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Sept 4, 2019 corp deck available
http://ir.tocagen.com/news-and-events/presentations?c=254300&p=irol-presentations
A ternary outcome for Tocagen
Jacob Plieth
https://www.evaluate.com/vantage/articles/events/company-events/ternary-outcome-tocagen
Tocagen’s Toca-5 trial has survived two interim reviews, and faces final readout by the end of this year.
A doctor and radiologist discussing brain scans results
It has been two years since Tocagen upsized its pivotal Toca-5 study, focusing its investment case squarely on the result, and since the trial involves recurrent brain cancer failure is much more likely than success. But the group’s chief executive, Marty Duvall, accepts that a third outcome is also a real possibility.
The trial could result in a smaller than expected survival benefit that misses statistical significance yet is clinically meaningful – a scenario that, if backed by supportive secondary endpoints, would be taken to regulators, he tells Vantage. Investors, who have sent Tocagen’s stock down 60% year to date, will know soon enough.
At issue is whether the 403-subject study is sufficiently powered to deliver its desired 4.5-month median overall survival benefit favouring Tocagen’s project, Toca 511 & Toca FC. In the setting of recurrent brain cancer a 4.5-month benefit is an aggressive goal.
Toca-5 is 85% powered to detect a 31.5% reduction in the risk of death at 257 events, expecting mOS of 14.3 months for Toca 511 & Toca FC versus 9.8 months for control. Mr Duvall accepts that this represents a big effect size, but says the assumptions are in line with what Tocagen had seen in phase I.
“In the case of a miss on the mOS endpoint with a trend on survival and positive secondary endpoints we’ll do everything we can to get this product over the regulatory line,” he states. Secondary endpoints include 12-month survival and durable response rate.
Project Toca 511 & Toca FC
Company Tocagen
Product NPV $638m
% of mkt cap 821%
Event Final readout of Toca-5 study
Due Q4 2019
The Tocagen project hinges on the view that 5-FU is an effective cancer chemotherapy that is plagued by haematological toxicities. To deliver high-dose 5-FU locally with improved safety the two-part project combines Toca 511, a retroviral replicating vector (RRV) coding for cytosine deaminase, injected locally, with Toca FC, a 5-FU prodrug, given orally.
RRVs are, like oncolytic viruses, believed to preferentially infect dividing cancer cells, but unlike oncolytic viruses they are non-lytic. Once the prodrug is dosed, the thinking goes, it is converted locally into 5-FU by the cysteine deaminase that Toca 511 has encoded.
If this sounds like rocket science Mr Duvall disagrees. “Neurosurgeons are fired up about this ‘additional tool’,” he says, insisting that injecting the retrovirus into the brain cavity is just an adjunct to normal surgery; Toca FC is then dosed orally every six weeks.
So has it got a chance? A big caveat is that a phase I effect tends to wane in the more rigorous pivotal setting, something that Celldex learned with Rintega.
A second question is how the control cohort will perform. Toca-5 enrolled subjects who had failed one or two lines of therapy; the control arm of Bristol-Myers Squibb’s Checkmate-143 study in recurrent subjects showed median OS of about 10 months.
Interim green light
A separate issue that has vexed the markets is the two interim analyses that Toca-5 passed. Neither was designed for a stop in the event of futility, largely to preserve statistical power and “provide the greatest possible opportunity to generate compelling data”.
However, the Tocagen bull case accordingly became an early study stop on knockout results; if Toca-5 was merely continued, which is what happened, futility could not be ruled out, and the stock sold off.
Toca-5 actually started out as a 187-patient study designed to yield final data in 2018, but the decision to upsize it was taken after Toca 511 & Toca FC got US breakthrough designation. “We saved two or three years’ development, but we took away a datapoint,” says Mr Duvall.
In the coming months he will find out whether this gamble was worth taking.
Understanding Patient Response to Improve Therapies with Dan Hogan
https://cofactorgenomics.com/wk-34-patient-response-therapies/
David: I’m really excited about the mission of Tocagen and hearing more about Dan’s work. Tocagen develops immune-oncology candidates for therapeutics and they’ve got a great tagline, “no one should die of cancer.” Dan, it’s great to have you here.
Dan: Thank you. At Tocagen, we utilize a replicating retrovirus that selectively infects tumor cells. Then we encode a gene within that retrovirus that we can inject into a patient’s tumor or even through an IV. The virus enters tumor cells, selectively infects them, and inserts that DNA into the cancer cell genomes and expresses whatever gene we put in there.
Our lead therapy is at the tail end of a registrational phase III trial in recurrent Glioblastoma, is called Toca 511. In this case, we have the replicating retrovirus encoding a gene or cytosine deaminase, which will convert an antifungal drug, which the patient takes in the form of a pill, 5-chlorocytosine, into a chemotherapeutic, 5-fluorouracil. This will happen specifically in the tumor. It then leads to a patient response of direct self-killing of the tumor cells. In addition to that direct self-killing, it elicits an immune response due to the direct cell killing, as well as a release of viral antigens, killing of some of the suppressor immune cells in the tumor. In a nutshell, that’s what Tocagen does.
