGM conversations Matt was clearly excited by this quicker (but rigorous) approval path in Europe, and eager to make it happen efficiently whenever "event driven" un-blinding occurs on any of our seven randomized trials.
Camelcoat43
--------------------------------------
I thought BT gave a good presentation.
I was a little put off by his answer to the question about what triggers the unblinding in the H&N trial. He seemed to say they haven't completely figured it out yet. That will leave him open to charges of incompetence.
He was also a bit testy when a questioner correctly pointed out that the company has enough information from the 6 week response unblinding to know which group some of the patients are in.
No deal yet with the sketchy Russian company but they have been in talks. Do we really want a deal with a company that issued a false press release?
daveau79
--------------------------------------
starsearcher40
> First off, I think management did a good job at the AGM. It's a double edged sword that we expect the company to make prudent and measured steps (which for the most part they do), and then have to wait (prudently) for the information we want to arrive. Brad was not going to jeopardize any of the trials, and on a number of occasions said that he would not divulge certain information at this time. This was the (only) correct move.
> What I liked the most from the AGM was the comments regarding Europe, and that Matt was on his way there on Monday to meet with Regulators. If the company is able to recieve regulatory approval based on the current studies, then this is an absolute game-changer. Approval equals cash flow, and cash flow is vastly important. Sure, they can get this through further dillution which no one likes. But with real cash flow from an approved product, dillution evaporates as an ongoing issue. European approval also lends a vast amount of credibility to the product, and as such, a vast amount of interest from the investment community.
> People think we're going to be waiting a long time here. Quite the opposite, I think things are going to be moving fast on several fronts here. For those who sell, or move on from a certain fatique of waiting thusfar, all I can say is I strongly believe you'll lose twice...once on the initial depressed sale, and then watching thosee who stayed the course, win in spades multiple times over.
--------------------------------------------
AGM Transcript V2 Board Thanks iisfoo
Audio Webcast at
https://event.on24.com/eventRegistration/EventLobbyServlet?target=registration.jsp&eventid=597378&sessionid=1&key=0930090C3098431330705E4095A94F84&sourcepage=register
Oncolytics Biotech, Inc 2013 Annual Meeting of Shareholders
Conference Call May 9, 2013 17:15 ET
Executives
[BT] Brad Thompson PhD — President & CEO
[MC} Matt Coffey, PhD – COO
[MAD] Mary Ann Dillahunty JD MBA – VP Intellectual property
[GG] George Gill MD – Senior VP Regulatory Affairs & Chief Safety Officer
[AJT] Alan J Tuchman MD MBA (FAAN) – Senior VP, Medical & Clinical Affairs, & CMO
[BT] Thank you all for coming today. It’s an absolute delight for us to be back in Calgary. This is our
home and many of our shareholders from the start and from the present are here today. And that’s
really, it’s a delight to have you all here and it’s a delight to be here. A comment on the room
geometry, it's a little unusual, so I’ll be doing a bit of game show hosting and moving back and forth a
bit.
After I've finished the presentation, I would urge you to direct anything of interest from a question
perspective to me and anything difficult towards my colleague Matt. And anything financial towards
Kirk. Unfortunately, Kirk, you’ll have to speak but this is fine. But thank you for that. And I might ask
you to leave your questions to the end of the presentation, I won’t be taking all that much of your
time.
What I wanted to do today is to give you a brief update of the year's achievements and take a little bit
of time to talk in more detail about three specific clinical studies - our two lung studies, and our head
and neck clinical study. I think those are things of interest that people should be brought their
attention to.
Before I begin, I would like to bring your attention to our forward-looking statements and I will do my
first walkabout here, where we draw your attention to our forward-looking statements and with the
SEC, our registration statements and with the 13 securities commissions in Canada, I believe; despite
Ontario’s best efforts to have a single securities commission we still have 13. I’m a big fan of the
Alberta Securities Commission so I’m actually a fan of keeping it the way it is. Aside: I had to just say
that, it's my one political statement for the day.
Today, I’ll be talking about the last year review, I’ll be talking about our financial status. I’ll be talking
briefly about some intellectual property developments, to talk about our manufacturing program,
which is a critical program, and to be talking and to get some more depth mostly about advances in
our clinical trial program. And I would encourage you to pay close attention to that particular part of
the conversation. I’ll also be talking briefly about the year ahead and then we’ll entertain questions
and comments.
So with respect to the year in financial. As many of you know, we are a development stage biotech
company, which means we don’t have revenues and certainly don’t have revenues to cover our cash
burn costs. And so it’s important for us to maintain sort of an ongoing financing activity that allows us
to fund the operations of the company. And it’s always been our sort of operation to attempt to have
at least a year of cash on balance at any time. And so when we drift down close to the year, we
always anticipate doing a financing to push that time envelope beyond that particular time.
So a year ago at this time or a year ago at the end of Q1, we had a little over $40 million in cash. We
spent money mostly on our Phase III study candidly. We had a very heavy expense year with respect
to clinical trial programs last year. And as a result of that we then kept our eyes open for
opportunities to do a financing and we did so earlier this year.
And so what you have is a cash balance that reflects very closely to where we were last year - it’s a
little higher - and that gives us cash operation certainly till the end of 2014, and arguably to early 2015
by the guidance that we've provided to the market. But it’s critical for everybody to remember that
that is how biotech companies operate until they actually have revenues from sales.
With respect to intellectual property, and this a very short slide for a very large amount of activity,
but we maintain a very vigorous and aggressive IP program inside this company. And this isn’t just
patents, it’s also trademarks, it’s also confidential information that’s kept that way - trade secrets.
And that's reflected in output, upfront what you see, which is patents being issued on a regular basis,
but not just here in North America and Canada and the United States, but around the world. We have
a very aggressive worldwide filing strategy and Mary Anne Dillahunty spearheads that program for us.
And I have to say, it’s a real strength in this company, it has been and always will be - we will continue
to maintain our efforts in this particular area.
Manufacturing – and it doesn’t do justice to give this one slide, but to do much more than that would
be telling things that we’re not supposed to talk about, candidly. But we’re very, very late in the
development stage of our manufacturing process. Again, we view this as a major strength of the
company. Imagine a scenario where we demonstrated that Reolysin works and then we can’t make it:
a little beyond embarrassing I would have to say; or can make it, but it doesn’t meet regulatory
scrutiny – also a problem.
And there are more products that fail registration at agencies like the FDA because of manufacturing
issues than there are because of clinical data issues. And so this is a program that we don’t talk about
that often, but I think it’s absolutely critical that we recognize the effort and the achievement of this
particular activity. In this coming year, we’ll see the last elements of that fall in place. And I have to
say that this is viewed as a major strength by other entities taking a look at Oncolytics on both noncommercial
and commercial.
With respect to the clinical program I think the thing, the highlight, is, from a major activity
perspective, is actually looking at the first stage of our REO 18 head and neck study. We completed
and expanded enrolment, which was about twice the original anticipated enrolment in this study,
quite expeditiously. And we actually released initial data off the very, very early preliminary data that
was available from the study just before Christmas last year. And I think this was a critical milestone
for us to anticipate and a critical milestone for us to look forward to in this particular study. And I’ll be
going into more depth about that data and I'll also be explaining why we did this analysis, because I
think it’s very important for people to understand how, I think, nuanced, the analysis of this particular
study has become.
This is our randomized clinical program, just as a placeholder to let you know what we’re doing. I
don’t have all the clinical studies that Oncolytics is involved with on this particular slide, that would
take another slide or two. We have a very broad-based clinical program now looking at a number of
different indications, different types of cancer. And I think the key thing for us in the last year has
been moving into a very broad randomized, which means we have a control and test group within the
same study program, looking at most of actually the major indications in oncology.
And this is a result, of course, of our belief that Reolysin actually is broadly active against most
cancers. And this is the result of that. This slide really just gives you an indication of the breadth of the
activity and the number of patients in each one of those studies. I'd just like to note that those last six
studies, those randomized Phase II studies, represent about as many patients as we’ve enrolled in
total for the entire history of the company in our previous studies including the REO 18 head and neck
study. And that most of those program costs are being supported by outside agencies. The equivalent
to that 600 plus patients is in essence the cost of a single study test as a corporation.
Now, what do those comprise of? There’s actually four randomized studies now ongoing in Canada.
These are actively enrolling in Canada and just very briefly, we are looking at castration-resistant
prostate cancer in a very interesting study. Our first study looking at what I think of as a new age
targeted therapeutic in combination with Reolysin, which is colorectal cancer, in combination with
Avastin and a drug combination called FOLFOX6.
Looking at actually both types of lung cancer both adenocarcinoma of the lung and squamous cell
carcinoma of the lung in a second line setting in a study here in Canada, randomized so it's in essence
two studies in one - there's actually four arms in the study. And finally, a study that’s I think very
important is to take a look at Reo finally in a randomized setting looking at breast cancer. And all
these studies are being run by NCIC here in Canada, it’s old name The National Cancer Research
Institute of Canada, which is now just NCIC, they've gone with the contraction of their official name.
We still have, and these are further advanced, two studies going on in the United States, one for later
stage ovarian and reproductive stage cancers in women. I have to tell the anecdote of a colleague
company of ours here in Canada, who was running an ovarian study many years ago and got a query
from Health Canada wondering about the gender imbalance in their study [laughter], but we have not
got that question about this particular study. Every time I look at that study, I think of Tony, I can't
help that. And a colleague of ours who unfortunately died of pancreatic cancer actually ran that
study.
And the other study being a very interesting study in pancreatic cancer, and just to note that these
are first line patients, but they are actually getting standard of care. Standard of care currently, (which
is about to change) is gemcitabine for first line patients in the United States and in Canada and we’re
not actually using that in first line patients, so it’s kind of an interesting study. And both of those are
sponsored for and mostly paid by the NCI, and the GOG, the Gynecologic Oncology Group, is actually
running the ovarian study.
So between those two jurisdictions, six studies which will either be substantially enrolled or
completely enrolled in this calendar year. And so next year when we are standing here, I’m hoping to
be able to be describing early data out of some or most of these studies. It’s a very significant step
forward for Oncolytics and it’s really, if you think of head and neck as the tip of the iceberg for
Oncolytics, this is the bulk of the iceberg underneath the water. These represent literally most of the
major indications from a numeric perspective for number of patients in oncology to date. Very critical
to be thinking in that term. This is Oncolytics future in these six studies.
Now, I want to talk briefly in more detail about three studies as I indicated and that’s our two lung
studies, single arm lung studies, one for adenocarcinomas of the lung and one for squamous cell
carcinomas of the lung. I think these are very critical, because they do lead into a number of our
existing studies, because we already have that second line study, but probably I think one of these
two studies is a candidate for our own next larger randomized study.
The first is looking at, and for different reasons, to take a look at these. First is the adenocarcinoma
lung or non-small cell lung cancer, and the primary objective of this particular study was to look at
response rates, but a unique feature of the study is us really getting for the first time into genotyping
patients, actually looking at their genetic makeup.
And as people are beginning to realize many of the cancers that we think of as one cancer, are
actually a number of different cancers. So I think, breast cancer now really is, what's the number,
Matt? six, eight diseases really, based on genotyping, and so if you don’t have balances of those in
clinical studies, your data is meaningless. It’s an issue. So you really need in certain indications to
understand the genetics.
Now, some cancers, you don’t have to, because we already understand that they are pretty
monolithic. Pancreatic cancer being I think the best example. The gene mutation that is linked with
pancreatic cancer is represented in over 90% of patients. That’s a pretty uniform patient population.
So you don’t have to do these sorts of things. Lung cancer, this type of lung cancer in particular, is one
that I think we’re going to have do that with.
This is just an example of actually metastatic disease and many of you have seen this slide before, this
is the same slide I showed last year, where you've got metastatic disease expressing. I’ll do it on both
hands, but the upper left is metastatic disease expressing through the lung wall and you’re seeing a
rather rapid reduction – post cycle two is only about four weeks out. And again in the lower and the
lung lobe there, for those at the other end of the room. I won't laser light you because I'll blind you.
And so, this is very typical of the responses we’ve seen in the studies, the key thing is however is this
rather crowded slide. I think the key element is that you will see there’s a number of different things
that can, that are associated with this – there are mutations at certain genotype or certain genotypes
due to mutation. There are certain things that we call over-expression, so the genetic makeup is the
same, but you’re actually getting more of something, so that's when we say it's over-expressed. You
can see it’s a pretty diverse set and sometimes you get more than one thing and you see BRAF and
EGFR amplified, over-expressed KRAF, all blended together and what we’re seeing is that there is
different patterns of response as a result of these different genotypes.
For example, if you have a KRAS involvement, you see a lot of stable disease, almost uniform stable
disease, which is almost unheard of honestly in this indication; and when you see EGFR involvement,
you’ll see a lot more partial responses, but you also see more progressive disease. So you’re getting
more aggressive responses but more aggressive failures, and so going forward into future studies we
will have to take this into account for entrance criteria, but this is honestly the future of some of
these diseases. It is this finer differentiation between the patient populations and it gets critical. So
you will see a lot more of this in future indications or future studies of Oncolytics when it’s warranted.
We are not going to do genotyping where it’s not warranted. Just, people ask us why we don’t
genotype head and neck, well, it's not necessary, they are pretty much, they are pretty uniform. It's
the same with pancreatic cancer.
The other one that’s interesting, on those Reo studies, I mean the really key thing I think for this first
one is looking at the stable disease or better in this relatively diverse patient population. The entrance
criteria they were all supposed to be stage 3B’s or 4’s, which is very late stage, it turned out all the
patients, except for one I think, were stage 4 and in this patient population you don’t expect to see a
90% or better stable disease rate by RECIST which is what we got out of the study It's probably,
arguably about twice, what you would expect to see with this particular patient population, these are
very late stage patients and we saw a very, very aggressive if you want to think of clinical benefit as
being stable disease or better.
The other thing that’s noticeable here, and this hasn’t actually been published yet, is that many of
these patients normally only get 3 or 4 cycle of therapy and we’re starting to see patterns beyond
that, so beyond the... we're starting to see duration of response become an issue, but that will be the
subject of a future... when the study is finally done.
The other lung cancer is squamous cell lung cancer. Sort of arguably about a third of lung cancers are
in this category and this of course was the subject of early disclosure of the very first patient who
showed up on a news article out of Texas. Actually Matt and I saw the first response of the study on
the TV screen when they actually showed it, and we were little unhappy with the investigator for that,
but the good news was that you had a very aggressive response in patients.
This one I want to highlight for a slightly different reason than the first one. The first one was looking
at genotyping, this one is looking at a somewhat different element of it. Again, you’re seeing, this is
actually patient one and with the circles, the top is the primary tumor and you can see, very rapidly,
post cycle two, it's just a few weeks out, and you’re seeing these very aggressive responses and this
actually is the 6th or 7th best response on this study.
There are six patients who are better than this with respect to this kind of response. And you also see
metastatic lesions which is represented in the lower slide. But the key thing to think about here isn’t
necessarily the response rate, which is impressive, but the speed of response. And I think – just keep
that in the back of your head about speed of response.
Anecdotally, for the last decade, George and Matt and other people associated with our clinical
program have been hearing reports about how patients quite often show tumor changes very rapidly,
often in the first week of therapy. It’s very unusual. So the speed of response is starting to be
interesting. And that’s the case here. You’re seeing post cycle 2, a few weeks out, you're seeing these
very aggressive responses. Now, if you look at – and this data just came out earlier this year – and this
is really a reflection of speed of response, not magnitude of response – this is what we call a waterfall
graph, where you actually graph the worst patient on the upper left at a certain timeframe and then
at (so these aren't in order of enrolment and have nothing to do with duration) but they're just
basically more or less at the same time – all but three of these patients were done at four cycles, a
couple were at two cycles and I think one was at six cycles. So it’s a pretty uniform timeframe, it’s not
absolutely pure.
But what you see is that 19 out of the 20 patients actually in that defined timeframe actually showed
shrinkage of tumors in a fairly short period of time. And we have this very bulky about a third of the
patients showing this rather aggressive speedy response. And so these waterfall graphs actually show
you a – are very handy, they are not a measure of response rate by RECIST as we call it, sort of
maximum response rate for a duration of time, but they are actually a reflection of speed of response,
if you want to think of it at that way. And so in this particular indication that’s quite interesting, and
this is one of the more impressive waterfall graphs honestly I have ever seen. So it’s quite interesting.
