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Exicure Presents Promising Interim Results from Ongoing Phase 1b/2 Trial of Cavrotolimod at Virtual KOL Event Today
It was revealed that in Merkel cell cancer, the company showed responses in 2 of 5 patients, 40 percent ORR, and one of the 2 responses was a complete response, which was discussed during the presentation.
09/16/2020
Confirmed overall response rate (ORR) of 21% in the dose-escalation stage across all doses, confirmed ORR 33% at the highest and selected Phase 2 dose
Target tumor shrinkage was observed in 37% of patients
Preliminary data show activity in patients with melanoma, Merkel cell carcinoma (MCC), and cutaneous squamous cell carcinoma (CSCC)
Phase 2 arms in both MCC and CSCC are currently recruiting
CHICAGO & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Exicure, Inc. (NASDAQ: XCUR), the pioneer in gene regulatory and immunotherapeutic drugs utilizing proprietary spherical nucleic acid (SNA™) technology, announced that it will host a virtual Key Opinion Leader (KOL) event to present preliminary Phase 1b efficacy and safety data for its intratumoral product candidate, cavrotolimod, the company’s SNA-enabled TLR9 agonist being developed for the treatment of solid tumors, in combination with pembrolizumab. The event will take place today from 10:30 am – 12:00 pm ET.
The principal investigators of the Phase 1b portion of the trial, Dr. Steven O’Day and Dr. Shailender Bhatia, will be presenting and joining Exicure’s leadership team in discussing the clinical data and trial progress to date.
"We are excited by the durable responses we have seen in anti-PD-1 refractory patients, and look forward to further exploring the efficacy of cavrotolimod in these highly treatment refractory Merkel cell carcinoma and cutaneous squamous cell carcinoma patients," said Dr. Douglas Feltner, Chief Medical Officer of Exicure.
The event will be webcast live today, September 16th at 10:30 am ET through a link on the Events and Presentations section of Exicure’s website. An archived webcast will also be available on Exicure’s website following the event. To RSVP for the event, please use the link here
(https://troutaccess.com/investor.php/c/ExicureKOLDay2020) or email rjohn@troutgroup.com.
Description of the Trial
The objectives of the Phase 1b dose-escalation stage of the clinical trial were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cavrotolimod alone and in combination with pembrolizumab, and to identify a recommended Phase 2 dose. Cavrotolimod was dosed weekly for 8 weeks then every three weeks thereafter. Pembrolizumab was added to the treatment regimen starting in week three of the study. The first two weeks of the trial, the period in which only cavrotolimod was dosed, allowed for the assessment of cavrotolimod safety, tolerability, pharmacokinetics and pharmacodynamics alone. Efficacy was assessed every 12 weeks. Twenty patients have been enrolled and dosed in the dose-escalation stage of the trial consisting of: ten (10) melanoma patients, five (5) MCC patients, two (2) CSCC patients, two (2) head and neck squamous cell carcinoma patients, and one (1) leiomyosarcoma patient. At the time of enrollment, 85% of patients were experiencing progressive disease while on anti-PD-1 antibody therapy.
Highlights from the data
Highlights from the data update include:
- Confirmed ORR 21% (4/19 patients) overall in the Phase 1b dose-escalation stage
- Confirmed ORR 33% (2/6 patients) in the highest dose cohort (32 mg), which was selected as Phase 2 recommended dose
- Overall responses occurred in two patients with advanced MCC and two patients with melanoma
- Three of four responders were progressing on anti-PD-1 therapy at the time of enrollment
- In addition to the four confirmed responses, target tumor shrinkage occurred in one CSCC patient and two melanoma patients. Systemic (abscopal) effects were observed, with regression in noninjected tumors distant from injected lesions.
- The cavrotolimod pharmacodynamic profile corroborated the efficacy data, as increased serum cytokines/chemokines, activated immune cells, and tumor infiltration by immune cells were observed.
The median duration of response has not been reached as all four confirmed responders have not progressed after a median follow-up of 11 months. The longest response to date is 16 months from initial dosing and is ongoing as of the data cut-off date.
Exicure continues to observe that cavrotolimod is well tolerated with 98% of all treatment-emergent adverse events (AEs) assessed as Grade 1 or 2 in severity. No treatment-related serious adverse events were reported to date. The most common adverse events were flu-like symptoms and injection site reactions, which are commonly expected effects from a TLR9 mechanism of action.