My role is primarily to lead the bioinformatics group. Part of that is doing the usual genomics correlation studies as a part of clinical trials, to better understand or characterize the tumor molecular profiles of the patients and relate that information to clinical outcomes. The goal is to utilize that information to better understand the mechanism and the mechanism of action, to improve the therapy. We also try to understand patient response – what distinguishes patients that respond very well versus those that don’t?
David: What are some of the things that you are learning? Both through research in general, but also through these clinical trials identifying patient response and who’s responding to what. That’s the big challenge of precision medicine, figuring out who’s in the 30% and who’s in the 70% and how you can dial in treatments to better serve those different populations.
Dan: Most of the work we’ve done has been with phase I studies. This is tough for a variety of reasons. In our phase I study, about 20-25% of patients showed an objective clinical response by MRI, meaning after treatment, the tumor would start to grow back but then regressed or stop growing. Those that showed durable patient response lived for quite an extended period of time, so we’ve spent a lot of time trying to understand what’s special about those patients. We have some leads from tumor profiling that we’ve done that suggest there are some intriguing differences in the immune cell populations.
The tumors are different in the patients that responded than in the ones who didn’t. It is important to remember, it’s a small sample size, and it’s phase I, so there’s no control arm. There are many caveats to that, but we are taking that data and the framework for distinguishing patient response. Now we’re going to apply that to the phase III trial. In that trial we have about 400 patients that are split one-to-one on Tocagen treatment versus the standard of care. We have done the RNA and DNA sequencing on all those patient’s tumors, as well as peripheral blood monitoring, so we’re in a much better position with the phase III study to have the power to find something significant.
David: Let’s talk a little bit about where samples are being derived from, whether it’s for diagnostic or monitoring purposes. Looking at liquid biopsy and a solid tissue allows for different angles. So how can we tie what we learned at the side of the tumor to what we see in the biofluids, and how are you approaching these different sources?
Dan: Glioblastoma is a particularly tough one to correlate what’s happening in the tumor with the blood. There’s been headway made in other solid tumor indications such as lung and melanoma. They longitudinally profile the blood for specific mutations as a way to monitor disease progression, which shows a heck of a lot of potential. Glioblastoma is difficult for a few reasons. We don’t have complete understanding of how the immune system works in the brain, either in a healthy patient or one with Glioblastoma. On top of that, Glioblastoma doesn’t seem to shed much DNA, so there is no way now to monitor either specific mutations or anything else peripherally. It’s an uphill battle. We’re not able to apply any methodology that’s being developed in other solid tumors for Glioblastoma. At least for us, it’ll be a question of trying to carefully connect dots.
David: What about some of the other tumor types? You mentioned lung and melanoma being two areas where oncology has made huge progress over the years, but with the addition of breast and colorectal cancer, they make up the majority of the literature in the field. There’s a huge number of other cancer types. I know work is being done, but where are we with these approaches to other cancer types?
Dan: Therapeutically, there’s been success in melanoma, lung, and colorectal cancer. I think the great breakthrough was checkpoint inhibitors, which essentially take the brakes off T-cells, but those are just a tiny part of what we can do. In tumors like lung and melanoma that have high mutation levels and fairly high levels of T-cell infiltrates that are being suppressed, taking the brakes off is enough. That’s why we’ve seen great success stories there. Even within those tumors, of course, there’s a lot of heterogeneity from patient to patient, and no pre-existing sets of T-cells in the tumor. How are we going to get the immune system going there? There are lots of trials going on with various approaches to solve this.
CAR-T cells have a lot of potential, but you you need specific antigens. Some of the myeloid suppressor cells such as the MDSC, are very sensitive to 5FU, which is one of the reasons our therapy works. I think there’s a lot of promise in other solid tumor types. We have the ability to collect so much data within the tumor, as well as peripherally, with next-gen sequencing and other emerging methods. This lets us monitor the immune system and measure patient response at an unprecedented level.
David: There’s a shift from focusing on DNA to RNA through RNA-seq in a more holistic, omics approach in nucleic acids, genomics, proteomics, metabolomics and others. Let’s talk about sequencing and its role in today’s immune oncology landscape.
Dan: I think of RNA as a diagnostic, but it’s lagged behind DNA. There’s just more complexity to it. Honing in on specificity and signal over noise takes a larger sample size and more time. Therapeutically, we’re starting to utilize RNA-based therapeutics, oligonucleotides mRNA-based therapeutics, and gene therapy, all of which have great potential.
David: There’s so much talk about big data, machine learning, and artificial intelligence. What are some of the tools and approaches that the scientific community needs to be using in order to handle this kind of exponentially growing massive data?
Dan: We do all the heavy lifting on cloud based servers for processing the data, and the subsequent analyses on a local Linux server. Integrating data from different sources and performing QC is half the battle. It’s the boring half, but an important one. One challenge is that the public data from other labs tends not to be that helpful for us. We’ve spent so much taxpayer money generating these giant data sets, we need to figure out how to do it in a way that’s more universally useful. Part of that is doing a better job collecting metadata on the patients and their clinical profiles. It’s very difficult because with clinical trials, there’s no obligation to share patient data, and there’s also concerns with patient privacy and intellectual property. We need to ensure that information is useful not just for us and for our therapy, but for the broader community. Then, how can that information be incorporated into subsequent trials by others to help move the field forward? Hopefully FDA will start requiring certain elements of the trials to be published or accessible to others.