When you switch over to more standard measurements, which is looking at and this was announced
after the first, the final, we’re actually seeing more on the duration of response, which is response by
RECIST. This particular patient population again you don’t typically expect to see stable disease or
better numbers up in the 90%-ish range, but again, we saw this. So overall, when you combine both
our squamous cell and our non-small cell lung populations, it basically covers most cancers of the
non-small cell lung, together you are getting 9 out of 10 patients getting some form of clinical benefit
by RECIST. And that’s impressive I have to say, and that’s something that we’re certainly very
interested in and I think will figure largely in our clinical trial progression, the clinical trial program
progression, not the patients, my apology.
Honestly, this slide, if everybody pays attention to this slide and goes away and just remembers
what's on this slide today, I’ll be thrilled. This is the slide – this is my chance to act a little tiny bit
professorial. Normally, we look at something by, called best responses by RECIST, where you measure
the patient at time zero, you measure it at some time out there, and that you hope to have some
form of response and you measure the response and you measure the percentage shrinkage by the
addition of some of the longest tumor measurements and so on. And then you have to maintain that
until – for a certain period of time. And so, you see – let’s say you have a -50% at Cycle 4 in this case,
potentially at Cycle 6 when we scan again, we want to see if we maintained it: if it's maintained then
that’s a response by RECIST.
These kind of responses are standard. This is the standard way of measuring in clinical studies, but
they are relatively time independent because it doesn’t matter whether it's between Cycle 4 and
Cycle 6, Cycle 12 and Cycle 15 – you're really measuring the best response and seeing if it’s
maintained and it doesn’t matter how long it takes to get to that response.
And when you think about what that means to a patient, what it means for a patient is that if you
don’t really care when the response happened this is more important for patient outcomes if they are
actually going to able to live to that event. Think about that for a second. Now if you’re only going to
live six weeks if you have an agent that is going to cause a response at Cycle 12, out maybe 6, 8
months, that doesn't do you much good. But what this does do, so when you look at RECIST, you look
at things that are much predictive of patients who are going to have better prognoses coming into the
study from the start.
So it’s a magnitude think of it as can you make this response bigger, but you are not really caring
about how long it takes you, that’s what we do now, that’s the system. The layer on top of that and
this is where the new agents, the new targeted therapeutics, have some wrinkles and some nuances
that are quite interesting.
You also have to take into account with all these things when you stop treating. Honestly a lot of the
new agents when you quit treating, you quit getting benefit. So let’s say a patient is only getting four
months of therapy, wondering about a response out at 9 months or 10 months or progression free
survival at 10 months or overall survival, doesn’t mean so much because you quit treating six months
ago, how can it be better than your control arm, when you’re not treating anymore? So these things
are important and we’re also starting to see a number of therapies not just Oncolytics Reolysin
potentially, but a number of existing therapies like Avastin and others that you are actually starting to
see lots of activity over time. You’re seeing a tolerance issue coming up or perhaps in some cases
toxicity issues coming up, so you have to layer that over the top of this. So that’s the second element
when you’re looking at things.
The third one is one that virtually is untouched. And this is something I think it’s really critically
important – I’ll go back to my six week analogy. You come into a clinical study or into a clinic before
it's an approved product and you have a 6-week lifespan, you don’t know that yet. You have no idea
that you have a 6-week lifespan, and that’s often the case. And you’re treated with an agent that
gives you a response say -30% of your tumor volume in two weeks. Well, that’s interesting, that’s
probably going to give you some clinical benefit. And actually there have been studies in other
products like Nexavar, which have actually shown that the rapidity of response actually provides
clinical benefit. If that same agent would only give you a response at 16 weeks, which is 10 weeks
after you're dead – not so much clinical benefit to expect. So the speed of response really matters.
So you have this relative thing – speed of response matters, magnitude of response matters. And that
makes complete sense. I mean if you’re going to have a really rapid response in a tumor and you need
it now then that’s more important than maybe getting a better response later - two things. So just
keep that in mind for now and for the future. But I would urge people to take a look, if you’re
interested in looking at things like that, look at the Nexavar studies for squamous-cell carcinoma,
where they actually didn’t see any progression free survival benefit, nor overall survival benefit, but
they saw clinical benefit in a pretty significant patient population, because it was faster at getting to
the same point. So driving to [indecipherable] as opposed to walking to [indecipherable] - when time
matters, you drive.
How does this relate to Reolysin in our head and neck program? Our head and neck study now
currently is in essence the same as it was before. It’s a double-blinded placebo-controlled study
looking at patients with advanced head and neck cancers. It’s a two stage study, it was always
designed to be a two stage study, and what we had originally intended was to run the first stage with
around 80 patients, look at an adaptive approach looking at progression free survival to determine
the probability of success in the second stage and then move into the second stage, which is where
we would definitely prove the statistical outcome of that particular study.
Along the way we discovered we actually thought we had two patient groups by response. Patients
who had just metastatic disease in essence had about twice the progression free survival of patients
who had local regional involvement. So they might have metastatic lesions but they also, they have an
active head and neck cancer in the local regional area. And so when we discovered that, we thought
we were fairly unique at that time. We went to talk with our investigators, talk with the FDA, and
what we agreed as a group was that we would double up in essence on the patient side, and analyse
these two patient populations separately, and that’s what we did.
So we enrolled 167 patients in the first stage instead of 82, which is where we were at the start, and
then we would go into an analysis once we see the results of that data then we proceed into the
second stage just like before. The overall endpoint, before and now – a reminder – the primary
endpoint is overall survival, that is the registration endpoint, that is the endpoint that matters in this
particular case.
The secondary endpoints, which we will still report on are progression free survival, we’ll look at best
response, and we added in a specific additional one, which is looking at tumor-specific response at a
specific time, and I’d like to draw back to my comments on the last slide, when we take a look at that
data because that’s important. We are also looking at some other things like HPV status and where
we could get biopsies, and we knew we wouldn’t get very many, at Ras pathway status.
So the analysis, where we are right now, we’re still doing the analysis of the first stage and as I said
it's167 patients. We are still blinded to overall response rates. We are still blinded with respect to
progression free survival and we are still blinded with respect to overall survival.
The patients, we still don’t know who is in control and who is in test. We're blinded, that’s critical. Our
Data Monitoring Committee has now reviewed the data on the patient population now three times
and has continually just said continue on with the study. Now that we are not enrolling, we're not
treating patients anymore, their job is done, I mean that’s categorically concluded.
The data we announced just before Christmas is I think quite interesting from two perspectives: one,
the first piece of data we looked at was looking at a set time; now it was all at a set time here, we're
all looking at the same point in time, was to see what percentage of patients had actually had no
growth, so 0% growth or better and compare just those two percentages and we looked at the
patients and we looked at metastatic tumors specifically because there was enough data to actually
give you statistics and that’s an important thing to note with these studies is that you're looking at
fairly small patient sets and it doesn’t necessarily mean with these small patient sets that you'll
actually reach a statistical endpoint when you think about the size of studies that you look at. I mean
there is about probably arguably about 70 patients with just distal mets, there is about a little under
100 patients with local regional involvement, they are pretty small patient numbers and, as we
originally intended, they're used as guidance to move into the second stage.
I think we were a little surprised honestly that we reached statistical significance with this particular
endpoint where we were looking at just comparing those two gross numbers. So in the control arm,
you had 67% of the patients and their metastatic disease with that 0% or better and the test arm was
86% – that’s a pretty big increase in percent.
If you look at it on a more fine basis, which is looking at again, the comparative waterfall graphs. and
what this waterfall graph is actually, is every patient in those categories graphed on here from the
worst to the best, so the worst is up at the left, so if you take that one up in the upper left, that
patient's metastatic lesions actually grew 100% in six weeks, and that’s on the control arm, and on the
lower right you’ve actually got the best patient, which was on -80% and again, that same six weeks, in
this case on the test arm. And what you found is that, over that same time period, six weeks, it’s
roughly about between a 10% and 15% on each patient benefit increase in shrinkage over that
timeframe.
And so, if you’re expecting to get a -30 on the control, you could expect to get -45 on test, and if
you’re +15 on control, you could expect to get 0 on test, more or less. But what this is, is a measure of
rate of shrinkage – this is the velocity thing again, so this is the early patients, this doesn’t mean
they’ll actually have better responses in the end, what it means is they’ll get more response sooner.
And in the other studies, again I’ll refer you to the Nexavar study, this actually translated into clinical
benefit in this case being, living longer.
So we’re hopeful, I mean, this is the only data we have out of the study to date, but certainly it’s a
very good indication early on that we are hoping to see something based on this, and I mean, of
course, the best would be to have increased rate of shrinkage, and also have increased magnitude of
shrinkage, but we don’t know that yet, that’s still blinded - and that will be coming out in the coming
months.
We’re quite excited about being at this stage of this particular study and I think it’s really quite
significant that we were actually [able] to get a statistically significant outcome of anything with this
small dataset. Just as I’m mentioning about the timing of data, because I know I’ll get asked the
questions, what we did when we doubled up on the patient number and looked at those two patient
groups was go to a different statistical endpoint. And instead of doing it at a fixed time to do a
predictive analysis, we are going to basically an event-driven outcome and while we roll that off our
tongue quickly and wish that events would happen quickly, events in this particular case are deaths.
What we’re talking about here is we have to have a certain number of deaths on study to reach a
comfort zone that our statistics won’t change based on the rest of the people dying after that point.
And so we are actually in waiting mode. We are waiting for events to occur and once we cross a
critical number of events, then we will do this statistical analysis and that is not predictable. People
do not die on schedule and we’re all thankful for that. So when we have that percentage of events
occur then we will do the statistical analysis, and not a day sooner. Well, this is the comment on that.
So looking at the year ahead, I think I can very comfortably say that sometime between next week
and the end of this year – how's that for a timeframe? – that we will complete the first stage of the
analysis of the 167 patients on REO 18 and that will be overall survival data, progression free survival
data, magnitude of response data, which is actual RECIST-based response data, and that will tell us
which patient group, maybe one, it may be the other or maybe both will be the candidates for the
second stage of the study, which will then finish off the program.
Now there is a possibility, just as a side comment. We will be consulting with primarily our European
regulatory friends about looking at this dataset from this first stage because it is now large enough,
167 patients is large enough, that if the outcomes were to fall our way, it might be considered for
some form of regulatory approval. But we do not know that – it will be completely dependent on the
outcome of the data and it will completely depend on the outcome of Matt and his colleagues'
conversations with our European regulatory friends. I guess we can call them friends, they're actually
quite helpful. So that’s something to watch out for this year, and start watching from soon to later.
We expect some time before the next AGM to either be completed, (and I'm hedging a bit because
one study is a little slower starting up) but five of the six I'm pretty comfortable will certainly have
finished, completely finished, enrolment in those, which is the future for Oncolytics – those major
indications in those randomized studies coming in behind. We will also have selected, and I think,
much sooner in the year than near the end of the year, our next indication that we’ll be taking into
our later stage development ourselves. And I think you can guess where I would like to go on that.
And I'm expecting our manufacturing group to deliver on what they have committed to deliver, which
is to finish our manufacturing development this year, which is the result of many years of, I think, very
fruitful investigation. Again, I can’t emphasize [enough], and that’s why I am finishing up mentioning
manufacturing last, how important an asset it is to have backing up everything that we do having a
completed and very productive manufacturing program. So I am very pleased about that.
So that concludes my comments and meanderings for today. I appreciate your time and attention. I
appreciate the fact that many of you have been associated with Oncolytics as shareholders as long as
I've been associated with this program, and I think the only one who has a longer tenure with this is
Dr Coffey who we are all very thankful has maintained his interest and presence on this particular
program.
So, again thank you and what we would like to do is open for questions, we would like people to
identify themselves, we’re going to hand a mike out, am I correct? for those people who like to ask
questions because we are actually webcasting the questions so, if you could identify yourself and
speak into the microphone and if for some reason I don't get a microphone I’ll repeat the question
and Matt will answer all your difficult questions and I will answer the soft lobs. Thank you very much. I
appreciate it.
Question andAnswer Session
[35:09] Jon Tyson
[JT] Hi, I'm Jon Tyson. I have a question about slide 17, that graph of tumor response. When you say
50% shrinkage, is that 50% sum of lengths or is it 50% volume?
[BT] These are all sum of lengths which is the standard basis for er...
[JT] So, it’s really like it shrinks 7/8ths of…
[BT] Yeah, the volumetric is by the cube of the radius so ... if they were spheres ... so, I mean they're
much more dramatic on a volumetric progression, I mean a 50% regression length wise. And you also
have to think of it, if you have a tumor that's like a sausage, the long dimension is the sausage and
then you could shrink it like this all the way towards a fine pencil line and it's zero. I mean it’s not, I
mean the length is the best, honestly, that people have actually come up with. Dr. Eisenhower who
actually works with the NCIC, is the former Director of the NCIC, was the principal author of the new
RECIST criteria - I'll put a plug in for a Canadian component in global oncology - and it’s very difficult
doing the evaluations on these things from an overall perspective, because it’s very variable with the
tumor type, but I think we stuck... this is RECIST-like measurements - they meet RECIST standards. It’s
just not the duration of RECIST because we were after velocity not magnitude.
[36:40] Dean Bradford
[DB] My name is Dean Bradford. Can you tell me with regards to REO 18, how many patients continue
to survive?
[BT] No, I can’t. That’s... there are certain elements of the study that we do keep confidential and the
number of patients that are alive is but one of them, so I apologize, sort of, for not being able to tell
you that.
[37:13] Darrell Scott
[DS] My name is Darrell Scott. So rather than telling us how many patients are alive, can you tell us
what the trigger is that you would need to unblind at that particular point?
[BT] At this time, I can’t disclose what the trigger is, partly because we’re still working on it. With the
change of going from 82 patients with a single patient group to 167 patients representing two patient
groups, and having actually basically two measurements because you’ve got each of those two
patient groups, required basically a complete redefinition of the statistical plan with respect to when
the endpoint was going to be, going to event-driven on those two groups.
And you needed some sense of the progression free survival that you were seeing in the combined
groups actually to do that math and that’s what’s going on right now. We’re actually defining that as
we go. And just as a mention on that, it’s kind of we thought we were very unique in this last year. We
thought that we had actually – for the first time – observed these two patient groups and that turns
out not to be the case.
In the last year since that decision was made, we found out that another drug done by our former
colleague company of ours where the drug is called Erbitux, actually in the registration studies in
Europe, actually found the same thing, it just never showed up in the publications and it never
showed up in the label. So in the publication they were still treating the group as a monolith,
combining met patients and local regional patients together. In the label that’s for the treatment of
all, but when you dig into the regulatory stuff, you know the discussions at the regulators and the
presentations, they were seeing the same thing – they were seeing that the metastatic-only patients
as a group were doing much better than the local regional patients, but they just didn’t choose to
differentiate between the two.
So we weren’t quite as clever as we thought, I think, but there is certainly a track record of people
seeing with this and coping with this before, so I think it was reassuring for us that we actually did
that. I still think it was the absolute right thing to do once we figured that out to deal with it the way
we did. But certainly the analysis of this study is proving to be extremely interesting both with respect
from that and with respect to the now-dawning information that there's different components that
affect clinical benefit – you know, rates, magnitude, tolerance, those sorts of things. So we have an
interesting few months ahead of us.
[39:50] Don Siegler
[DS] My name is Don Siegler and I have two concerns on the Phase 3. Dr. Tuchman recently said the
data would probably be the end of the third quarter, I'd like your comments on that, and there is
something about a six month blackout on the V2 board. Anybody...?
[BT] Well, a) I don’t read the V2 board
[DS] I know, I don't...
[BT] And I would urge anybody not to read anything on a chat board but that would offend half the
people in this room so... I would urge people to either call us or read the stuff that we have to put out
because we have to put our hands over our hearts and warrant [indecipherable] whatever, but I am
not disparaging the V2 board because I think it’s a very good board. I don’t know about what a six
month blackout is, I don’t know what that reference is.
Does somebody have some texture on that or... Oh, yeah, that’s the, I’ll explain that – in the
information circular there was, we have a provision on our option plan that if we are inside an
internal blackout for whatever reason and a person’s options expire, of course, they can’t – they
could exercise, but they can’t sell them – which doesn’t seem to be particularly fair.