Updated guidance
Exicure expects to provide interim ORR results from the MCC and CSCC cohorts of the Phase 2 portion of the clinical trial in the first half of 2021 and final ORR results by year end 2021.
About Exicure, Inc.
Exicure, Inc. is a clinical-stage biotechnology company developing therapeutics for neurology, immuno-oncology, inflammatory diseases and other genetic disorders based on our proprietary spherical nucleic acid, or SNA technology. Exicure believes that its proprietary SNA architecture has distinct chemical and biological properties that may provide advantages over other nucleic acid therapeutics and may have therapeutic potential to target diseases not typically addressed with other nucleic acid therapeutics. Exicure is in preclinical development of XCUR-FXN, an SNA–based therapeutic candidate, for the treatment of Friedreich’s ataxia (FA). Exicure's therapeutic candidate cavrotolimod is in a Phase 1b/2 clinical trial in patients with advanced solid tumors. Exicure is based in Chicago, IL and in Cambridge, MA.
For more information, visit Exicure’s website at www.exicuretx.com.
Exicure Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements in this press release other than statements of historical fact could be deemed forward looking including, but not limited to, statements regarding the company’s ongoing Phase 1b/2 clinical trial of cavrotolimod (AST-008) including the design, clinical development, therapeutic potential and clinical results and expectations as to the reporting of data;. The forward-looking statements in this press release speak only as of the date of this press release, and the company undertakes no obligation to update these forward-looking statements. Forward-looking statements are based on management’s current beliefs and assumptions that are subject to risks and uncertainties and are not guarantees of future performance. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including, without limitation: the risks that the ongoing COVID-19 pandemic may disrupt the company’s business and/or the global healthcare system more severely than it has to date or more severely than anticipated, which may have the effect of impacting or delaying the company’s ongoing Phase 1b/2 clinical trial; unexpected costs, charges or expenses that reduce the company’s capital resources; the company’s preclinical or clinical programs do not advance or result in approved products on a timely or cost effective basis or at all; the results of early clinical trials are not always being predictive of future results; the cost, timing and results of clinical trials; that many drug candidates do not become approved drugs on a timely or cost effective basis or at all; the ability to enroll patients in clinical trials; possible safety and efficacy concerns; regulatory developments; and the ability of the company to protect its intellectual property rights. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the company’s actual results to differ from those contained in the forward-looking statements, see the section titled “Risk Factors” in the company’s Annual Report on Form 10-K for the year ended December 31, 2019, as updated by the company’s subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and the company undertakes no duty to update this information, except as required by law.
View source version on businesswire.com: https://www.businesswire.com/news/home/20200916005263/en/
For Media:
Karen Sharma
MacDougall
781-235-3060
ksharma@macbiocom.com
For Investors:
Thomas Hoffmann
Solebury Trout
+1-646-378-2931
thoffmann@troutgroup.com
Recent MDS data and what it means for Onconova?
Rating: OUTPERFORM from Noble Financial
Friday, December 27, 2019
New data in MDS. Onconova presented data at the American Society of Hematology (ASH) annual meeting in December. The data update included genomic profiling from INSPIRE study patients, who suffer from higher risk myelodysplastic syndrome (HR-MDS). We don’t expect any value generating data until topline readout from INSPIRE study in 2020. In this report, we have highlighted recent data readouts in MDS landscape.
What’s new in MDS and what it means for rigosertib. Forty Seven (FTSV, Not covered)’s magrolimab and Abbvie (ABBV, Not covered)’s venetoclax made the most impact in HR-MDS field. Onconova’s rigosertib has shown similar ORR to magrolimab (92%), but superior ORR to venetoclax (90% versus 70%). Magrolimab showed the highest CR rates with 50%, compared to 34% for rigosertib and 32% for venetoclax. Magrolimab’s clinical benefit was shown in a small patient population (12 patients), while venetoclax treatment resulted in concerning levels (61% grade 3/4) of neutropenia in patients. As we remain on watch for data updates on these assets, we continue to believe rigosertib’s competitive advantage in MDS space. In coming years, we expect multiple approvals in MDS landscape with biomarker segmentation.