David: I’d like to bring it back to biomarkers and the specific things and we may see in the future. Is there anything that you’re really excited about in terms of specific biomarkers or pathways?
Dan: I’m in the brain cancer space and I’m hopeful about merging imaging techniques with genomic data sets. I think it’s even a term called radio genomics where you can go back and do correlation studies between MRI, PET, or other types of scans with genomic features, then use that to sort the imaging as a way to get proxies on the molecular profiles of the tumors. There’s a lot of promise there. Also, some of the spatial transcriptome profiling methods may hold a lot of insights into tumor heterogeneity and the role of the architecture fit within the tumors and how that may be affecting patient response to immunotherapies. I’m also excited about the ability to cheaply and quickly monitor the immune system at any given time. This would be valuable for disease and healthy states to provide a lot of information that we will be able to utilize for next generation early and noninvasive diagnostics.
David: I’m excited to see this next iteration of immune-oncology and precision medicine. Thanks for all of your insight and it’s been a lot of fun. Tell people where they can go to find out more about you and Tocagen.
Dan: Tocagen has a pretty rich source of peer reviewed papers that others can check out. Keep an eye out for our results on the phase III trial over the next month or two. It’s going to be a little big inflection point for the company and hopefully the field. In this field, the needle hasn’t moved so patients and physicians are desperate for something that shows promise and fills that progress, so hopefully that’s what we’re doing.
David: We’ll be looking forward to seeing those results. Thanks again for your time. It’s been a real pleasure.
Validation of an effective implantable pump-infusion system for chronic convection-enhanced delivery of intracerebral topotecan in a large animal model.
Al's Comment:
This is early - only in animals so far - but would be a major step forward int he fight against brain tumors. We have some effective treatments that have to be delivered by convection enhanced delivery, such as Toca 511 and PVSRIPO. These experimental treatments showed some remarkable results after just one (or 2) course of treatment. With this new technology, we could use these therapies on an ongoing basis and perhaps drastically increase their effectiveness!
https://virtualtrials.com/newsarticle.cfm?item=6724
Sectoral Asset Management is now TOCA's 3rd largest institutional investor after starting a HUGE initial position. Board member Berger previously worked here. This is significant because Sectoral specializes in healthcare.
https://www.sectoral.com/
Sectoral Asset Management (Sectoral) is an investment advisor exclusively focused on the global healthcare sector. The company manages public and private equity healthcare strategies for investors around the world. The company has one of the world’s longest track records in managing biotech equities.
8/8/19 Corporate Presentation
http://ir.tocagen.com/news-and-events/presentations
Targeting Myeloid Cells in Combination Treatments for Glioma and Other Tumors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664066/
Another creative chemotherapy with effects on the myeloid compartment utilizes the retroviral vector Toca 511. With this technique, Toca 511 selectively delivers a cytosine deaminase gene to cancer cells. Cytosine deaminase is then expressed by the infected cells, causing them to convert the pro-drug 5-fluorocytosine (5-FC), commonly delivered in the oral extended-release form of Toca FC, into the potent chemotherapeutic 5-fluorouracil (5-FU), which causes death of the tumor cells (173). Besides tumor cell death, 5-FU has also been shown by Vincent et al. to selectively kill MDSCs in tumor cells while preserving other immune populations and resulting in greater T cell IFN? production (126). Mitchell et al. then confirmed this effect in the context of Toca by pretreating tumor cells before flank implantation with Toca 511, followed by treatment with Toca FC (127). Intratumoral injection of Toca 511 in gliomas by Hiraoka et al. (128) and colorectal cancer by Yagiz et al. (129) also resulted in immunological benefit. The immunological effects were correlated with survival and long-term resistance to tumor rechallenge. Survival effects were preserved on combination therapy with both TMZ (130) and lomustine, another chemotherapeutic (131). Additionally, Takahashi et al. demonstrated a decrease in radioresistance caused by treatment of gliomas, although this was done in athymic mice, and thus the possible immunological contribution is unclear (132). The success of Toca supports the findings of Mathios et al. where localized chemotherapy was beneficial for cultivating an immune response (170). The exact mechanism of the synergistic anti-tumor effects of combining myeloid targeted therapies with chemotherapy is unclear. It has been postulated that chemotherapy, similar to radiation therapy, generates new antigenic targets and boosts antigenic uptake and presentation thereby priming the TME for adaptive anti-tumor immune responses. Combination with myeloid targeted therapies can further abrogate alternative immunosuppressive pathways to enhance anti-tumor effects of chemotherapy.