And so the provision is that if you have, if you are in a blackout period for any reason, financial, which
is often the case, we go into blackout every quarter for our financial statements from the time they
are prepared until the time they are actually, when Kirk prepares them or his colleagues prepare
them to when I read them, that’s when I get blacked out, when they are distributed to our board,
they get blacked out at that point in time.
And there’s other events that cause blackouts as well. If you have information about a clinical study or
you can have rolling layered ones like you might be talking about squamous cell and then you roll into
head and neck, and we were in, so you’re blacked out a lot of the time. We just don’t put a press
release for blackouts, blacked out, blacked out, blacked out, but if there – if your options actually
expire during, while you’re blacked out, what they do is, the options expiry is extended until 10 days
after the blackout period is lifted. So that’s all that refers to in that particular case - because there was
an information period and that’s when the financials actually deal with all those particular option
blackouts.
The other question was? [question repeated from the floor] Alan answered the question or made a
comment about end of third quarter and left out the word 'by' at the end of the third quarter. So, I
will plead Alan missing a word in his presentation and that is his opinion. We honestly don’t know
when the event threshold will be crossed, a) because we don’t know what that event threshold is, we
don’t know when people will die and b) so we don’t know that... that would be I think Alan’s probably
internal estimate in his own mind, that sometime between tomorrow, or last week, and tomorrow
and the end of Q3 because that’s really what his opinion was, but that’s a personal opinion not based
on any data because I don't have that data either.
[43:20] Bill Langford
[BL] My name is Bill Langford I had a question about the Phase 3 trial and you alluded to this yourself I
think, but given that there are two patient groups sample size is perhaps, in the metastatic group, 35
versus 35 ballpark, that’s not a large number, not a powerful statistical test which I believe means
that you have to have quite a substantial difference in performance to get a statistical significance.
Could you comment on that a bit Brad and the second thing would be what is the test for whether or
not they would be proceeding to the next stage. Thank you.
[BT] Matt? [laughter]
[MC] Awesome, this is fun, we’ve been kicking this around a bit as well. I was speaking with Wang
Chong who is the analyst over at Edison and it’s interesting because we obviously don’t have the data,
so I don’t sleep at nights and I worry about these things and drive my wife crazy.
If you look at the Erbitux study, the metastatic group lasted about 50% longer so not unlike ours
collectively, but what’s interesting if you look at the hazard ratio Erbitux in the metastatic only patient
has a hazard ratio of 0.99, which means basically 99% of the events on one arm happen on the other
one. So there is really no difference. But when you look at what they do in the local regional group,
it’s really quite an impressive outcome for those patients, they do really well. So that collectively as
you said, there is enough events for the entire study to say that the study was successful. Now if it
had gone the other way, they probably would not have had a successful study and would have had to
pick one patient population.
We are still at a point where we’ll be looking at the two groups and hopefully there's... When we
looked at the initial data, we reported there was a statistically significant trend in the metastatic-only
group. There was also a numerical trend in local regional. So it could be that the metastatic shrinks
more rapidly than the local regional, we don’t know at this point, the jury is out, but it looks like it’s
having an effect both in local regional and metastatic. I’m off to Europe Monday to talk to our
regulatory group because there is – I think there is some misunderstanding. In North America, there is
a requirement for two well-controlled randomized studies, you have to have two, and people are
going – Are you going to be selling this on Tuesday? It's like 'No!'. No – we have to do another study
and I think we’ve made that clear for the most part, but there is some confusion.
Europe is a little bit different. If you have one well controlled study in a very difficult to treat
indication, you can get a limited drug registration so we’re looking at that. So we are planning for
being successful in both groups or one group or the other. But as you said, the metastatic is probably
going to represent about 40% of the 167 patients. So you are going to have to see a bigger magnitude
to reach statistical significance. With the local regional as you said it's probably about 100, so you may
not have to have as big of a difference.
But then there is also the question of – if we ran a million patient study and we had a p-value of 0.003
and patients lived one day longer, it is statistically significant, absolutely it is. Are you going to spend
$100,000 for the one day, that’s really the question, so we’ll take a look at the data: statistically
significant is one thing, but you want the patients to derive a clinical benefit. Now, in this patient
population, their survival times are very well [documented?]; historically, if you look at it, their
median survival's about four months. so if you can extend that a month, for them, a 20 -, 25%
increase is going to be meaningful. Especially when you look at the tox profile – these patients aren’t
paying any real toxicology consequence, like they’re doing, really, really well.
So we don’t have kind of thing, but we are going to position ourselves to get a European opinion as to
what they feel about the product, how much of a difference they’re going to need to see pricing on
this type of agent. So I’m assuming that it’s going to hopefully work in both groups. Realistically
though, I think one group will show more pronounced effect than the other one and that will be what
we pursue in the second study.
[Inaudible question] It’s a small group, so I mean if we reach statistical significance I’d be over the
moon. and I'd probably quit and move to Jamaica. But it is, as you said, it’s probably like 100 versus 70
patients, what we'd look for then is a clear trend. I mean, you can look at some of these curves and
see, the curves are very descriptive of what the patients are doing. You can tell if it’s a delayed
immunological consequence, if there’s a more pronounced initial effect, if it’s a proportional effect
and they do better to the whole thing... You know, you could get a three, four, five-week advantage
and it's not statistically significant, but if you can see that much of a magnitude of response, we’ll
move it ahead.
[BT] You’ll need it [the microphone] again. Thank you, Matt. Interesting in your choice of successful
place to go being Jamaica. But they don’t have an advantageous tax regime. I thought that you should
just know that.
[48:35] Unidentified [Alf Conradi?]
[U1] I’d like to congratulate you on a very successful year building on the foundation and planting the
seed for future success, certainly is worthwhile, so congratulations. The question I have – I have two
questions. Can you elaborate on where pancreatic trials are at – both pancreatic trials, and secondly,
can you make a comment on where you’re at, if you’re talking about potentially approaching Europe
for registering the product, what sort of funding formula are you thinking about, if you could
comment on both of those, please?
[BT] Well, the randomized pancreatic study, we can’t comment on – they’re still enrolling, it’s ongoing
with many patients still on study. And so that’s the status. We don’t have interim data to discuss
about that. The single-arm gemcitabine/Reolysin combination pancreatic study, there are still several,
[to MC: a couple?] several patients still on study that are still being treated and that’s rather
remarkable on itself but I think the final-ish data on that will be presented later this year, if I had to
guess. [Inaudible interjection by MC] That’s good. So I mean that’s where we are on that. We’ve done
the interim releases on that data but I think we wait until we actually get later in the year to actually
do a final release on pretty much final data on that particular study. The funding part – referring to
like how we get reimbursed in Europe? or…
[U1] What sort of – Matt just alluded to $100,000 to get... for a day of life – I don’t understand that.
[BT] We actually had this conversation once with the FDA, which they're not supposed to have and
they said Well, you know, it's one thing to show a statistical significance. What’s clinically relevant or
however they... [interjection from MC] What’s clinically significant? And I said, so that means we’re
talking about pricing right, and they were like Yes, and I said, so if we want to charge $100,000 for a
month of life that’s probably not clinically relevant. How about if I charge a dollar for a month? And
they went, Oh yeah, you’re right. Oh, we can’t talk about this. I mean they’re not supposed to – the
FDA regulators aren’t supposed to consider that. Reimbursement is a completely different issue and
in different jurisdictions, you get different reimbursement regimes, like in England forget it.
[MC] Quality of life...
[BT] Yeah, quality of life here, there... In the United States are you not going to treat a patient and
give them four extra hours of life and potentially be sued? Of course not, which is why we have the
most aggressive pricing in the United States. I mean those sorts of things vary by jurisdiction all over
the place.
But in essence when you get down near to the end, I think we’re heading towards this in a general
trend worldwide. It’s that, however you prove clinical benefit, in the end quality of life will actually...
is becoming a mathematical art, and actually determines pricing more and more. And so, until we
actually know what kind of benefit we’re deriving for an indication... It kind of makes it a little fuzzy
talking about pricing candidly. I mean a rule of thumb in the air, I mean $40,000 for a six month
treatment course is cheap for a biologic and a 100 is getting pricey. Well, that’s kind of – there are
cases over a 100,000 but that’s just kind of the range that people talk about for therapies.
So, if you’re only going to treat somebody for two weeks, unlikely you’ll be getting $100,000 for it, if
that’s all they’re getting. If you extend their life, and quality of life, six, eight, nine months or
whatever time for a severe indication, you charge a $100,000. I mean that’s... Then you get quotas
where people, you know, if you get sick in October, they've run out of their money, so you don’t get
reimbursed at all, but if you are going to get cancer, get it in January or February or at the start of the
fiscal year. I mean those are the realities in our healthcare system, and that’s not just Canada, it’s
worldwide it’s different everywhere.
[52:55] Oliver Murtaugh
[OM] I'm Oliver Murtaugh. You’ve often said that you expect to partner before you go to market. This
is many years later now, do you still have that feeling or do you think we can go it alone on this
product?
[BT] Well, you know it was interesting, I mean as you refer it’s been many years that we’ve been
consistent in saying that and I’d like to happily report we’re still being consistent with that. I think
knowing what you are capable of and the organization is capable of is important and we're not a sales
and marketing organization, we don’t have that capability. And to build that capability would both be
time-consuming and extremely expensive and so I think it's our anticipation that we would continue
on with that course that we set on day one now many years ago, which would be to take it to fairly
late stage and then to seek out an affiliation however we wanted to call it with an entity that has
those capabilities. Whether that's worldwide or different jurisdictions or whatever would be that
case, and there is a variety of different relationships you can do for that, but that is consistent as
what, I mean we believe that our strength is doing what we do, not doing that.
[54:17] Andre Techine
[AT] Kind of another follow-up question on head and neck. So I think in the original plan for this study,
I think the plan was to look at the overall survival, but six months after enrolment?
[BT] The original, the primary endpoint in the original study plan was looking at overall survival, but
not at a fixed time. Again, you could look at it at six months, but that was in anticipation they’d all be
dead by six months, so that's a convenient timepoint, right. And that’s also the timeframe in which
you see about 8 cycles of therapy, which is the maximum number of cycles on study of the drug triplet
the carboplatin, paclitaxel and Reolysin together.
The endpoints are the same as they were at the start, it’s just different patient populations now and
that’s why we doubled up on the numbers.
[AT] So, I guess, as a kind of follow-up to that, right now if you’re looking at going out potentially to
12 months of the events, is there any indication or any concern that the control arm is doing
significantly better than originally expected? And is there any data from that Erbitux study that would
indicate how the control arm for mets-only went?
[BT] The control arm in the mets-only did much better than I think anybody expected in the Erbitux
study, but that didn’t affect the registration. Matt, I think, would be quite happy to go into detail
about that and probably could provide that?
[MC] Send me an email and I’ll send you the graphs and you can post them wherever, they’re public
documents. They are not easy to find public documents like really not easy to find public documents.
And actually to your question about pricing, in the discussion they talk about quality of life years and
pricing and how they come to it. So it’s kind of an interesting, because at the end of the day, NICE
didn’t actually... - they said, Oh, it doesn’t work at all for the metastatic group, so we’re not going to
reimburse for it. And it’s less than a quality life year so, you can't charge more than £30,000 and since
you’re assuming it’s going to be more, we’re not going to reimburse for that either. But it’s all very
medicinal how they go through it.
But it was interesting, I don’t... As people get more savvy with these clinical studies, as Brad alluded
to, breast cancer is kind of considered to be a number of different indications based on the genetic
phenotype of it. Head and neck cancer it was interesting that Erbitux did have this effect in the study
that it wouldn’t work in metastatic and would work in local regional, that the metastatic group lived
50% longer than the local regional, but George and I have been over this, over this, over this, and over
this because when we first saw this event we were just like…
[BT] and over this, over this, over this…
[MC] ...over this, over this. It’s interesting the patients die differently: if you have metastatic disease
to your lungs or to your liver eventually you will die of cachexia and just you'll waste. If you have a
massive lesion and that’s threatening your carotid or your jugular or your breathing or your air supply,
I mean all of the plumbing to your head and all the rest of it goes right up through that one little pipe.
So, if you have lesions threatening all of the structural integrity of those things, those patients die
catastrophically. So, they just have different risks, so maybe it’s not that surprising that they are
different. What’s surprising is that it didn’t end up on their package inserts, to me.
We’ve shared this with doctors and we said did you know this and they said 'No, and I was on the
study', but you can imagine when it's in a 14 patient, 14 country study you don’t get to see all the
data. And the companies collect it all and they share what they share and you can’t really see the
trends if that’s not what they're looking for. So, I think you know we made this discovery, but when I
went off to ITF or the Innovation Task Force in Europe I said, we are blinded still but we are seeing this
in this group, and this in this group and they said Oh we’ve seen it before.
But they are regulators, they can’t tell you where they’ve seen it before because it's under
confidentiality but we've had all kinds of conversations with the FDA where they go, out of the blue,
We want you to do this, and we were like Why? Mmmm.. we can’t really say, but just do it, and then
you will read in the popular press somewhere that someone had this problem, and you're like Oh,
that’s why we're doing that. So, you do get these little titbits from the regulators and in this particular
instance they came up and they said, We’ve seen this before. So we’re not unique. It just wasn’t
something that ended up, but if you send me an email, I'll send you those curves and if you want just
post them or post the link to where they are, it makes it very, very clear. But I think no-one... if there
wasn't a difference in the PFS and the OS, you could just group them all together and no-one would
care about where it is.
I mean statistically they do better. So it's very hard to run a study when you have two different
patient populations, it's like trying to run a colorectal and lung study in the same study, there is
different risk, different.... Surprising to us, certainly would have been surprising to the EXTREME
study, because they didn't stratify for it, it was an after type of effect as well.
[BT] Many of our investigators were the same investigators that were on that study and they didn’t
know.
[MC] No.
[BT] It’s interesting. Quick clear.
[MC]But send me an email, I will send you the curves.
[AT] So with regard to a follow-up study, will it be possible to use data from one of the other
randomized trials as justification for a follow-up study?
[BT] Yes, I think is the short answer; we're... There's some interesting kind of nuances and again
Matt’s going to be discussing this with our European colleagues in the very near future about lumping
and clustering different types of studies together for looking at approval paths, so... But until that's
settled, you can’t really…
[MC] We'll have to see the data too.
[BT] Yeah, that's right.
[AT] So, and one other question... any... There's been some discussion about the neoadjuvant type of
therapies?
[BT] Neoadjuvant is interesting. And part of my PhD is radiation biology, so I’m really interested in
neoadjuvant therapy, but that’s a different and very old story, sadly. But I mean neoadjuvant in its
purest form is treating patients prior to surgery in essence. And you are doing that for one of two
reasons, either to improve the outcome of the surgery by reducing the tumors prior to the surgery, or
potentially making the patient operable on when they were not operable before.
And so, the practical use of looking at a set timepoint in a short timepoint is if you could take... is 67%
of patients worth the surgeons treating somebody for six weeks prior?... Probably not, because that
means 33% of them grew, that’s not good. Is 87% shrinking over that timeframe or at least stable?
Mmmm yeah, it’s probably worth it for a surgeon because that actually gives them... And that’s how
they think – this has improved my outcome on surgery.
You get surgery, surgery is kind of the ultimate in velocity because you go in with a tumor and you
come out with a complete response, I mean in few minutes. But it’s the, [MC alive!] well hopefully
yeah, the duration of that response can vary rather markedly, but that’s, I think that’s a key
underpinning of all this stuff. I mean, you know in some of the lung cancers in particular if you could
reduce the tumor burden you would take a lot of patients who are inoperable into operable and you
take operable patients and give them a better outcome and so I think that’s something we will always
keep in mind in studies going forward.
[AT] Are there any plans to follow-up on that?
[BT] Well, if you incorporate the endpoints into further studies then you basically get that for free and
we’ll be doing that, and these velocity, these velocity type considerations are neoadjuvant endpoints.
I mean that’s what you are in essence measuring. So…
[MC] From December until March, April I had four unsolicited protocols in renal cell, [patA?] cell,
panc, and head and neck from various key opinion leaders around the world saying we saw your
results have you thought about using it here. So we got draft protocols coming from major key
opinion leaders saying you know, if you can cause that much shrinkage that quickly have you
considered using it for this. So, it is interesting because I think the scientific community... If you look
at biologics, biologics either work in the tail of the Kaplan-Meier curve like if you're trying to develop
an immune response, it takes a while to do that in the patients. You know IL2 – 10% of the patients
live forever – they have this long tail.
The other thing is if you look at things like Sorafenib, there's this bulbous, you know the curve goes
sigmoidal because everyone is deriving benefit for a finite period of time and things like Sorafenib
they will use it for four to six cycles followed by surgery. Because you get this massive effect, a very
profound initial effect and then you lose it over time because it’s a biologic. They don’t have... and
they generally have to use the cytotoxics.
Things like Avastin, the VEGF inhibitors, depending on the indication, have a period of activity lasting
from 4 months to 11 months typically. So it really is tied to that. So if you can go in and use something
that has really no side-effects to enhance the effectiveness of the cytotoxic, to get a more desirable
outcome, it is very attractive but like I said four different indications from four different people
unsolicited said Hey, can we look at this? So it's something we are obviously in discussions with a lot
of pharma partners. Those are the kinds of studies they tend to be larger, it would be nice to have
them pay for them, do them, so…
[AT] Actually one last question, then. With regard to any of the trials and data so far, any plans for
looking for applying for a big breakthrough therapy?
[BT] Yeah, I get asked about breakthrough therapy designation quite a bit. And I don’t think anybody
really understands what that means yet particularly. You get – you get a breakthrough designation,
what does that mean? It’s specific to you, so it’s not general and this isn’t a criticism but the FDA
keeps layering programs on top of each other to fix programs without changing the old program. The
Special Protocol Assessment was to fix the fact that they were approving Phase IIIs but they had no
intention of approving the product after the study, and things like that. And so I'm not sure, the
breakthrough therapy. what it means honestly. So until we actually figure that out...
[AT] It could help the share price...
[BT] Mmmm?
[AT] It could help the share price.
[BT] Well, I’ll give you another example about things, I mean people talk about... [To MC: Where's one
where they would say yes or no in a hurry?]
[MC] Fast track.
[BT] Fast track. We'll, get fast track designation. All that meant was that they had to review it within a
certain shortened review period, and if they weren’t prepared to say yes, they'd just say no. Well
that’s not a benefit and people were getting 'fast track' and their stock could go up and then they get
said 'no' fast, and you're like , that's not very helpful. So until we understand what breakthrough –
that designation – means, we won't be touching it, and I haven't had anybody able to demonstrate to
me that it means something defined, at least for our case.
I’d say the agency, the agency – I’m speaking of the FDA in particular – and this is a pattern back... if
they're faced with a therapy that is safe and highly efficacious in a disease like cancer, like AIDS,
anything that has bad outcomes they are very good about moving through their approval process.
They are extremely focused on things like that. So I'm not sure that program is absolutely needed
candidly.
[66:00] Doug Shoemaker
[DM] Metastatic cancer is that an actual designation by the FDA or is it that currently it's thought that
a particular kind of cancer metastasises and they're all different diseases? Can you comment on that?
[BT] George is shaking his head, correctly – it is not generally accepted as being a separate disease,
it’s the outcome of a sort of... you have metastatic head and neck, metastatic colorectal, metastatic
breast, the primary, what I think of as primary and George will correct me because I always misuse
the terminology and I apologize, but the initial occurrence is what you're characterized at. Many of us
think it should be otherwise.
[DM] OK
[BT] But, so what, that’s not the way it is. George is a...
[DM] So, to change that with the FDA would be a major…
[GG] The indications in the package insert are stage-specific in most cases so the package insert
doesn’t say this drug is approved for colon cancer. Period, that’s the end of the story. It’s approved in
the population that it was studied in, so if you do your trials in metastatic colon cancer, let's suppose
you limit your trial to only patients who have metastases in the liver, that’s what the indication will
say in the package insert when you get your approval. So when we study, when we write the protocol
and we write the inclusion and exclusion criteria, you've defined the population and that’s going to be
what you get an approval for if your trial is positive.
[BT] I mean the one case that I always refer to with people and that is Delcath's metastatic ocular and
melanoma where the primary is no longer there because they've taken the eye out already and that’s
an interesting disease because there are always mets it metastasizes to the liver, which I don't
understand, but their study was looking at actually specifically just at the liver mets resulting, but it
was liver mets resulting from primary of ocular and melanoma – that’s what the label says.
[GG] One addition to that comment is that that doesn’t mean that’s where the drug is restricted in its
use, out in the community. Oncology is probably the largest off-label specialty there is because what
happens is, good trials get published, the company may or may not have access to the data legally to
submit it. You have to remember trials are done by cooperative groups in Canada, the United States
and so forth. They often do it with approved drugs already, that are on the market, but they do it in
an indication or at a point or in a combination that’s new, and if it works well it gets published and as
soon as that data is out, the use begins all over the country in cancer communities everywhere, if you
see suddenly a new advantage.
The first trial I was ever involved in – just couple of months ago – [laughter] we were looking at
children with leukemia and looking at methotrexate as a remission – maintenance of remission drug -
which is how it was being used. And the trial looked at two different dosing regimens, that’s all: same
drug, different doses. And in fact the duration of remission on one arm was six months and on the
other was 18! You don’t see advances like that very often anymore, unfortunately, but the point is,
there is a big separation. People say, well if head and neck works, it’s just... there's not many patients,
although in truth if you look at the numbers worldwide, there is a lot of patients. The answer is, if it’s
out there and other positive information is coming out, clearly it's going to get used far beyond the
indication that’s in the package insert.
[70:20] Alf Conradi
[AC] So Alan, Alf Conradi again, I have two questions. The first has to do with what are your thoughts
with respect to the role for a potential maintenance therapy?
[AJT] And the second question?
[AC]: The second question is coming back to pancreatic, the carboplatin/paclitaxel study, where are
you at with enrolment for that study?
[BT] Well I can answer that one quickly - we don’t comment on enrolment in studies while they are
ongoing, so that will answer that question.
The first question – maintenance therapy is always an interesting thing, from two perspectives. One,
maintenance therapy doesn’t attract particularly good pricing so one has to be cautious one gets too
far into thinking about maintenance therapy. But secondly, to be candid an agent like Reolysin which
for a variety of good scientific reasons that we've disclosed really shouldn’t be expected to show that
much activity by itself. The agent by itself has difficulty penetrating tumors – the chemo and other
agents actually potentiate this activity within the tumor in a very specific way and there's some things
that Matt and his colleagues on the research side are demonstrating right now that will I think
enhance our understanding of that. So I think Reolysin should be viewed as yet another biologic that
does better when it's mixed with something else.
And I think that’s getting to be quite, almost the standard for biologics - the standalone biologics
either as primary therapy or as maintenance therapy just are unlikely to be used particularly a great
deal. Keep that in the back of your mind - if we prove it otherwise, wonderful, but that’s I think the
sort of standard operating line that we have to be thinking about.
[MC] What's interesting now if you look what’s happening in colorectal, typically you take a drug until
you fail it, then you don't see it again because they assume it doesn't work anymore. With biologics
that doesn't necessarily have to be the case because biologics enhance the effectiveness of other
cytotoxics.
So Folfox or Bevacizumab was approved in the first-line setting for colorectal cancer with FOLFOX. So,
you would take 6 or 8 or 9 months of this and you would progress and patients would go on to
irinotecan-based therapy. Some bright bulb decided to add Avastin back to FOLFIRI and they actually
increased the PFS again. So, Avastin actually now has approval for FOLFOX in the first-line setting and
FOLFIRI in the second-line.
So, reovirus, if you look at the biochemistry of it, it affects the cell kill a certain way with taxanes, if
you add it to something like VELCADE you get a different kind of cell kill, one around ER stress. So,
theoretically what we could potentially look at is an induction phase or an early treatment phase with
one cytotoxic or family of cytotoxics or platinum doublets or what have you. And then if toxicities
ensue or there is a problem, switch out that drug combination for another one and continue on with
the virus, because we actually have seen patients who failed a drug regime and you add the virus to it,
and all of a sudden they’re active again.
There has been reports even of on our crossovers it was on the news that the mayor of Bexley
actually had failed carbotax on the panc study, they added the virus to it and he had an objective
response, which is a fantastic internal control because you know he is resistant to the carbotax, but
when you add the virus it adds a unique cell kill mechanism. So, I agree with Brad, I don’t think
reovirus – it’s huge, it’s a bus, when you compare it to like a diffusible chemotherapeutic. It’s an
actual particle.
Our pathologists now can actually receive samples from the clinic in a blinded fashion so that you just
get the block of tissue, and he can tell us now whether or not that patient has received the virus as a
monotherapy or in drug combination based on the distribution of the virus, which is completely
different and the ratio of transcript to protein. So, I think there will be a role for reovirus in like longterm
maintenance therapy, but only in the context of a cytotoxic. It’s just, it needs to be delivered
effectively and the cytotoxics really do a very good job with that.
[AC] Thank you
[74:47] Jon Tyson
[JT] I have a question about blinding - what does that exactly mean, does that mean you know
everything about the patients?1
[BT] It means we know nothing about the patient. But blinding is – it’s awful and important, awful
from Matt's perspective because he doesn’t know, and very important for the doctor not to know I
think, and the patient not to know.
I mean imagine you come into a clinical study, and you’re a doctor, and you've got your favourite
patient, and you’ve got your less favourite patient, for whatever reason, and they're not going do
well. You are going to put the favourite patient on the test arm and because you have to balance out,
the less favourite patient, because they don't have the better outcome, on the control arm. You’re
just going to do that, it’s just human nature.
You have to blind the doctor from knowing what he’s treating the patient with, or she. And you have
to blind the patient, he or she, from knowing what they are getting, so they’ll stay on study because if
they know they are getting the control, they will go off-study. So it’s critical that they be blinded.
Now the company I would argue doesn’t need to be blinded, but my arguments don’t mean anything,
so we are blinded too, and that’s because then we can’t influence – but we can’t influence anyway –
but we can really not influence things if we don’t know either. It’s better when everybody is blinded,
our statistician is blinded, our data collection people are blinded, there’s people who know little slices
of things, but nobody knows enough for the whole picture, and that’s critical.
[JT] So on September, you knew that the metastatics were doing better than the…
[BT] But that was blinded, basically we knew – no just back up for a second. Last summer, when we
looked at the case report forms, you could see the case report forms for every patient, you just don’t
know what they are being treated with.
[JT] Right.
So I know, we know where the tumors are, we know whether they’re responding or not, I just don’t
know what they are being treating with.
[JT] All right. So you know everything except what they are being treated with?
[BT] Except what they are being treated with.
[JT] OK.
[BT] So you look at that and you go OK, well... somebody noticed - a couple of somebody actually -
noticed a pattern where patients with local regional disease were progressing quicker than patients
with just metastatic disease. But that was as combined groups. That’s what was noticed last summer.
[JT] OK. So if you…
[BT] Still blinded though.
1 I am informed that the full question here (inaudible on the recording because BT spoke over the end of
it and thus misinterpreted the question) was 'I have a question about blinding. Does that mean that you
know everything about the patients except whether they are controls or not?'
[JT] If you look at slide 23 then every patient whose tumor shrank by more than 50% is a test subject,
and every patient whose tumour...
[BT] No.
[JT] On slide 23.
[BT] No that’s a misreading.
[JT] Do you have the graph there?
[BT] No.
[MC?] That one.
[BT] No. These are individual patients. These are individual patient points and this is a waterfall graph,
so this is a patient – a single data point. And this is another single data point...
[JT] If you have a patient and you see his tumour...
[BT] But I don’t know, I don’t know who those patients are. I don’t have a clue who those patients
are. Our doctors don't know who those patients are; those patients don’t know who those patients
are!
[JT] But you said you had access to their medical data, except...
[BT] But I do not know, we do not know what they were treated with.
[JT] Right, right. If you knew here I have a patient whose tumors grew by 100%, and you have that
plot there, you now know that that patient is a control subject [inaudible background discussion
starting with "no you don't"] but none of the test subjects... [inaudible] ...No, but look... [Inaudible]
[BT] But honestly, honestly yes we could sit around and find a patient and maybe in an extreme case
find out what one patient was treated with.
[JT] [Inaudible interjection]
[BT] Please... But we didn’t — we don’t do that.
[JT] OK, OK.
[MC] Just when a patient gets randomized it goes to a group in California that has an algorithm that
says the patient – and this is to the pharmacists at the site – this patient will go on X or Y so that code
gets given to the pharmacists on that site. The pharmacist is the only person (because the pharmacist
has to make it up) so the pharmacist will either hand the physician a bag of saline or a bag of saline
with virus in it but even the doctors and the nursing staff don’t know. So, there is no bias from the
doctor’s point. So the only person who really knows who got what is the pharmacist but the
pharmacist has no contact with the patients so they wouldn’t be able to identify...
[BT] And that’s only one site out of 94.
[MC] Yeah, the 94. And the group in California who said this patient on this day gets randomized X or
Y, when that information went out, it went from that group in California to a group in Orlando and
bypassed the company. So we can see the case report forms as he said so we can see... and it’s all
patient identifiers, so we don’t know the patient's name, we know the sex and sometimes you know
the initials. But, we don’t know what the person's got and so the only way to finally unblind is to get
the unblinding codes from the group in California, but they can’t do that until a predetermined time
so we’re kept completely in the dark which drives me flipping crazy.
You're looking at these things and you're going – Oh, God I hope he's on the control arm, and then
you’re like Oh, that’s an awful thing to say, but I really hope that guy's on the.... So it’s scientifically
the best way of doing it. It’s driving me batty.
Because, it was a small study designed to create a bigger study, so you want to be able to have some
of that information to make the bigger, more expensive, study better. So, that’s the problem with it.
The NCIC studies and the NCI studies will guide us to design hopefully a Phase 3 study or Phase 3
studies based on generic markers that predict for success and patient characteristics like, you know,
the one thing that we were looking at there with the lung mets, is the lung mets do really, really well.
There wasn’t a big enough patient sample to say whether or not lymph node lesions do well or liver
mets although the liver looked good it was just the sample size was really small. There is a lot you can
learn from these studies. But when they're blinded you can’t learn anything until the blind's broken.
So it’s maddening as a scientist to be in this situation.
[JT] Thanks
[80:51] Andy Lee
[AL] Andy Lee, a question for Matt. Matt, concerning the Erbitux data. Obviously, when you saw it,
you were quite alarmed, I think, initially, I’m guessing here, but based on one or two of your
comments today, when I saw the data and I came across it in the fall of last year, I just chose to wish it
away. You I think...
[MC] Erbitux data or our data?
[AL] Erbitux data. The Erbitux mets data is what I’m referring to.
[MC] OK, yes.
[AL] Now, you’ve probably done quite a bit of an analysis and thought about this, had some time to
ponder over it – what can you say concerning your conclusions that would relieve my concerns at this
time, related specifically to the Erbitux mets data?
[MC] The Erbitux I mean – data is just data. I looked at it and it’s funny, if you actually read the NICE
arguments, they kind of explain why wouldn’t the mets work better and there was a few sort of things
in there. Erbitux is a great product. I mean it works in a lot of different indications. But it doesn’t work
in a lot of indications as well, so I think when we get information like that, it helps us refine the
patients who are going to derive the most benefit. And in refining the patients who derive the most
benefit we get the most competitive pricing.
So based on what we saw from early tumor changes it looks like we get more rapid and better
magnitude of response in the local mets, but we also see activity in the local regional disease, it's just
the kinetics could be potentially different. So when looking at the Erbitux data, I find it fascinating
that they’ve identified two different patient populations in the head and neck because trying to
explain it to somebody... Like there was a competent authority that said Well, has there ever been
another example of this? and you pull out the NICE document, when we sent in the protocol
submission and they went, Oh, OK, well, that’s just the case. Other people have reported it, it’s not
just you.
So those precedents, I don’t know, I was alarmed to see it because I know patients who have
metastatic disease are taking Erbitux and they are not deriving any benefit. And that’s what was
alarming to me. I thought, I’m a scientist through and through and yeah, I would love to treat every
single person with reovirus, and have it be a trillion dollar product, but at the end of the day, I don’t
want to give it to somebody who is not going to derive any benefit, it's awful to do that to the
patients, it's awful to do it to their families, it’s expensive, it’s a drain on their healthcare.