Toca presented at the Jefferies 2019 Healthcare Conference. Download the pdf to follow along with the presentation. CEO emphasized that second group's data has not matured.
http://ir.tocagen.com/events/event-details/jefferies-2019-healthcare-conference
Toca 5 Continues Without Modification at Planned Interim Analysis
http://ir.tocagen.com/news-releases/news-release-details/tocagens-toca-5-pivotal-phase-3-clinical-trial-patients-0?fbclid=IwAR3_qhD1khseAzDDrarBOLJcdILb_Wsuo96gawy75xfPDh9nMJjZkh_GYbw
SAN DIEGO, May 21, 2019 /PRNewswire/ -- Tocagen Inc. (Nasdaq: TOCA), a clinical-stage, cancer-selective gene therapy company, today announced the Toca 5 Phase 3 clinical trial evaluating Toca 511 & Toca FC in patients with recurrent high grade glioma (HGG) continues without modification following a planned interim analysis of data conducted by an Independent Data Monitoring Committee (IDMC). The IDMC completed its analysis and recommended the trial continue without modification. The global trial enrolled patients across two periods of time and completed full enrollment of 403 patients in November 2018.
"We are encouraged by the recommendation from the IDMC to continue the Toca 5 trial without modification and are looking forward to reporting the final analysis of the Toca 5 trial by the end of the year," said Marty Duvall, chief executive officer of Tocagen. "We believe the longer-term follow-up of patients in the final analysis, particularly for those randomized in the second enrollment period, will be important in assessing both primary and secondary endpoints."
The Toca 5 trial is one of the largest randomized trials conducted in patients with recurrent high grade glioma. The international trial is a Phase 3 multi-center trial evaluating the safety and efficacy of Toca 511 & Toca FC compared to standard of care in patients undergoing resection for recurrent high grade glioma (HGG). The primary endpoint of the trial is overall survival (OS). The statistical plan for the primary endpoint assumes a median OS of 9.8 months for the control arm versus 14.3 months for the Toca 511 & Toca FC arm. A total of 257 events will provide the trial with 85% power to detect a hazard ratio of 0.685. The U.S. Food and Drug Administration (FDA) granted Toca 511 & Toca FC Breakthrough Therapy Designation for the treatment of recurrent HGG and the European Medicines Agency (EMA) granted Toca 511 PRIME (PRIority MEdicines) designation for the treatment of glioma. More information about the Toca 5 trial can be found on ClinicalTrials.gov using the clinical trial identifier NCT02414165.
ASCO: Use of Replication Competent Oncolytic Viruses as Therapeutics in Glioblastoma
Article Highlights:
Glioblastoma (GBM) is a rare but uniformly lethal disease, with a median overall survival of fewer than 21 months. Effective interventions are critically needed.
It is hoped that oncolytic viruses can immunologically engage the tumor microenvironment, transforming it from “cold” to “hot.”
Therapy with PVSRIPO has been developed for the treatment of recurrent GBM due to its grim prognosis, poliovirus’ natural neuroinvasive properties, and widespread expression of the poliovirus receptor, CD155, on tumor cells.
Evidence is now accumulating that we may be able to identify patients with GBM who experience durable responses to viral oncolytic therapies based on molecular biomarkers.
https://dailynews.ascopubs.org/do/10.1200/ADN.19.190198/full/
AANS: 2120. Immune Monitoring of High Grade Glioma Patients in a Phase 1 Clinical Trial of Toca 511 and Toca FC
Conclusions
? Human immune monitoring results support an immunologic mechanism
of action for Toca 511 & Toca FC treatment. Preliminary analyses
identified potential immune signatures that may reflect patient outcomes
and should be explored further.
• Tumor infiltrating NK cells, M0 macrophages and activated CD4+ memory T-
cells may predict patient outcomes including objective response and survival
• Peripheral serum cytokine modulations during Toca 511 & Toca FC treatment
could be useful to monitor patient responses and indicate long term survival
• Post-treatment expansion of PD-1+ and Ki-67+ T-cell subsets in the peripheral
blood of responding patients suggests potential immune activation related to
therapeutic benefit
? This clinical research helps support and clarify the immune-related
mechanism of action for Toca 511 & Toca FC previously observed in non-
clinical models
? Potential immunological associations with patient outcomes will be
evaluated in the ongoing randomized Phase 3 trial in patients with rHGG
(NCT02414165), Toca 5
https://360.aans.org/AppSearch/Eposter?eventid=48888&itemid=EPOSTER&propid=46117
Tocagen to Present Updated Data from Clinical and Preclinical Studies at Two Scientific Conferences
https://www.prnewswire.com/news-releases/tocagen-to-present-updated-data-from-clinical-and-preclinical-studies-at-two-scientific-conferences-300819528.html
Tocagen at 8th Annual SVB Leerink Global Healthcare Conference -- worth a listen.
http://wsw.com/webcast/leerink32/toca/
3/1/19 corp presentation posted
http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-presentations
Expert opinion: These early studies provide very encouraging results for Toca 511 and Toca FC in rHGG.
https://www.ncbi.nlm.nih.gov/pubmed/30676111
Early clinical trials of Toca 511 and Toca FC show a promising novel treatment for recurrent malignant glioma.
Philbrick BD1, Adamson DC1,2.