So I’d rather identify early which patients are deriving benefit. So in a way I was actually kind of
encouraged by the Erbitux data, although shocked that it wasn’t made available. And the one thing
that sort of stuck in the back of my head when reading that paper, they said, you know, there's 42%
male and 58% female and age of this and age of that... They do call out, they do say, 65 % of the
patients have local regional only and 35% only had mets. And then all the other analysis, it’s like here
is the response for females and here is the response... they never gave the curves for the local
regional versus metastatic and that... It must have twigged with NICE because NICE asked the
question, but it never ends up in a publication or the package inserts. So it is one of those things that I
was alarmed by not because it was a good bit of science, it was just the fact that it could have helped
a lot of other people design head and neck cancer studies to have pre-stratified for these patient
populations if there is an expectation they’re going to respond differently.
[BT] This is an add on though, I think it has absolutely no carry over to how or how not Reolysin will
work in either of those patient populations because the two drugs work quite differently.
[AL] I think my concern is that mets are only a subgroup. There is potential there that it’s a sweet
spot, that you’re seeing this extended PFS, doubling of the PFS, that there's a potential it's because of
the activity of Reolysin within that group, unblinded group. I think that with the Erbitux mets-only
data and their identification of this group…
[MC] Oh, I see what you're saying.
[AL] Yeah, that’s what I’m getting at. That I think is a concern and I’m wondering what you've thought
of over the past many months that may have relieved your concern with respect to that?
[BT] I’m missing what the concern is.
[MC] Erbitux demonstrated that the mets patients do differently.
[BT] Yeah.
[MC] And….
[BT] Which would have been nice to know three years ago.
[MC] Yeah because we could have stratified for it and it would have been nothing.
[BT] Yes.
[MC] But what he's saying is are you concerned the reason the met group does better is because they
do better anyways.
Looking at the early tumour changes, you know it's funny because someone said what does that
mean? Yes, there's an enhanced kinetic response, yes there's more patients that respond, yeah it
looks like it’s doing something but it's not RECIST. And I said OK but if it worked worse what do you
think the outcome would be on PFS and OS? Oh, it would be awful. I said so why can’t you think of it
in reciprocal terms – the fact that you’re getting more dramatic responses earlier isn’t that likely or
more likely to lead to benefits on the patients' prognosis. Well, yeah... And because we are seeing
changes in both local regional and metastatic, I don’t think the responses are going to be the same, I
think there is going to be a patient population that does better, like in the local regional versus the
mets, I think one of them is going to do better in the presence of the virus.
In terms of it being different one might have a four-week and one might have a two-week, or one
might have six weeks and one might be one week, I just think the early changes demonstrated that
there was a benefit for being on the viral arm on both local regional and metastatic at that six week
timepoint. So I think what it does do is it identifies two different patient populations, it identifies that
we have to change the second follow-on study to better treat the patients. But I’m not... The data's
blinded, I mean I can keep myself up all night by thinking oh mets is doing differently because of this.
The EXTREME study, the problem with it is it’s not looking at this patient population. So if it was the
exact same patient population, I’d be looking and comparing those numbers saying OK well they had
100 days, so we should have 100 days. The problem is those patients hadn’t failed platinum. So both
sets of them are doing better, so I can’t make a comparison, so I’m not overly fussed but you're right
– if it was the same patient population, I'd be drawing those curves out and comparing directly, but
our patients have a far worse prognosis.
[AL] Thanks, that’s what I needed to hear. Thank you.
[MC] Yes, no... it drove me bonkers...
[BT[ Yeah but I think we have to resist comparing apples to oranges – other agents have different
activity than our agent. And as they continue to demonstrate, it doesn't necessarily mean they
understand how those agents work, like Avastin. Our understanding of Avastin is quite different than
it was five years ago or three years ago.
[87:25] Mark Gray
[MG] Mark Gray. I have a couple of questions. Regarding the Phase 3, can you explain what stage two
is and regarding the second study that you need, when would you pursue that?
[BT] The study has always been – think it more of as a program – it’s always been designed to be two
stages, which is in effect two studies under the same umbrella, and the study originally was designed
to enrol 80 patients in effect in a single patient group. See how they were doing after a set period of
time and then use that as a predictor of success in the second stage and run a larger sample size in
the second stage and that would count as our two studies for filing in the U.S. That's how it was
designed.
In essence it's the same now, it's just that we're using different endpoints if you want think of that
way, we’re using an event-driven OS endpoint as the final endpoint in the first stage, with two patient
groups. So it’s a nuance really when you think about it and so the second stage is basically a second
study and it’s under the same umbrella of the program, that’s all.
[MG] Would you be looking for a partner at that point?
[BT] It depends. It depends on so many different things – how big is the study, how long is the study
going to take, how many countries we’ve run the study in, which patient population is benefiting, and,
and, and, and... There’s so many depends that, my board's nodding and smirking to themselves
because they've heard this story too many times from me – when they ask me questions, it depends, I
do it all the time.
But it does, it depends. I mean we have too many variables and because of all those variables you
can’t say whether you do a partner or not do a partner before you know anything about it. I don’t
know if it’s going to be a 100 patient study, a 200 patient study, a 5,000 patient study, don’t know,
don’t have a clue. I don’t know which patient population, don’t know if we run it in 2 countries, 14
countries, 30 countries, I mean all the things will really change how and when and with who, you
would run that study.
[MC] What we’re hearing from... I mean if you think about it any approval requires two well
randomized studies, so that 167 patient local regional metastatic accounts for one study, we still have
to do the other one. Keep in mind, we’re doing studies in lung, colorectal, panc, ovarian, prostate…
[BT] Breast
[MC] Breast, thank you. Those are all one half of your registration program as well. So it’s interesting,
we’re talking to pharma partners and some of them go – Listen, we really like what you're doing with
head and neck, it’s a niche market you could probably get an approval with a smaller number of
patients. Then you get the other spectrum going – Well, it’s not a billion dollar market, we would look
at it at proof of concept, and we would follow up with a lung program or colorectal or breast or one of
the larger indications you have. Even though, I mean if you look at the some of the lung studies
people have run... George, what's the largest lung study you've seen? I've seen them with over 1,200
patients
[GG] 5,000
[MC] 5,000. I mean some of these lung programs are huge, there's no way our organization could run
a program like that. But everyone's interested in the results, not everyone is interested in the
indication. So it comes into play I mean if we have a good response there, but then turn around and
have like a home run in the largest market, say, colorectal, pharma is going to invest where they get
the biggest rate of return and it’s going to be in the larger market place.
[BT] Well, the profile (this is a sidebar), but the profile of the disease really does matter. More women
die of ovarian cancer than breast cancer: where's the profile in womens' cancer? Breast. I mean,
profile matters, and head and neck does not have a favorable profile. It’s a self-induced disease in a
patient population that does not have sympathy generally.
[91:23] [OM] Going back to the concept of maintenance therapy, you once mentioned that when
somebody dropped off the test (off the product) the cancer returned aggressively. Of the current
Phase 3 and double-blinded Phase 2, how many of these tests are continuing Reolysin treatment
after, say, the initial six cycles or whatever it is that they're set up for?
[BT] All the randomized studies do not have a maintenance therapy component, the Phase 2s. The
Phase 3 study had the option for a patient to go after eight cycles to go on just Reolysin monotherapy
or saline if they were on the control arm -– they don’t know which – and again because we don’t
know who’s what, I don’t know how many patients went onto maintenance therapy on Reolysin or
not.
Again, you’re running into doctor perceptions and everything else. Many of the doctors in our head
and neck study thought that after eight cycles of carbotax and Reolysin or carbotax and saline that
that was pretty much it. So they weren’t really encouraging patients at that stage, you know they’re
getting closing to death, to stay on, come in for a week out of every month to get possibly saline all by
itself. So, I mean, you have I guess... a long-winded way of saying we don’t know yet, we will find out.
[MC] The panc study has a maintenance phase.
[BT] Just Reo?
[MC] No, it's Reo/platinum
[BT] Right. When I think of maintenance I think of Reo by itself, but you're right.
[MC] What they were seeing is patients would go up to eight cycles and they would go on to
monotherapy on some of these single arm studies that we’re doing and they would progress after a
cycle or two. And a few of the doctors have said – Listen it's interesting you know, we think based on
your biochemistry it has to be delivered with a cytotoxic. The problem with the platinum doublet like
a carboplatin/paclitaxel is it’s toxic as all get out. On lung studies, you typically only get four or six
cycles, even if you’re responding, because it is such a toxic intervention if you will. They typically get
neuropathies from the taxane, so one of the investigators at CTRC said – Listen, I’m just going to drop
the taxane and keep them on the platinum. And it looks like on these single arm studies you can stay
on platinum/reovirus for extremely long periods of time. And in some of the other indications we
have where like gemcitabine...
[BT] Gem... Gem/Reo, what’s the maximum [inaudible] almost two years with it...
[MC] So you can continue to treat with it.
[OM] So on the Phase 3 then, there are patients who are still alive and they're still being treated with
Reo or saline?
[BT] I cannot comment on that.
[OM] [inaudible]
[BT] No, because that would tell you whether they had progressed or not. We cannot talk about
whether patients have all progressed or not it's against... it's trial detail that has to remain
confidential. The patients are treated with whatever until they progress and if I were to say patients
were still being treated I would tell you that there were patients that hadn’t progressed which would
be like me telling you how many people were still alive on the study. That’s trial detail. Alan will come
and slap my wrists rightfully for saying this, and you're correct.
[94:45] Unidentified
[U3] Brad, I got quick question for you. You said maintenance therapy was only on the Phase III?
[BT] Reolysin monotherapy, maintenance therapy, was only for the Phase III that’s my narrow
definition, so yes.
[U3] I just wanted to make sure of that, for some reason I thought it was on the pancreatic
carbotax/Reo too.
[BT] No, that evolved into taking the taxane out of it and just doing a platinum/reo doublet, because
the platinum and reo seems to be...
[MC] [Inaudible interjection]
[BT] And ovarian has that too I think, doesn't it?
[MC] The NCIC studies and the ovarian studies are all... because we don’t have it they tend to be a
weekly taxane.
[BT] They dropped the taxane.
[MC] Well no, it's just weekly taxane so they don't get the acute effects. It's treatment until
progression.
[U3] OK that makes more sense on that. I want to expand just a little more on the pancreatic one
since we’re talking about that. This comment you made last year in the Needham Conference, so it’s a
year ago, and it says you said so it's your quote...
[MC] Where did that come from?
[U3] The Needham Conference last year.
[BT] And where did the quote come from?
[U3] It’s the transcript.
[BT] And who's transcripted it?
[U3] It’s mine.
[BT] So it’s an alleged quote. OK.
[Inaudible]
[BT] An unofficial transcript taken by not my official biographer.
[Laughter]
[U3] Well, I have a couple of 'em in here, which, er...
[BT] I do have an official biographer, but…
[U3] A couple would make them interesting, but it’s nothing, it's just more of an expansion hopefully
from last year, it says again people are actually starting to talk about second-line pancreatic patients
for the first time in my experience which is nice, it’s actually nice to be developing a patient group
that actually might be living long enough to be second line. We’re talking a year later; can you expand
at all on that?
[BT] No, I cannot.
[U3] OK, well I...
[BT] I'm firm in my alleged comment from last year – I would support that statement whoever may
have made it. And I don’t think, I mean it’s clear, I mean there has been news about at least one
crossover patient who failed in carbotax and went on to carbotax and Reolysin and then went on to
have a response. So I mean it’s not unusual to expect it, we’ve seen other ones like that, and that
would be the case. But I think that not just with potentially our program, but with some of the other
advances that are going on in pancreatic cancer that you are going to see a very large number for the
first time of what we think of as second line patients.
I mean there is some really – I mean the Gem/Abraxane study is looking kind of interesting and of
course that one is interesting that the Abraxane looks like the neuropathy caused by Abraxane is
actually recoverable after you've finished therapy and you can re-treat again which is a major
advance. And a colleague of ours, who was the principal investigator on that study and we’re quite
thrilled that his study came out so well. It’s a very important study.
But you got some of the other drug combinations that people are using outside of gemcitabine are
actually starting to show some fairly aggressive activity in patients – they don’t cause severe damage,
because they’re quite toxic – so you’re generating patient populations that are gem naïve that have
failed first line so they become second line. So it’s really – pancreatic cancer is changing. I don’t think
panc is going to be quite the death sentence it was very soon, which is nice. But I think Reo is part of
that and I think we’re consistent in that. I mean we've been open about the gem/reo data I mean
we're seeing a subset of patients that seem to be doing extremely well on gem/reo. And that’s
generating a second line patient population, I mean that's just by definition, so whoever said that, I
would support their statement.
[U3] I like that, you’re saying that whoever would support that statement. How many – I didn’t get it
this time – how many patients have you treated to date so far? I know last year it was about 700 –
500 in-house and 200 by…
[BT] We’re about… I don't know, about 640 or 650 in-house and I honestly between the NCIC doing
their data and everything else we're probably narrowing in on 900 would be my guess.
[U3] OK, so we’ve increased it quite a bit. I have another alleged statement – as we're talking a year
later it's more sort of general update on comments: 'I mean I can pretty well say confidently say now
if you have a KRAS mutation driven disease, I can almost guarantee you a stable disease or better on
Reo, it doesn't matter what it is, panc, non-small cell lung, colorectal it's interesting it's not statistical
yet, but it's getting there.' We're talking a year later and then I looked at your REO 021 up there with
all the people with KRAS, EGFR mutation, stuff like that.
[BT] REO 016.
[???] Pretty statistical.
[BT] I mean the lung data I think is looking quite intriguing, though it’s still a relatively small patient
population but if you have the KRAS mutation involved, you have an overwhelming preponderance of
stable disease by RECIST, it’s quite, quite remarkable. Matt I think would, I mean it’s…
[MC] Looking at that line if I'm not mistaken anyone who had KRAS mutation in the lung had stable
disease or better.
[BT] Well they had one PD.
[Inaudible discussion]
[BT] So I think that is a baseline. I think the whole KRAS story is becoming important, which is why
we’re focusing more time and attention, where it’s relevant, to do genotyping when it's appropriate.
So but I mean people are starting to find out the differences between the different RAS elements too
in other diseases you know. And I think for some indications it’s absolutely critical that everybody get
a handle on what genotype you're looking at and we don't even know the genotypes that are
important for a lot of subsets.
That’s a pretty large amount of effort being done by some pretty large groups on that, I mean some of
the big pharmas that we deal with have massive typing groups, hundreds of people, working on just
that one element. It’s... I think a lot of belief that that’s important, but 'asterisks' there's been cases
where people have run studies where they’ve done genotyping, where they think they have pure
patient populations coming in and maybe get one out of nine patients showing a response when
there should have been 100% – it doesn’t mean you know everything just because you have a couple
of markers.
[U3] One other one, it’s not directed to you. Mary Ann – there we go let somebody else do a little
talking. I understand, I could be wrong, might be mistaken, was there a couple of patent challenges
before? In regards to some of the intellectual property that you guys had, and if so, has it been
resolved?
[MAD] Well, we did have a challenge to one of our European patents, it was in our possession and yes
we resolved that, so that patent has granted and has been reregistered in all the states in Europe
where we had it. The only other patent challenges when we actually sued the commissioner of
patents in the United States for additional term and we won that one too, so we were real pleased
with that.
[U3] Thank you very much.
[BT] It should be called the Dillahunty exemption, not [inaudible]. There was not a lot of love in the
patent office for Mary Ann on that day.
[102:36] Unidentified
[U4] I will ask you another question...
[BT] Yes, if we could, we'll take just one more question and then we’ll, which will be official question
and then we’ll be available for a while to actually talk on one-on-one if we could please.
[U4] Now that you have clarified or told us again that the likely route for this company is eventually to
be bought out or partnered, hooking up with some larger entity in some way or other, what in your
mind are the events that have to happen to be in that position where a larger entity will make a
serious – what you would consider a serious offer for this company?
[BT] I would think that generally, I think at this stage of development that having relatively clear cut
randomized clinical data in one or more indications would be the trigger for something to happen
whether it would be M&A, or partnering, an association, along those lines. And I think we've been
pretty much settled in our own minds internally in the company that that was probably the trigger
probably for three or four year now, so…
[U4] So you’ve said that the Phase 3 unblinding will happen sometime by, before the end of the year.
When do you expect, or, of the six Phase 2 randomized trials, when do you expect that one or two of
them will release some results, either preliminary or final results?