Author information
Abstract
Glioblastoma and anaplastic astrocytoma are two of the most aggressive and common glioma malignancies in adults. These high-grade gliomas (HGG) universally recur despite aggressive treatment modalities and have a median overall survival (mOS) of approximately 14 months from initial diagnosis. Upon recurrence, there is no standard of care and these patients have a dismal prognosis of around 9 months at time of recurrence. Areas covered: In this article, we assess the newly published phase I data of Toca 511 and Toca FC, a two-drug combination therapy for recurrent HGG (rHGG) tumors, for effectiveness and safety. Expert opinion: These early studies provide very encouraging results for Toca 511 and Toca FC in rHGG. This therapy had a response rate of 11.3% and a mOS of 11.9 months in 56 patients, an improvement compared to historical controls. Furthermore, all responders were complete responses after extended follow-up. The drug is well tolerated for most patients. Responders tended to be young and have high performance scores prior to beginning therapy, but more studies are necessary to understand the patient profile that receives the most benefit. Randomized-controlled trials are warranted for Toca 511 and Toca FC to confirm drug efficacy.
Citadel took a small position in TOCA.
12/11/18 corp deck out. Some insight into the NRG-BN006 trial - newly diagnosed HGG
1st patient enrolled in 2H19
SOC arm allows Optune / Toca 511 arm does not allow Optune
12/5/18 corporate presentation posted on company's website
http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-presentations
Looks like all 6 CRs have passed the 3 yr mark so 3-yr survival has been updated to 26%
Retroviral replicating vectors (RRVs) have been shown to achieve efficient tumor transduction and enhanced therapeutic benefits in a variety of cancer models. In the present study, we evaluated a possible combinatorial effect of prodrug activator genes delivered by two different RRVs derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV) on human hepatocellular carcinoma Hep3B cells. Both RRVs showed efficient replicative spread in culture and can overcame superinfection resistance each other. Notably, the replication and spread of each RRV in culture remained unaffected by pretransduction with the counterpart RRV. We further transduced cells with RRVs which individually possessed the prodrug activator genes yeast cytosine deaminase (CD) and herpes simplex virus thymidine kinase (TK) alone or in combination, and evaluated the cytotoxic effects of RRV-mediated gene therapy with CD and TK in the presence of the respective prodrugs, 5-fluorocytosine and ganciclovir. All combinations of the two prodrug activator genes produced synergistic cytocidal effects, but the combined effects of the different genes were significantly greater than those of the same genes when delivered by two different vectors. The present findings indicate the potential utility of dual-vector gene therapy using two different RRVs carrying different prodrug activator genes.
In conclusion, our results demonstrated AMLV and GALV can coinfect and replicate independently in cultured cells, suggesting their ideal combination for dual-vector gene therapy. The dual RRV-mediated CD/5FC and TK/GCV combinatorial gene therapy achieved synergistic cytotoxic efficacy compared with single-vector gene therapy. Thus, coinfection of cancer cells with AMLV and GALV vectors supplied with different prodrug activator genes may be employed for combination intracellular chemotherapy, leading to enhanced cytotoxic effects while avoiding drug resistance.
https://www.nature.com/articles/s41417-018-0051-0
Common considerations for immuno-oncology drugs include objective response rates in a select subset of patients with prolonged duration of response, a delayed separation, and a late plateau of survival curves, as well as a median overall survival that may obscure the long-term benefits in the minority of patients with responses.38 Therefore durable response rate may represent a new and clinically meaningful surrogate endpoint for overall survival in brain cancer trials, to more accurately assess clinical benefit of novel immune-oncology drugs for the treatment of brain tumors.
Very thorough examination of phase 1 results: Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC
https://academic.oup.com/neuro-oncology/article/20/10/1383/4995454
Responding Patients Have Low Genomic Mutational Burden
Response to checkpoint inhibitors correlates with tumor mutational burden, which is a proxy for the presence of “neoantigens” that can be recognized by tumor-infiltrating lymphocytes.33 As it appears that responses to Toca 511 treatment have an immunologic basis, we tested whether mutational burden correlates with response, by “exome” sequencing of all available patient tumors resected immediately prior to Toca 511 treatment. Consistent with previous characterization of HGG,34 most patient tumors had relatively few total mutations (or nonsynonymous mutations)—of approximately 100 or about 2 per/Mb sequenced using blood DNA as baseline (Fig. 3). Two patients (011 and 030) displayed hallmarks of temozolomide-induced hypermutation with about 100-fold more mutations and a strong bias for CG to TA. Neither patient responded and both patients had isocitrate dehydrogenase 1 (IDH1) R132H/S driver mutations. Patient 011 did not take Toca FC and Patient 030 was on fifth recurrence. Neither patient lived longer than 7 months, whereas most responding patients took 6 to 19 months to respond. All responding patients had few mutations and thus responses observed were not associated with tumor mutation load determined by exome sequencing. No patients were reported to have 1p/19q mutation.
retroviral replicating vectors (RRVs) have emerged as a potential backbone for useful therapies across a wide range of oncologic malignancies. RRVs selectively infect tumor cells without directly lysing them. This differentiates them from directly oncolytic and highly inflammatory viruses such as adenovirus and herpes viruses (1–3). Thus, RRVs provide a platform for therapies based on tumor-specific gene delivery strategies without the inherent limitation of rapidly killing infected cells. RRV are selective for tumor cells partially due to virus-selective advantages in the tumor microenvironment from blunted innate immune responses as well as suppressed adaptive immune responses relative to normal dividing cells (3–6). Viral dependency on mitosis for integration contributes to cancer cell selectivity (7), and the noninflammatory nature of the infection (and replication competency) allows subsequent spread
http://clincancerres.aacrjournals.org/content/24/19/4680
Toca 6 updates coming. At stake is frontline for multiple solid tumors. Presentation and poster available for review on the corporate site. http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-presentations
$2 mil payment triggered by completion of enrollment, which was 3 months ahead of schedule.
https://www.prnewswire.com/news-releases/tocagen-announces-early-completion-of-enrollment-in-toca-5-pivotal-phase-3-brain-cancer-trial-300715141.html
Thank you, both. Hearing good things about Tocagen.
Good summary of current events:
https://seekingalpha.com/instablog/20587681-quadrant8/5208696-tocagen-riding-high-positive-momentum
Tocagen Riding High On Positive Momentum
Sep. 5, 2018 3:39 PM ET|About: Tocagen Inc (TOCA), Includes: AVXS, RGNX
Summary
Top analysts initiate Buy recommendations.
Another patient reporting Complete Response.
Expanding globally.
Top analysts initiate Buy recommendations
4-star rated Robyn Karnauskas from Citigroup initiated coverage on Tocagen Inc. (TOCA) with a Buy rating and a price target of $27.00 on September 4, 2018. She based her recommendation on the company’s innovative treatment approach.
5-star rated Gbola Amusa (Chardan Capital) initiated coverage of TOCA with a Buy rating and $30 price target on August 30, 2018. Mr. Amusa indicated that his rating was due to the following factors:
The initial Phase 1 study produced impressive and in some cases durable results in rHGG patients who otherwise die in eight to 11 months.
The risk-adjusted 2030 sales is $877.6 million for Toca 511 and Toca FC in HGGs.
BTD and PRIME designations for Toca 511 & Toca FC.
Tipranks reports that he has a 57% success rate and 27.4% average return per rating. It should be noted that back in November 2017 Mr. Amusa rated REGENXBIO (RGNX) as a Buy, when the stock was in the $20 range. The stock has since climbed to over $80 and currently sits at around $75. In December 2016, Mr. Amusa rated AveXis Inc (AVXS) as a Buy, when the stock was in the high $40 range. In April 2018, Novartis announced that it entered into an agreement to acquire AveXis Inc. for $8.7 billion ($218 per share).
Another patient reporting Complete Response
Tocagen’s latest presentation (August 2018) reports that in its Phase 1 Resection Study “6 responders received higher Toca 511 dose and are durable complete responders.” On Biden Cancer Initiative one patient (J.W.) is reporting that her husband enrolled in the Toca 5 clinical trial on December 2016, and “he’s doing amazing!” Additionally, she indicates that he “leads a completely normal life! Works full time.” In addition to this patient, other patients have also indicated that they are doing well and surviving long-term while in the Toca 5 clinical trial. While these data points are positive indications for Toca 511 & Toca FC, they are but a few data points and are not statistically significant.
Expanding globally
Tocagen’s latest presentation (August 2018) reports that the company will expand by:
Advance Toca 511 & Toca FC combined with SOC in newly diagnosed HGG - 2018
Define European regulatory path under PRIME designation - 2018
FPI for Toca 511 & Toca FC combined with SOC in newly diagnosed HGG - 2019
Advance European regulatory path under PRIME designation - 2019
Globally, Tocagen and ApolloBio entered into a license agreement (April 2018) to develop and commercialize Toca 511 & Toca FC in the greater China region.
Recently, Tocagen held pre-IND (Investigational New Drug) meetings with Japan’s PMDA (Pharmaceuticals and Medical Devices Agency).
With Tocagen expanding to other indications and regions, impressive patient results, and bullish analyst ratings, Tocagen is riding high on positive momentum.
Citigroup Robyn Karnauskas initiates Buy recommendation. Another impressive analyst.
https://www.tipranks.com/analysts/robyn-karnauskas
Chardan buy rating, followed by Citigroup
Chardan's Amusa has an impressive track record: https://www.tipranks.com/analysts/gbola-amusa
Updated September presentation - check it out:
http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-presentations
Another long-term survivor - close to 2 years on Toca.
https://bidencancer.org/cancer-fierce/
“I wanted to share my husband’s story because I think it’s very encouraging to anybody who is fighting this beast! He was diagnosed with a walnut sized glioblastoma in November 2012 at the age of 33. His only symptom was a headache that wouldn’t go away. The week after we found out was quite a whirlwind, that included us getting married! He had surgery to remove over 99% of the tumor followed by 6 weeks of chemo and radiation then 18 months of chemo and did great!"
"Fast forward to January 2016 (I was 7 1/2 months pregnant with a baby doctors said we might never have because of my husband’s cancer treatments) and his doctor found a small recurrence at the original tumor site during a routine MRI. This was small enough to be treated with stereotactic radiosurgery and more chemo. We got less time between recurrences this around, December 2016( our son was 10 months old) they found another recurrence and this time it was treated with surgery and he was enrolled in The Toca 511 clinical trial. It didn’t come without complications but after all was said and done he’s doing amazing! He will be a 6 year survivor in November and leads a completely normal life! Works full time as a registered nurse, drives, helps care for our two year old son, etc.... I hope his story provides some hope and encouragement for everybody who is fighting!” (Jillian Wasko, PA)
Good observations for direct injection: A surgeon injects the virus into the site of highest tumor concentration in the brain. Later, the patient is given oral, extendedrelease 5-fluorocytosine, which the CD gene converts into 5-fluorouracil, activating the immune system against cancer. Other engineered viruses work by inserting RNA rather than DNA into cancer cells.