[BT] I am going to decline to put a timeframe on timelines for the results from those other clinical
studies. Just, when the enrolment gets to a certain stage that the investigators are comfortable with
the data that's coming out of them, then we’ll talk about it and, you know, we'll leave that to them.
[U4] And for Mrs Dillahunty – or Miss, sorry – the strategy of the company I understand has always
been to keep on renewing and updating and expanding our patents, so that the 20-year patent
coverage is extended. Are you comfortable that we are doing that? If this process is going to take
more time that we are continuing to increase our intellectual property protection?
[MAD] Well, yes, as you’ve said that's really always one of our goals is to make sure that every
inventive aspect that we come up with whether that’s a formulation or a novel proprietary Reolysin
and those patents don’t expire until 2028. So, and we are, we continue to file patent applications
including some that have not yet published over aspects that we are discovering as we work through
all these things so.
[U4] Thank you.
[BT] OK, one more, one more.
[105:21] Bill Thompson
[BillT] Hi, I'm Bill Thompson. Brad, I was wondering if you could comment on that association with
that Russian company? I mean, there was a comment that they made, but then there was nothing
came from your office?
[BillT] Didn’t I cut-off the questioning a question ago? [laughter] And here I was, answering a question
because we share a common name. This is what you do to me.
We do not have an agreement with a Russian company and until we do have an agreement with a
Russian company that’s valid and going forth, we will not comment on it. That is as much as I could
say. We have all sorts of things on the go that are at different stages of development and sometimes
some people get enthusiastic about talking about things prior to them actually being concluded and
that would be my Russian friends.
So, if we do conclude something with somebody in Russia, and it becomes active then we’ll be talking
about it specifically. I didn’t mean to make fun of that, I just was like I got out of answering that
question and here I am answering it.
I mean, in all seriousness, we have relationships under different stages of development with different
types of entities all over the world. And they get to a certain stage when they become concrete, they
become real. For example, our NCIC relationships, which allow us to do those – now four randomized
clinical studies in Canada. I mean you can move along, and you cross a threshold when they’re real,
and then you talk about them.
And that’s the same for discussions and contract work with anything that we do, and whether it’s in
Russia or any other country in the world, we’re not at that stage, and so no. When we get to that
stage, we’ll talk about it. That's all I can say. I’m a little unhappy with my potential colleagues in Russia
for talking about something that didn’t exist yet, so we’ll leave it at that.
[107:40] Summing up
Well again, thank you for coming today, thank you for the questions, thank you for the time and
attention, and thank you for the many of you that have been following us as shareholders and just
following us generally here in our home base in Calgary for being there for us all these years and for
following us in what continues to be I think a very interesting program and I think we are near to the
end of about to find out whether Reolysin works or not in the way that matters and so there is many
years of work and many years of dedication that is about to liberate Matt from his insomnia, and we'll
leave it at that. As Matt descends into a number of addictions.
So again thank you for coming today and we will be around for a short period of time – we have
another meeting unfortunately we have to go to soon but for a while we’ll be here and again thank
you.
Canaccord Genuity Daily Letter – May 10, 2013
Oncolytics Biotech Inc. (ONC : TSX : C$2.89) - Buy - Target:C$8.00
Q1/13 results: Awaiting further updates on study results; maintain BUY rating and C$8.00 target price
Investment recommendation
Oncolytics has reported Q1 financial results. Net loss for the quarter was $6.6 million or ($0.08) per share, lower than our estimate for a net loss of $9.9 million or ($0.12) per share. The primary driver of this variance was R&D spending in Q1, which, at $5.1 million, was much lower than our estimate of $8.5 million. Based on recent evidence of efficacy for Reolysin, we would be buyers of the stock in anticipation of more impactful data from the head and neck trial and the Phase II study in pancreatic cancer, both expected within the next six months.
Investment highlights Cashed up.
Oncolytics ended the quarter with cash and equivalents of $43.5 million. We believe this represents almost 18 months of cash at projected burn.
Hungry for more randomized data.
Because data from the ongoing H&N study is event-driven, exact timing of final data is uncertain. While we currently anticipate an announcement in H2/13, we suggest investors await firmer guidance to avoid disappointment.
Next steps in a long journey.
We expect that ONC will use recent positive Phase III data and the validation of its thesis to design a pivotal study focusing on the treatment of metastatic lesions.
Valuation
We value Oncolytics using a probability-weighted NPV model of lead drug Reolysin in key indications including head and neck cancer. Based on this analysis, we arrive at a 12-month target price of C$8.00, which supports our BUY recommendation.
Reovirus Activates a Caspase-Independent Cell Death Pathway
New research published for Reovirus
http://mbio.asm.org/content/4/3/e00178-13.full#abstract-1
Address correspondence to Pranav Danthi, pdanthi@indiana.edu.
Editor Mary K. Estes, Baylor College of Medicine
ABSTRACT
Virus-induced apoptosis is thought to be the primary mechanism of cell death following reovirus infection. Induction of cell death following reovirus infection is initiated by the incoming viral capsid proteins during cell entry and occurs via NF-?B-dependent activation of classical apoptotic pathways. Prototype reovirus strain T3D displays a higher cell-killing potential than strain T1L. To investigate how signaling pathways initiated by T3D and T1L differ, we methodically analyzed cell death pathways activated by these two viruses in L929 cells. We found that T3D activates NF-?B, initiator caspases, and effector caspases to a significantly greater extent than T1L. Surprisingly, blockade of NF-?B or caspases did not affect T3D-induced cell death. Cell death following T3D infection resulted in a reduction in cellular ATP levels and was sensitive to inhibition of the kinase activity of receptor interacting protein 1 (RIP1). Furthermore, membranes of T3D-infected cells were compromised. Based on the dispensability of caspases, a requirement for RIP1 kinase function, and the physiological status of infected cells, we conclude that reovirus can also induce an alternate, necrotic form of cell death described as necroptosis. We also found that induction of necroptosis requires synthesis of viral RNA or proteins, a step distinct from that necessary for the induction of apoptosis. Thus, our studies reveal that two different events in the reovirus replication cycle can injure host cells by distinct mechanisms.
IMPORTANCE
Virus-induced cell death is a determinant of pathogenesis. Mammalian reovirus is a versatile experimental model for identifying viral and host intermediaries that contribute to cell death and for examining how these factors influence viral disease. In this study, we identified that in addition to apoptosis, a regulated form of cell death, reovirus is capable of inducing an alternate form of controlled cell death known as necroptosis. Death by this pathway perturbs the integrity of host membranes and likely triggers inflammation. We also found that apoptosis and necroptosis following viral infection are activated by distinct mechanisms. Our results suggest that host cells can detect different stages of viral infection and attempt to limit viral replication through different forms of cellular suicide. While these death responses may aid in curbing viral spread, they can also exacerbate tissue injury and disease following infection.
INTRODUCTION
Induction of an apoptotic or necrotic form of cell death constitutes an intrinsic response of the host cell to viral infection (1, 2). Though both apoptosis and necrosis function to limit viral infection, they each have markedly different effects on the cell. While apoptosis results in membrane blebbing, nuclear condensation, and DNA fragmentation, the integrity of the plasma membrane is maintained (3). In contrast, necrosis results in cell rounding, cell swelling, and ultimately a loss of plasma membrane integrity, leading to the leakage of host cytoplasmic contents (3). In addition to the morphological differences in dying cells, apoptosis and necrosis also influence host physiology in a distinct manner. While cells dying by apoptosis do not activate the immune system, the leakiness of necrotic cells recruits immune cells and promotes inflammation (4), potentially enhancing pathology associated with cell death. Though necrosis was generally considered to be an unregulated, uncontrolled form of cell death, recent evidence indicates that at least one form of necrosis, necroptosis, is programmed (5). In addition to the leakiness of membranes observed in all forms of necrosis, necroptosis is characterized by the activation of signaling from death receptors, the dispensability of caspase activity, and a requirement for the kinase activity of receptor interacting protein 1 (RIP1 or RIPK1) or 3 (RIP3 or RIPK3) (3). Though both apoptosis and necroptosis have been shown to occur during viral infection, it is not known if similar events in viral infection trigger apoptosis and necroptosis (1). Conditions that favor one form of cell death over the other during viral infection are also not understood.
The importance of apoptosis to viral pathogenesis (6–16) has led to numerous studies to examine the molecular basis of proapoptotic signaling following infection with mammalian orthoreovirus, henceforth referred to as reovirus (17). Following receptor-mediated endocytosis, reovirus particles disassemble in the endosome and viral cores are deposited into the cytosol via the function of the viral membrane-penetration protein (17, 18). Steps following escape from the endosome but prior to viral RNA and protein synthesis are required for initiation of the apoptotic pathway (19). This induction process involves the I?B kinase (IKK)-mediated activation of the classical form of the transcription factor NF-?B, comprised of RelA and p50 subunits (20, 21). Activation of NF-?B early following infection is required for the cleavage of the BH3-only member of the Bcl-2 family of mitochondrial proteins, Bid, via the initiator caspase, caspase-8 (14, 22). The cleaved form of Bid, truncated Bid (tBid), amplifies the apoptotic signal through the mitochondria to activate the initiator caspase, caspase-9 (23–25). These events result in activation of the effector caspase, caspase-3, and culminate in cell death. In addition, the protein kinase JNK (c-Jun N-terminal kinase), the cytosolic cysteine protease calpain, and the transcription factor IRF-3 have been shown to contribute to efficient induction of apoptosis by reovirus (26–29). It remains unknown if components of the signaling cascade described above are required for reovirus-induced cell death in all cell types.
In a variety of cell lines, prototype type T3 reovirus strains, T3D and T3A, induce significantly more apoptosis than the type T1 reovirus strain T1L (30–34). In this study, we investigated how T3 and T1 reovirus strains differ in their capacity to evoke cell death. We found that T3D activates NF-?B, initiator caspases, and effector caspases to a greater extent than T1L. Unexpectedly, when T3D-induced NF-?B activation was inhibited, it did not diminish cell death. Caspase inhibitors also failed to block reovirus-induced cell death. Blockade of the kinase activity of RIP1 resulted in a reduction in cell death. Because reovirus-induced cell death in L929 cells fulfills all the criteria that are used to describe necroptosis—activation of death signaling, dispensability of active caspases, the requirement for RIP1 kinase activity, diminishment of cellular ATP levels, and membrane permeability of dying cells (3)—our findings indicate that reovirus is also capable of killing cells by necroptosis. Moreover, we found that induction of this form of cell death following reovirus infection requires de novo synthesis of viral mRNA and proteins. These studies therefore highlight a second mechanism by which reovirus infection interfaces with host signal transduction pathways to evoke cell death.
RESULTS
Strain-specific differences in cell death induction correlate with caspase activation.Previous studies have suggested that blockade of the prosurvival function of NF-?B by T3A but not T1L late following infection controls the differences in the capacity of these two strains to elicit apoptosis (34). While following up on these studies, we investigated the extent to which T1L and T3D differ in their capacity to block activation of NF-?B at late times following infection of L929 cells. We found that each strain inhibits tumor necrosis factor alpha (TNF-a)-induced NF-?B nuclear translocation to an equivalent extent (see Fig. S1A in the supplemental material). To determine if T3D and T1L continue to maintain a difference in their capacity to evoke cell death, we performed acridine orange, ethidium bromide (AOEB) staining on infected cells at 48 h after infection. Rather than subjective determination of the staining pattern of the nuclear material to distinguish between apoptotic and necrotic cells (35), all cells that stained with EB were counted as dead cells. Evaluation by this method indicated that T3D induced significantly greater cell death than T1L (Fig. 1A), consistent with previous results (30, 31). Both T1L and T3D were capable of establishing efficient infection in these cells (Fig. S1B). Thus, despite efficiently establishing infection and blocking NF-?B activation late in infection to an equal extent, T3D induced cell death to a much greater extent in L929 cells than did T1L. These data suggest that unlike that reported for HEK293 cells (34), differences in the capacity of T3D and T1L to evoke cell death in L929 cells are not related to inhibition of NF-?B late in infection.
To define how prodeath signaling following T3D and T1L differs, we compared the activations of initiator and executioner caspases following infection of L929 cells by these two strains. Measurement of the activity of the effector caspases, caspase-3 and -7, by chemiluminescent enzymatic assays 24 h after infection indicated that T3D activates these enzymes to a significantly greater extent than T1L (Fig. 1B). Consistent with these results, we found that a greater amount of cleaved caspase-3 was detectable following infection with T3D (see Fig. S1C in the supplemental material). Bid cleavage, a marker for caspase-8 activation following reovirus infection (14), also occurred more efficiently in T3D-infected cells than T1L-infected cells (Fig. S1D). Collectively, these data demonstrate that initiator and effector caspase activity following infection of L929 cells with T3D is significantly higher than that following infection with T1L.
Activation of NF-?B is not required for reovirus-induced cell death.Previously, we have suggested that activation of NF-?B early, 6 to 8 h after reovirus infection, is required for caspase-8-mediated generation of tBid and attendant activation of effector caspases (14). To determine if NF-?B activation following infection of L929 cells with T1L and T3D differs, we measured the activation of NF-?B by measuring the loss of I?Ba inhibitor from the cytoplasm and the consequent translocation of the NF-?B RelA/p65 subunit to the nucleus (21, 36). Immunoblot analysis of I?Ba levels 7.5 h after infection indicates a greater decrease in I?Ba levels following infection with T3D than following infection with T1L (Fig. 2A). Consistent with these data, we found a significantly greater level of RelA in the nuclear extracts of T3D-infected cells than in those of T1L-infected cells (Fig. 2B). To test the idea that the enhanced death-inducing potential of T3D in L929 cells may be related to an increased capacity to activate NF-?B, we determined if blockade of NF-?B activation would diminish cell death following T3D infection. For these experiments, we assessed the capacity of T3D to promote cell death in cells treated with an I?Ba kinase (IKK) inhibitor, BAY-65-1942 (21, 37). We found that blockade of IKK activation had no effect on the induction of cell death by T3D (Fig. 2C). Treatment of cells with TNF-a in the presence of the IKK inhibitor resulted in cell death, demonstrating that the IKK inhibitor is functional in L929 cells and can block TNF-a-induced prosurvival NF-?B signaling. To ensure that the IKK inhibitor also blocked the unusual IKK complex activated by reovirus (21), we assessed the effect of IKK inhibition on effector caspase activation following reovirus infection. Consistent with the requirement of IKK activity in promoting proapoptotic signaling following reovirus infection (21), we found that in comparison to dimethyl sulfoxide (DMSO)-treated cells, effector caspase activity following reovirus infection was significantly diminished following treatment of cells with the IKK inhibitor (Fig. 2D). Thus, despite blocking proapoptotic signaling following reovirus infection, the IKK inhibitor failed to block reovirus-induced cell death. These studies reveal that T3D is capable of activating a cell death pathway that is not dependent on target gene transcription by NF-?B. Though this observation matches that from primary cardiac myocytes, it is distinct from that reported for other cell types (20, 34, 38). The unexpected dispensability of NF-?B signaling for cell death in L929 cells prompted us to focus on defining the nature of this cell death pathway.
Reovirus induces caspase-independent cell death.Our experiments using the IKK inhibitor suggested that reovirus may induce cell death even in the absence of active effector caspases. To directly test the idea that T3D can evoke cell death in a caspase-independent manner, we assessed cell death 48 h after reovirus infection in the presence of inhibitors of caspase-8 (Z-IETD-FMK) or caspase-9 (Z-LEHD-FMK) or a broad-spectrum inhibitor of caspases [Z-VAD(OMe)-FMK]. Surprisingly, we found that T3D remained capable of inducing cell death in the presence of each of these inhibitors (Fig. 3A). To ensure that the inhibitors were functional in L929 cells at the concentration used, we assessed their capacity to prevent effector caspase activation in T3D-infected cells. For these experiments, caspase-3/7 activity in infected cells treated with each inhibitor was quantified 24 h after infection. We found that in comparison to mock-infected cells, there was an ~10-fold increase in caspase-3/7 activity by infection with T3D in the presence of DMSO (Fig. 3B). Inclusion of inhibitors of caspase-8 or caspase-9 or inclusion of a pan-caspase inhibitor completely blocked effector caspase activation. Thus, despite being capable of blocking the proapoptotic signaling pathway activated by reovirus, these inhibitors failed to prevent virally triggered cell death. These data indicate that reovirus T3D is capable of inducing a distinct cell death pathway in L929 cells that is independent of caspase activation.