It was initially thought that oncolytic viruses killed just the cancer cells into which they were injected, but Masahiro Toda, M.D., Ph.D., and colleagues demonstrated that the technique acts systemically, shrinking tumors that are both at and distant from the injection site. This could play a critical role in generating durable responses in patients with metastatic or aggressive disease.
Rabkin and Howard L. Kaufman, M.D., chief medical officer of the biotechnology company Replimune, agreed that, because of new techniques in interventional radiology and minor surgery, direct injection of the virus is possible for most tumors and would be more effective than IV administration, which tends to kick off an immune response against the drug. “With modern neurosurgical techniques, almost all areas (of the brain) are accessible to biopsy,” Rabkin said. “If you can perform a biopsy, you can deliver the virus.”
https://www.curetoday.com/publications/cure/2018/immunotherapy-special-issue/contagious-enthusiasm
6/11 Corporate Presentation
http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-presentations
Toca 6: A phase 1b study of Toca 511 and Toca FC in patients with advanced solid tumors or lymphoma.
Presented Monday, June 4, 2018
Authors:
Jaime R. Merchan, Jordi Rodon Ahnert, Gerald Falchook, Derek Ostertag, Dalissa Tejera, Harry E. Gruber, Douglas J. Jolly, Jolene Shorr; University of Miami, Miami, FL; Vall d'Hebron University Hospital, Barcelona, Spain; Sarah Cannon Research Institute at HealthONE, Denver, CO; Tocagen, Inc., San Diego, CA; Sylvester Comprehensive Cancer Center, Miami, FL, US
Background:
Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector that selectively infects cancer cells. Toca 511 spreads through tumors, stably delivering an optimized cytosine deaminase (CD) gene that converts the prodrug, Toca FC (investigational, extended-release 5-FC), into 5-FU within the tumor microenvironment. Preclinical studies show 5-FU kills infected dividing cancer cells and diffuses and kills surrounding cancer cells, myeloid derived suppressor cells, and tumor associated macrophages, thus reestablishing tumor immunity. A prior clinical study showed CD protein expression in resected high grade glioma tumors after intravenous (IV) Toca 511 (1Cloughesy T, Walbert T, Bota D, et al. Neuro Oncol 2016; 18(suppl 6):vi17). In animal models of metastatic colorectal cancer, IV Toca 511 infected metastases; subsequent 5-FC treatment resulted in decreased tumor size, improved survival, and durable antitumor immunity (2Yagiz K, Rodriguez-Aguirre ME, Espinoza FL, et al. Molecular Therapy: Oncolytics. 2018; 8:14-26).
Methods:
Toca 6 is a Phase 1b, multicenter, open-label study (NCT02576665) investigating changes in immune activity after treatment with Toca 511 & Toca FC in patients with advanced solid tumors or lymphoma. Toca 511 is injected IV daily for 3 days, then intratumorally following biopsy or, for patients with brain metastases, into resection cavity walls following resection. Oral Toca FC is started ~4 weeks later and repeated every 4-6 weeks. Changes from baseline in intratumoral immune activity (infiltrating T-cell subpopulations, B cells, monocytes) at 4 weeks after start of Toca FC are assessed. Peripheral blood is analyzed for effector, memory, Treg, and myeloid lineage cells. Viral RNA, DNA, and CD protein expression in tumor after IV Toca 511 are measured. Safety and efficacy are assessed. Approximately 30 patients will be enrolled at 4 sites in the United States. Enrollment progress by tumor type will be provided at the time of the meeting. Clinical trial information: NCT02576665
Madhu Kumar has a pretty good success rate.
https://www.tipranks.com/analysts/madhu-kumar
Tocagen and Beijing Apollo Venus Biomedical Technology Limited have entered into a license agreement
https://www.prnewswire.com/news-releases/tocagen-and-apollobio-enter-license-agreement-to-develop-and-commercialize-toca-511--toca-fc-in-the-greater-china-region-300632706.html
https://www.last10k.com/sec-filings/toca/0001193125-18-121883.htm?utm_source=stocktwits&utm_medium=forum&utm_campaign=8K&utm_term=toca
SAN DIEGO and BEIJING, April 19, 2018 /PRNewswire/ -- Tocagen Inc. (Nasdaq: TOCA), a clinical-stage, cancer-selective gene therapy company, and Beijing Apollo Venus Biomedical Technology Limited, an affiliate of ApolloBio Corp. (NEEQ: 430187), a biopharmaceutical company focused on oncology (collectively, "ApolloBio"), today announced they have entered into a license agreement providing ApolloBio with an exclusive license to develop and commercialize Toca 511 & Toca FC within the greater China region, including mainland China, Hong Kong, Macao and Taiwan.