Reovirus induces RIP1-dependent necrosis.One such caspase-independent cell death pathway requires the kinase activity of RIP1 (39, 40). To assess whether the caspase-independent cell death pathway activated by reovirus is dependent on the kinase activity of RIP1, we determined the capacity of reovirus to induce cell death following treatment of cells with necrostatin-1 (Nec-1), an inhibitor of RIP1 (41). We found that reovirus-induced cell death was blocked by Nec-1 (Fig. 4A). Simultaneous treatment of cells with Nec-1 and a pan-caspase inhibitor did not further diminish cell death, suggesting that a RIP1 kinase-dependent form of cell death is the primary mechanism of cell death in these cells (Fig. 4A). The effect of Nec-1 on reovirus-induced cell death was independent of its effect on the blockade of indoleamine 2,3-dioxygenase (IDO), an additional target of Nec-1 (42, 43), since direct inhibition of IDO using 1-methyl-L-tryptophan did not prevent reovirus-induced cell death (see Fig. S2A in the supplemental material). The capacity of reovirus to establish infection and grow in Nec-1-treated cells was not affected (Fig. S2B and C). Nec-1 also did not diminish caspase-3/7 activity in T3D-infected cells (Fig. S2D). These data suggest that RIP1 kinase activity is required for reovirus-induced cell death.
Cells undergoing all forms of necrosis, including necroptosis, are characterized by a depletion of cellular ATP levels (44, 45). To determine whether ATP levels were affected in T3D-infected cells, we compared ATP levels over a time course of infection using a chemiluminescent assay. While an ~35% to 40% reduction in ATP was observed at 24 h after infection with T3D, ~75% and ~95% of the ATP was lost in T3D-infected cells at 36 and 48 h after infection, respectively (Fig. 4B). Moreover, the rate at which loss of ATP occurred in T3D-infected cells was diminished by treatment of cells with Nec-1 but not by treatment with a pan-caspase inhibitor. These data provide further support for the idea that T3D-infected L929 cells undergo necroptosis following reovirus infection. Necroptosis alters cellular architecture quite differently from apoptosis. In particular, necroptosis damages the integrity of the plasma membrane. To assess whether plasma membrane integrity was compromised following infection with T3D, we evaluated whether high-mobility group box 1 protein (HMGB1) was released into the medium of infected cells. This protein is not released from apoptotic cells undergoing secondary necrosis, and therefore, leakage of this chromatin-associated protein from cells is considered to be a marker for necrosis (46, 47). We found that HMGB1 was released into the medium at 24 h following infection. A greater level of HMGB1 was detected in the medium at 36 and 48 h after infection with T3D (Fig. 4C). Along with the capacity of EB to gain access and stain the nuclei of unfixed, reovirus-infected cells, a measurement equivalent to propidium iodide or sytox staining of necrotic cells (48), the data presented here indicate that the L929 cell plasma membrane is leaky following infection with T3D. Based on the dispensability of caspases, the requirement for RIP1 kinase activity, the dramatic loss in cellular ATP levels, and the release of HMGB1 from infected cells, we conclude that reovirus is capable of inducing an alternate cell death pathway, which has been described as necroptosis.
To determine if infection with T1L also results in necroptosis, we assessed whether ATP is lost from T1L-infected cells. We found that ~30% to 40% ATP was lost after T1L infection at 48 h (see Fig. S3A in the supplemental material). Thus, in comparison to T3D-infected cells (Fig. 4B), ATP loss following infection with T1L is delayed. The loss of ATP in T1L-infected cells was able to be diminished by Nec-1 but not pan-caspase inhibitor treatment, suggesting that cell death following T1L infection also occurs via necroptosis. We also used AOEB staining to determine the kinetics and mechanisms of T1L-induced cell death. We found ~10% and ~30% cell death in cells infected with T1L at 48 and 72 h after infection, respectively (Fig. S3B). Because cell death following T1L infection is sensitive to Nec-1 and is substantially lower than the ~60% cell death induced by T3D at 48 h after infection, our data indicate that T1L induces necroptosis in L929 cells with slower kinetics than T3D.
Induction of necroptosis requires viral RNA or protein synthesis.To define the triggering event in viral infection that ultimately leads to necroptosis, we assessed the requirement for viral genomic RNA and viral replication for induction of necroptosis. To determine whether viral genomic RNA is required for induction of cell death, we infected cells with equivalent numbers of genome-deficient (or top-component) particles and infectious virions and assessed their capacity to elicit cell death. To rule out the effect of secondary rounds of infections from the contaminating infectious particles in the top-component particle fraction, we assessed the induction of cell death at 24 h after infection (19). We found that ~35% and ~20% of the cells were dead following infection with a multiplicity of infection (MOI) of 17,700 particles/cell (equivalent of 100 PFU/cell) or 5,840 particles/cell (equivalent of 33 PFU/cell), respectively, of infectious virus (Fig. 5A). In contrast, infection of cells with an equivalent number of top-component particles killed a substantially smaller amount of cells, ~10% and ~5%, respectively. These data indicate that viral genomic double-stranded RNA (dsRNA) is required for induction of necroptosis.
To determine if genomic dsRNA is sufficient to trigger necroptosis, we assessed the capacity of UV-inactivated virus to evoke cell death. UV-inactivated reovirus contains genomic dsRNA, but the RNA is not competent to serve as a template for viral mRNA synthesis. We observed that UV-treated reovirus particles had a significantly lower capacity for inducing cell death than an equivalent dose of infectious virus (Fig. 5B). These findings indicate that genomic dsRNA within incoming virus particles is insufficient to evoke necroptosis in infected cells and suggest that de novo synthesis of viral RNA is required for induction of necroptosis following reovirus infection. Since viral genomic RNA and virus replication are dispensable for induction of apoptosis (19, 49), these findings suggest that apoptosis and necroptosis following reovirus infection are initiated at different stages of viral infection.
DISCUSSION
Reovirus-induced apoptotic cell death has been extensively investigated (see Fig. S4 in the supplemental material). On examination of strain-specific differences in the cell death pathways activated by reovirus, we made a surprising observation that reovirus was capable of inducing cell death even in the absence of NF-?B signaling and active caspases. We found that T3D-induced cell death requires the function of RIP1 kinase, results in a drop in cellular ATP levels, and renders the host cell plasma membrane leaky. These data indicate that in addition to apoptosis, reovirus is also capable of inducing necroptosis following viral infection. We also found that induction of the necroptosis pathway following reovirus infection occurs later in infection and requires the de novo synthesis of viral RNA or proteins.
RIP1-dependent necroptosis pathways are initiated via at least three different mechanisms. One pathway for initiation of necroptosis is dependent on death receptor signaling (50). Experiments presented here and in several other studies indicate that death receptor signaling is activated following reovirus infection (14, 22, 51). While this observation may suggest that necroptosis following reovirus infection may be a consequence of death receptor signaling, our findings using the IKK inhibitor, which fails to inhibit necroptosis despite blocking classical apoptotic pathways, argues against this idea. An alternate pathway for the induction of necroptosis involves recognition of pathogen-associated molecular patterns by pattern recognition receptors. Among these, TLR3, a sensor of dsRNA, and DNA-dependent activator of interferon regulatory factor (DAI), a sensor of dsDNA, have been implicated in initiating necroptosis following viral infection (52, 53). Based on the requirement for viral genomic RNA and for viral replication, our data may suggest a role for TLR3-mediated detection of viral RNA in induction of necroptosis in these cells. If so, it remains to be determined how viral genomic RNA within the reovirus core or viral mRNA, which is present in the cytoplasm, may be detected by endosomally localized TLR3. A third pathway for necroptosis is thought to occur independently from Toll-like receptor (TLR) or death receptor signaling and requires the loss of inhibitors of apoptosis (IAPs) (52). Interestingly, there is evidence for the loss of IAPs during reovirus infection (25). Thus, it is possible that necroptosis following reovirus infection may be initiated by any of these pathways. It is also possible that one of the eleven reovirus proteins synthesized by translation of viral mRNA triggers this death response. Our ongoing studies are targeted toward understanding how necroptosis is triggered by reovirus infection and how strains T3D and T1L differ in their capacity to evoke necroptosis.
Induction of necroptosis by any of the pathways described above requires the formation of the ripoptosome or a similar multiprotein complex (54). This 2-MDa signaling complex is comprised of three core components, RIP1, caspase-8, and FADD (54). In addition, it also contains regulators such as cFLIP, cIAP1, cIAP2, and XIAP. The decision between cell survival, apoptosis, and necroptosis occurs at the level of the ripoptosome and depends on the activity of caspase-8 (40). When procaspase-8 is sufficiently processed and caspase-8 activity is high, apoptosis ensues. In contrast, when caspase-8 activity is lower due to heterodimerization of caspase-8 with cFLIPL, no apoptosis occurs. Under these conditions, caspase-8-cFLIPL complexes retain sufficient activity to cleave RIP1, preventing necroptosis. Thus, when activity of caspase-8 is low, cells survive. If, instead, caspase-8 is blocked by binding to cFLIPL or the presence of cIAPs, RIP1 is not cleaved and the cells undergo necroptosis. Thus, we should anticipate that when caspase-8 is active, reovirus infection results in apoptosis, and when it is inhibited, by inclusion of caspase-8 or pan-caspase inhibitor, reovirus infection produces necroptosis. In our studies, reovirus-induced cell death was sensitive to Nec-1 even in the absence of treatment with caspase inhibitors. These data suggest that the activity of caspase-8 following reovirus infection is not sufficient to cleave and inactivate RIP1, thereby allowing induction of necroptosis.
Though reovirus-induced cell death has been extensively examined in a variety of cell lines (8, 20, 30–34, 49, 55–57), this is the first demonstration of necroptosis following reovirus infection. One possible reason for why this observation has not been previously reported is that prior studies on reovirus apoptosis, including our own, have not examined this possibility. In the majority of studies, cell death following reovirus infection has been considered apoptotic due to the presence of morphological and biochemical features, but the effect of treatments that block cell death has been evaluated in some (8, 14, 32, 58) but not all (27–31, 51) cell types. Alternatively, it is possible that this pathway has been discovered in L929 cells due to peculiarities in the amounts or activities of proteins that regulate various forms of cell death. Because L929 cells are among the most permissive to reovirus infection, a related possibility is that reovirus alters the levels of these signaling or regulatory molecules differently or to a different extent than in other cell types. Regardless, our data indicate that necroptosis following reovirus infection is an alternate mechanism of cell death.
Analogous to studies on reovirus-induced apoptosis (14, 20, 21), we found no effect of inhibition of necroptosis on reovirus replication (see Fig. S2 in the supplemental material). Thus, regardless of whether reovirus induces necroptosis in other cultured cell lines, the physiological relevance of necroptosis to reovirus infection can be determined only by in vivo experiments, as has been necessary for the demonstration of the pathogenic role of reovirus-induced apoptosis (7–12, 14–16, 59). T3 reoviruses cause bile duct injury, leading to biliary atresia (60–63). Histological examination of the reovirus-infected bile ducts has revealed the presence of necrotic tissue (61, 62). Some studies on reovirus-induced myocarditis also report the presence of necrotic lesions (12, 13, 64). Consistent with the induction of the necrotic form of cell death, inflammatory cells are detected in the injured tissues (12, 13, 61, 62). In each of these cases, it is not clear if the necrotic tissue observed is secondary necrosis as a consequence of apoptosis or whether direct induction of necrosis contributes to cell death in these tissues. In at least two of these studies (12, 13), cell death in the infected tissue appears to occur even in the absence of molecules previously shown to be required for apoptosis in cultured cells (20, 26), suggesting the existence of alternate mechanisms of cell death. Further work is needed to determine whether this alternate form of cell death is indeed necrotic and occurs via a caspase-independent, RIP1-dependent pathway that we have identified here. Such studies will enhance our understanding of reovirus pathogenesis.
The two forms of programmed cell death pathways observed following reovirus infection, apoptosis and necroptosis, are part of the intrinsic host defense response (1, 2). Analogous to a few other viruses (65–73), apoptosis following reovirus infection is activated prior to synthesis of the viral RNA by the proteinaceous components of the incoming viral capsid (15, 16, 19, 49). Though there are fewer studies that indicate how necroptosis is initiated following virus infection, extant information and our findings presented here indicate that necroptosis is initiated later in infection following synthesis of new viral genomes or gene products (53, 74–76). Based on these findings, we propose that apoptosis and necroptosis are two complementary mechanisms that sense and respond to different stages of pathogen invasion with a common goal of limiting viral infection through cellular suicide.
MATERIALS AND METHODS
Cells and viruses.Murine L929 cells (ATCC CCL-1) were maintained in Eagle’s minimal essential medium (MEM) (Lonza) supplemented with 5% fetal bovine serum (FBS) and 2 mM L-glutamine. Spinner-adapted L929 cells (obtained from T. Dermody’s laboratory) were maintained in Joklik’s MEM (Lonza) supplemented to contain 5% FBS, 2 mM L-glutamine, 100 U/ml of penicillin, 100 µg/ml of streptomycin, and 25 ng/ml of amphotericin B. Spinner-adapted L929 cells were used for cultivating and purifying viruses and for plaque assays. ATCC L929 cells were used for all experiments to assess cell death and cell signaling. No differences were observed in permissivity between ATCC L929 cells and spinner-adapted L929 cells. Prototype reovirus strains T1L and T3D were regenerated by plasmid-based reverse genetics (77, 78). No reverse genetic system is available for T3A, and thus, a laboratory stock was used. Infectious and genome-deficient viral particles were purified by Vertrel XF extraction and CsCl gradient centrifugation (79). Viral titer was determined by a plaque assay using spinner-adapted L929 cells (80). UV-inactivated virus was generated using a UV cross-linker (CL-1000 UV Crosslinker; UVP). T3D virus (1 × 109 PFU/ml) was irradiated with short-wave (254-nm) UV on ice at a distance of 10 cm for 1 min at 120,000 µJ/cm2 in a 60-mm tissue culture dish. Particle numbers for top-component and infectious virus were determined by estimating the protein concentration in each sample. One hundred eighty-five micrograms of protein was considered equal to 2.1 × 1012 virions (81). Relative per-particle infectivity of intact, genome-deficient virions and UV-inactivated virions was determined using indirect immunofluorescence.
Antibodies and reagents.Antisera raised against T3D, T1L, and sNS have been described (82, 83). Rabbit antisera specific for cleaved caspase-3 and HMGB1 were purchased from Cell Signaling, rabbit antisera specific for RelA and I?Ba were purchased from Santa Cruz Biotechnology, and rabbit antiserum against poly(ADP-ribose) polymerase (PARP) was purchased from Roche. Goat antiserum specific for Bid was purchased from R&D Systems. Mouse antisera specific for tubulin and PSTAIR were purchased from Sigma. Alexa Fluor-conjugated anti-mouse IgG, anti-rabbit IgG, and anti-goat IgG secondary antibodies were purchased from Invitrogen. IRDye-conjugated anti-guinea pig IgG was purchased from LI-COR. TNF-a was purchased from Sigma and used at a concentration of 10 ng/ml. Inhibitors of caspase-8 and -9 (Z-IETD-FMK and Z-LEHD-FMK), purchased from R&D Systems, and a broad-spectrum caspase inhibitor [Z-VAD(OMe)-FMK], purchased from Santa Cruz Biotechnologies, were used at a concentration of 25 µM. The RIP1 inhibitor necrostatin-1 was purchased from Santa Cruz Biotechnologies and used at a concentration of 50 µM. IKK inhibitor, described by Bayer (BAY-45-1962) (37), was used at a concentration of 5 µM. The IDO inhibitor 1-methyl-L-tryptophan (1-MT) was purchased from Sigma and used at 10 and 100 µM. As shown in the respective experiments, none of the inhibitors displayed any cytotoxicity at the concentration used.
Infections and preparation of extracts.ATCC L929 cells were adsorbed with either phosphate-buffered saline (PBS) or reovirus at the indicated MOI at room temperature for 1 h, followed by incubation with medium at 37°C for the indicated time interval. For assessment of NF-?B activation, serum-starved cells were infected in the presence of serum-free medium. All inhibitors were added to cells in medium 1 h before virus adsorption and returned with medium after the 1-h adsorption period. For preparation of whole-cell lysates, cells were washed in phosphate-buffered saline (PBS) and lysed with 1× RIPA (50 mM Tris [pH 7.5], 50 mM NaCl, 1% TX-100, 1% deoxycholate, 0.1% SDS, and 1 mM EDTA) containing a protease inhibitor cocktail (Roche), 500 µM dithiothreitol (DTT), and 500 µM phenylmethylsulfonyl fluoride (PMSF), followed by centrifugation at 15,000 × g for 10 min to remove debris. Nuclear and cytoplasmic extracts were prepared by hypotonic lysis and high salt extraction, respectively, as previously described (20, 21).
Immunoblot assay.The cell lysates or extracts were resolved by electrophoresis in polyacrylamide gels and transferred to nitrocellulose membranes. Membranes were blocked for at least 1 h in blocking buffer (PBS containing 5% milk or 2.5% bovine serum albumin [BSA]) and incubated with antisera against Bid (1:1,000), RelA (1:1,000), I?Ba (1:500), sNS (1:750), cleaved caspase-3 (1:500), PARP (1:1,000), HMGB1 (1:500), tubulin (1:500), or PSTAIR (1:10,000) at 4°C overnight. Membranes were washed three times for 5 min each with washing buffer (Tris-buffered saline [TBS] containing 0.1% Tween-20) and incubated with a 1:20,000 dilution of Alexa Fluor-conjugated goat anti-rabbit Ig (for RelA, I?Ba, caspase-3, HMGB1, and PARP), goat anti-mouse Ig (for PSTAIR and tubulin), donkey anti-goat Ig (for Bid), or IRDye-conjugated anti-guinea pig IgG (for sNS) in blocking buffer. Following three washes, membranes were scanned and quantified using an Odyssey infrared Imager (LI-COR).
Quantitation of cell death by AOEB staining.ATCC L929 cells (2 × 105) grown in 24-well plates were adsorbed with the indicated MOI of reovirus at room temperature for 1 h. The percentage of dead cells after 24, 48, or 72 h incubation was determined using AOEB staining as described previously (30). For each experiment, >100 cells were counted, and the percentage of isolated cells exhibiting orange staining (EB positivity) was determined by epi-illumination fluorescence microscopy using a fluorescein filter set on an Olympus IX71 microscope.
Assessment of caspase-3/7 activity.ATCC L929 cells (2 × 104) were seeded into black, clear-bottom 96-well plates and adsorbed with 10 PFU/cell of reovirus in serum-free medium at room temperature for 1 h. Following incubation of cells at 37°C for 24 h, caspase-3/7 activity was quantified using the Caspase-Glo-3/7 assay system (Promega).
Assessment of cellular ATP levels.ATCC L929 cells (2 × 104) were seeded into 96-well plates and adsorbed with 10 PFU/cell of reovirus in serum-free medium at room temperature for 1 h. Following incubation of cells at 37°C for the indicated time interval, ATP levels were assessed in opaque white 96-well plates using the CellTiter-Glo assay system (Promega).
Assessment of viral infectivity by indirect immunofluorescence.ATCC L929 cells (5 × 104) in 96-well plates were adsorbed with 2 PFU/cell of reovirus at room temperature for 1 h. Following incubation at 37°C for 18 h, reovirus-infected cells were visualized by indirect immunofluorescence using an Olympus IX71 fluorescence microscope as described previously (15). Reovirus antigen-positive cells were quantified by counting fluorescent cells in at least two random fields of view in duplicate wells at a magnification of 16×.
Assessment of viral replication by plaque assay.ATCC L929 cells (2 × 105) in 24-well plates were adsorbed with 2 PFU/cell of T3D at room temperature for 1 h. Cells were washed once with PBS, and medium with DMSO or RIP1 inhibitor was added. Cells were frozen immediately or following infection for 24 h. Cells were frozen and thawed twice before determination of titer by plaque assay using spinner L929 cells. Viral yields were calculated according to the following formula: log10 yield = log10(PFU/ml)24 h - log10(PFU/ml)0 h.
Dr. David Cohn - Virus Therapy Innovations in Science
http://www.standup2cancer.org/innovations_in_science/view/virus_therapy
INNOVATIONS IN SCIENCE
Virus Therapy
by David Cohn, MD
Dr. Cohn
David Cohn, MD specializes in gynecologic oncology at The Ohio State University Medical Center in Columbus, OH. His research areas include genetics of gynecologic oncology, prevention of gynecologic cancer, and vaccine therapy for ovarian cancer.
No cancer diagnosis is good news, but ovarian cancer can be particularly unsettling since more than eighty percent of patients are diagnosed with the disease after it has already spread. Despite several effective treatments for this type of cancer, most women whose cancer has spread to distant locations in their bodies, or whose tumors return after treatment, find themselves in a tough battle for survival.
In my eight years as a practicing gynecologic oncologist, I have been continually frustrated that recurrent ovarian cancer remains incurable.
It’s difficult to deliver bad news to these patients, particularly after they undergo a failed regimen of chemotherapy and all its side effects. “Isn’t there anything else we can try?” is a question I hear all the time.
Each year nearly 22,000 American women are diagnosed with ovarian cancer. Despite all the progress we’ve made in treating ovarian and other cancers, close to 16,000 women die from ovarian cancer every year.
My practice at the James Cancer Hospital at The Ohio State University is currently testing a new treatment for women whose ovarian cancer has recurred or progressed either during or shortly after chemotherapy treatment. The treatment, Reolysin, is an entirely new agent in the war on ovarian cancer or, for that matter, on any type of cancer: Reolysin happens to be a live, infectious virus.
But before getting into the specifics of how we came to use a virus to treat cancer, it would be useful to provide a bit of background on ovarian cancer and its treatment.
Conventional Treatments
Most women with suspected ovarian cancers undergo surgery to remove the main tumor and to confirm that it originated in the ovaries. Once ovarian cancer is confirmed by examining a slice of the tumor under a microscope, the surgeon typically removes the woman’s ovaries, uterus, fallopian tubes, and sometimes other nearby tissues. Depending on the stage of the cancer, some women will subsequently receive chemotherapy.
First-line chemotherapy for ovarian cancer is comprised of platinum-based drugs (carboplatin or cisplatin), often in combination with a taxane (paclitaxel). New combinations of drugs are helping women live cancer-free longer than at any time in the past. Most women respond well to these drugs, which is good news. Unfortunately, in many patients the cancer returns.
If the patient had responded initially to a chemotherapy regimen, most physicians (including me) will try the same drug or combination of drugs again. If it worked once, it is most likely to work again. But once the tumor returns it is not considered curable.
If the treatment used initially fails to shrink the tumor during the second round of therapy, an oncologist may try any of the half-dozen other chemotherapy agents approved specifically for ovarian cancer, or even prescribe drugs normally used for other cancers. The goal of therapy for recurrent ovarian cancer thus shifts from curing the disease to improving quality of life by slowing or stopping tumor growth. I have many patients who are still in remission after many years of being treated in this way.
Hope Out of Despair
For women whose tumors fail to respond at this stage, one potential and interesting treatment option may be a clinical trial.
A clinical trial is a specialized human study of an experimental drug performed under carefully controlled conditions. Pharmaceutical companies, hospitals, and government institutions use clinical trials to evaluate new treatments and to investigate the optimal use of already-approved drugs.
Participation in a clinical trial can be fulfilling and beneficial to patients in many ways. Participants in clinical trials receive the best evaluation and care available, usually from highly trained physician-researchers. While no study will promise a long-term remission or even prolonged survival, those outcomes do occur in patients treated in clinical trials.
In addition to direct benefits, study patients can take satisfaction in the knowledge that they are advancing medical science, and in so doing may help not only themselves, but other patients with their disease.
Virtually every important medicine on the market today, including all cancer drugs, was tested extensively in clinical trials. Taxane chemotherapy agents, which are part of the standard of care for first-line ovarian cancer treatment, were first tested during the 1980s and 1990s and have greatly extended the lives of millions of cancer patients, including those with ovarian cancer.
The Reolysin Study
Our clinic is currently testing one of the most interesting, and potentially promising, cancer therapies to emerge in many years. The treatment, Reolysin, consists of a virus that attacks tumor cells while leaving normal cells unscathed. The treatment is being developed by Oncolytics Biotech, a Canadian biotechnology company.
Virus therapy works by exploiting a genetic mutation inside cancer cells that does not exist in normal cells. The mutation allows the virus to enter tumor cells and produce thousands of copies of itself.
Eventually, the cancer cells bursts, releasing the virus particles, which in turn will infect other cancer cells. To date, 270 patients with various forms of cancer have been treated with Reolysin in various trials in Canada, the U.S. and the U.K.
Side effects of oncolytic virus treatment are extremely mild compared with those of chemotherapy or radiation. Some patients report a combination of mild, flu-like symptoms, low-grade fever, and a feeling of fullness in the abdomen (more on that in a minute). Side effects usually resolve rapidly. Several of my patients have commented that the side effects of Reolysin therapy have been much less severe than those of chemotherapy. In our clinic, no patient has had to drop out of a Reolysin study due to side effects.
Women in the Reolysin study receive the virus intravenously for five consecutive days. On two of those days patients also receive an infusion of Reolysin into their abdomens (hence the feeling of fullness mentioned above). The treatment cycle is repeated every 28 days as long as the patient continues without undue side effects.
Several ovarian cancer studies suggest greater effectiveness with chemotherapy agents when the drugs are administered into the abdomen as well as intravenously. Researchers believe this effect is due to the drug being in closer contact with the cancer. Based on these findings, the National Cancer Institute, under whose auspices we are conducting this study, was interested in testing if abdominal administration could improve outcomes with virus therapy as well.
Reolysin is currently under investigation in ten U.S. and U.K clinical trials for a variety of cancers, including tumors of the lung, head and neck, bone or soft tissue, colon, skin, and ovaries. In some trials, as in the ovarian cancer trial, Reolysin is administered alone; in others patients receive it along with chemotherapy. So far, reported results have been extremely encouraging, with many patients seeing their cancers stabilize or shrink significantly.
The appeal of Reolysin is that unlike chemotherapy, which affects many different cells, the oncolytic virus kills only cancer cells. Normal cells, such as hair follicles and intestinal cells, are undisturbed, so patients do not lose their hair or appetite. Compared with conventional chemotherapy and radiation, this alone is a huge step forward.
Experience has shown that oncolytic viruses are not only well tolerated, but offer hope for cancer patients who otherwise have limited options. Oncolytic viral therapy is a welcome addition to the fight against ovarian cancer.
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Women with cancers of the fallopian tube, ovaries, or the abdominal cavity who are interested in entering the ovarian cancer study at the James Cancer Hospital at The Ohio State University should call (614) 293-3873 or visit their website, www.jamesline.com.
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David Cohn, MD specializes in gynecologic oncology at The Ohio State University Medical Center in Columbus, OH. His research areas include genetics of gynecologic oncology, prevention of gynecologic cancer, and vaccine therapy for ovarian cancer.
New General Council Appointed Dr. Jeremy Grushcow
http://finance.yahoo.com/news/oncolytics-biotech-inc-announces-addition-220000234.html
Oncolytics Biotech® Inc. Announces Addition to Senior Management Team
Press Release: Oncolytics Biotech Inc.
CALGARY, Feb. 20, 2013 /PRNewswire/ - Oncolytics Biotech Inc. ("Oncolytics" or the "Company") (TSX: ONC, NASDAQ: ONCY) today announced the appointment of Dr. Jeremy Grushcow to the role of General Counsel.
Dr. Grushcow has more than ten years' experience in the legal profession representing public and private entities, as well as venture capital and private equity firms in the acquisition, financing, development, operation and sale of pharmaceutical and life sciences companies in the U.S. and Canada. He holds a B.Sc. from the University of Toronto, a Ph.D. in molecular genetics and cell biology from the University of Chicago, and a J.D. with honors from the University of Chicago Law School. He has been admitted to the Bar in Ontario, New York and Illinois. Prior to joining Oncolytics, Dr. Grushcow was a partner in the Norton Rose LLP pharmaceuticals and life sciences group. He also previously held positions in the Shearman & Sterling LLP capital markets group and the Kirkland & Ellis LLP intellectual property transactions group.
"We are delighted to welcome Jeremy to our management team," said Dr. Brad Thompson, President and CEO of Oncolytics. "He brings a unique combination of scientific, legal and business expertise that will support Oncolytics' continued evolution and we look forward to benefiting from his specific experience and insight."
Public Offering - 8 Mil Shares@$4.00 Approx US$32Mil
Oncolytics Biotech® Inc. Announces Pricing of Common Share Offering
Oncolytics Biotech, Inc. (MM) (NASDAQ:ONCY)
Wednesday 20 February 2013
CALGARY, Feb. 20, 2013 /PRNewswire/ - Oncolytics Biotech Inc. ("Oncolytics") (TSX:ONC; NASDAQ:ONCY) announced today the pricing of an underwritten public offering of 8.0 million common shares, at a public offering price of US$4.00 per common share. The Company estimates that the gross proceeds from the offering, before deducting underwriting discounts and commissions and other estimated offering expenses payable by Oncolytics, will be US$32.0 million. The offering is expected to close on or about February 25, 2013, subject to customary closing conditions.
Piper Jaffray & Co. and Wedbush PacGrow Life Sciences are acting as joint book-running managers for the offering in the U.S. and Paradigm Capital Inc. is acting as co-manager in the U.S. and book-running manager in Canada.
The Company has granted to the underwriters participating in the offering a 30-day option to purchase up to an additional 1.2 million common shares to cover over-allotments, if any.
Oncolytics intends to use the net proceeds from the offering to fund its clinical trial program, manufacturing program and for general corporate and working capital purposes.
The common shares are being offered in each of the Canadian provinces of British Columbia, Alberta, Manitoba and Ontario by way of a prospectus supplement to the Company's base shelf short form prospectus and in the United States pursuant to a prospectus supplement to the Company's effective shelf registration statement on Form F-10 (333-182260) previously filed with the United States Securities and Exchange Commission. Copies of the prospectus supplement and accompanying base prospectus relating to the offering may be obtained from the Securities and Exchange Commission website at http://www.sec.gov, from the System for Electronic Document Analysis and Retrieval (SEDAR) website at http://www.sedar.com or from the underwriters at:
Piper Jaffray & Co.
800 Nicollet Mall, J12S03, Minneapolis, MN 55402
Email: prospectus@pjc.com
Telephone: (800) 747-3924
Wedbush Securities Inc.
One Bush Street, 17th floor, San Francisco, CA 94104
Attn: SF Prospectus Department
Phone: 415-274-6819
Fax: 415-274-6887
Before you invest, you should read the prospectus supplement and accompanying prospectus, the registration statement, and the other documents that the Company has filed with the Securities and Exchange Commission for more complete information about the Company and this offering.
This press release does not and shall not constitute an offer to sell or the solicitation of an offer to buy any of the securities, nor shall there be any sale of the securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration of qualification under the securities laws of any state or jurisdiction.
About Oncolytics Biotech Inc.
Oncolytics is a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of human trials including a Phase III trial in head and neck cancers using REOLYSIN®, its proprietary formulation of the human reovirus.
This press release contains forward-looking statements within the meaning of the U.S. Securities Act of 1933, as amended, and U.S. Securities Exchange Act of 1934, as amended, and forward-looking information within the meaning of Canadian securities laws. Statements, other than statements of historical facts, included in this press release that address activities, events or developments that Oncolytics expects or anticipates will or may occur in the future, including such things as the closing of offering of common shares and the intended use of proceeds and other such matters are forward-looking statements and forward-looking information and involve known and unknown risks and uncertainties, which could cause the Company's actual results to differ materially from those in the forward-looking statements and forward-looking information. Such risks and uncertainties include, among others, risks related to the closing conditions of the offering and risks related to the Company's business which may result in the intended use of proceeds changing. Investors should consult the Company's quarterly and annual filings with the Canadian and U.S. securities commissions for additional information on risks and uncertainties relating to the forward-looking statement and forward-looking information. Investors are cautioned against placing undue reliance on forward-looking statements and forward-looking information. The Company does not undertake to update these forward-looking statements and forward-looking information, except as required by applicable laws.
SOURCE Oncolytics Biotech Inc.
ONCY Updated Investor Presentation January 28, 2013
http://oncolytics.s3.amazonaws.com/presentations/25/original.pdf?1353946216