Toca 511 & Toca FC is a cancer-selective immunotherapy currently under evaluation in an international Phase 3 trial, called Toca 5, for patients with recurrent high grade glioma (HGG), a type of brain tumor. The product candidate has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) and PRIority MEdicines (PRIME) designation from the European Medicines Agency (EMA).
Under the terms of the agreement, ApolloBio will make an upfront payment of $16 million to Tocagen, plus potential payments of $4 million in near-term development milestones, including completion of enrollment in the Toca 5 study. Tocagen will be eligible for additional future payments totaling up to $111 million upon meeting certain development and commercial milestones. In addition, low double-digit tiered royalty payments will be made based on net sales. ApolloBio will be responsible for all development and commercialization costs in the licensed territory.
"As an innovative biopharmaceutical company in China, ApolloBio is well positioned to leverage China's recent regulatory changes supporting the development of new medicines," said Marty Duvall, chief executive officer of Tocagen. "ApolloBio brings valuable regional expertise in product development, regulation and healthcare access, positioning our lead product to advance towards patients in the greater China region as quickly and efficiently as possible."
The total number of new diagnoses of HGG expected in 2018 is about 180,000 worldwide and about 47,000 in the greater China region. Standard treatment for newly diagnosed HGG includes safe surgical removal of as much of the tumor as possible, followed by radiation therapy and chemotherapy. However, HGG recurs in most patients even after maximal treatment and there are currently very few treatment options available.
"We are committed to accelerating the availability of novel immuno-oncology treatments to patients with high unmet medical needs in the greater China region," said Dr. Weiping Yang, chief executive officer of ApolloBio. "Toca 511 & Toca FC is a highly promising, best-in-class cancer-selective immunotherapy and we look forward to working with Tocagen to advance this innovative late-stage product towards commercialization."
The license grant to ApolloBio is subject to the satisfaction of customary conditions and is expected to become effective in the second quarter of 2018. For more details, please refer to the corresponding Form 8-K filed today with the U.S. Securities and Exchange Commission (SEC).
Abstracts: Toca 6 Phase 1 Data and Immune Profiling Data - AACR 2018
http://ir.tocagen.com/phoenix.zhtml?c=254300&p=irol-newsArticle&ID=2338235
Presentation Type: Poster (Abstract: CT067)
Title: A phase 1b study of Toca 511, a retroviral replicating vector, followed by Toca FC in patients with advanced cancer
Presenter: Jaime Merchan, M.D., director, Phase 1 clinical trials program at Sylvester Comprehensive Cancer Center, part of UHealth, the University of Miami Health System; associate professor of medicine at the University of Miami Miller School of Medicine
Date and Time: Monday, April 16, 8:00 a.m. - 12:00 p.m. CT
Presentation Type: Poster (Abstract: 5630)
Title: Immune profile of tumor microenvironment helps predict response in patients treated with an investigational immunotherapeutic consisting of a retroviral replicating vector (Toca 511) and an extended-release formulation of 5-fluorocytosine (Toca FC)
Presenter: Derek Ostertag, Ph.D., senior director of R&D Diagnostics at Tocagen
Date and Time: Wednesday, April 18, 8:00 a.m. - 12:00 p.m. CT
If TOCA is successful I hope VBLT explore TOCA's delivery mechanism vs IV every 8 wks.
I think there were some folks that misunderstood how TOCA was delivered, saying that it required major surgery. That's not the case. The delivery mechanism is considered minimally invasive.
Here's a summary:
http://abc13.com/archive/9414603/
First he makes a small hole in the skull. Using MRI to guide a catheter to the brain, he then injects a virus directly into the tumor, which lights up on scans.
"So, we can actually see in real-time where the virus is as we inject it," Dr. Chen said.
...
To ensure that the adequate amount of Toca 511 is delivered to the region of the tumor, neurosurgeons use state-of-the art MRI guidance, called ClearPoint, to monitor the delivery and injection processes in real time. It provides visual confirmation that the desired amount of drug is delivered into the tumor and provides physicians the ability to make adjustments to optimize the location of drug delivery.
...
The treatment is given as part of a phase one clinical trial. It's considered a minimally-invasive brain procedure, and patients are discharged one day after having it. Because it's a targeted approach, Dr. Chen says there are fewer side effects. In fact, he hasn't observed any unwanted side effects in his patients.
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I have pushed for something like this in the past (drip in VB-111 to the tumor area during surgery) but I like TOCA's approach much better.
Yes, Ariad was quite the ride! Back then, I think some of the investors continued riding on the Denner train and jumped over to ARRY, which is turning out to be a good investment if they had held on until now.
Thanks for the update on the earnings call. I was about to email them as well when I noticed no conf call info was provided on their website.
All the best to you as well!
Welcome, biotech_researcher. As you can see this is (for now) a quiet board. I seem to recognize your username. Were you over in IMGN? ARIA?
Btw, that link didn't work for me but this one does:
https://seekingalpha.com/article/4154397-u-s-biotech-pharma-sector-daily-observations-letter-march-7-2018
Agree, wcopeland. I was thinking about the patients that left the trial early due to AEs (but not know if the AEs were caused by Avastin or VB-111) ... What if they received at least 4 doses? We'll never know.