What changed for Onconova? Nothing much apart from cash position. We think Onconova’s progress have been hindered by not having the capital required to speed up development of its pipeline assets. Following equity offering, the company not only can maintain NASDAQ listing but also gained optionality to develop rigosertib and other assets. We think there is potential upside upon meaningful clinical data. We believe the current share price doesn’t reflect the potential of Onconova’s pipeline. We are reiterating our Outperform rating and $1.30 price target.
Click to view the full report
(full report available on Channelchek desktop)
did there used to be a search for stocks trading below cash?
Take a look at Exicure if you want to look at an undervalued RNA company that can deliver RNA to many organs.
They can also target multiple pathways with a single drug using bi specifics
OncoSec Provides Letter to Shareholders Regarding Recently-Announced $30 Million USD Strategic Investment at a Premium to Market
https://ir.oncosec.com/press-releases/detail/2011/oncosec-provides-letter-to-shareholders-regarding
Download as PDFOctober 21, 2019 9:00am EDT
SAN DIEGO and PENNINGTON, N.J., Oct. 21, 2019 /PRNewswire/ -- OncoSec Medical Incorporated (OncoSec) (NASDAQ: ONCS), a company developing late-stage intratumoral cancer immunotherapies, today released the following Letter to Shareholders from CEO Daniel J. O'Connor regarding the recently-announced strategic transaction with Grand Decade Developments Limited, a direct wholly-owned subsidiary of China Grand Pharmaceutical and Healthcare Holdings Limited (CGP) (HKG:512) and its affiliate, Sirtex Medical US Holdings, Inc. (Sirtex).
OncoSec Medical Incorporated logo (PRNewsfoto/OncoSec Medical Incorporated)
Dear Fellow OncoSec Shareholders,
On Thursday, October 10, 2019, we announced an important strategic transaction with China Grand Pharmaceutical and Healthcare Holdings (CGP) and its U.S. affiliate, Sirtex Medical Holdings, Inc. (Sirtex) that we believe is in the best interest for all OncoSec shareholders1. In summary, upon approval of our shareholders, this transaction would bring a $30 million cash infusion at a premium to our recent price per share and fund both of our ongoing KEYNOTE clinical trials of TAVO in combination with Merck's KEYTRUDA® to completion.
Over the next several weeks, we will be actively communicating with you regarding the shareholder value this strategic transaction creates.
While we believe there are numerous shareholder positives, we wish to begin by calling to your attention several very important benefits of this strategic transaction:
Should CGP seek to offer to acquire the outstanding shares of OncoSec within the 12 months following the closing of the transaction, the offer price for the outstanding shares of OncoSec must be the greater of $4.50 per share or 110% of the last closing stock price of the common stock on the date prior to making such an offer. This is not a right to acquire the outstanding shares of OncoSec for $4.50 or higher, but rather the ability to offer to do so. The OncoSec Board is not obligated to accept any such offer and would evaluate it based on the best interest of OncoSec shareholders at that time. In addition, following the initial transaction, CGP and Sirtex will not have a majority of the Board of Directors and would be entitled to a total of only three of nine seats on the OncoSec Board of Directors as a result of the transaction.
This establishes a very favorable floor, not a ceiling, on a potential acquisition price at a significant premium from our current valuation. For example, should the stock be trading above $4.50 and CGP wishes to offer to acquire the outstanding shares, CGP would be required to offer at least 110% of the stock price at that time (i.e., if the stock is trading at $7.00, CGP would need to offer at least $7.70). Again, the OncoSec Board of Directors is not obligated to accept any such offer and would evaluate it based on the best interests of OncoSec shareholders.
For this transaction to be approved, an affirmative vote from a majority of OncoSec's shareholders is required. Please note, because of the nature of the proposed transaction, your broker cannot vote your shares for you. Therefore, in order for your vote to count, you will need to vote yourself.
To this end, you will receive a Proxy Statement seeking your "YES" vote regarding the strategic investment by CGP and Sirtex. This Proxy will guide you through the voting process and how to vote using the WHITE proxy card that will be included.
We look forward to continuing to communicate to you the advantages we believe this strategic alliance would offer OncoSec and you as its shareholder.
Sincerely,
Daniel O'Connor
President, Director & CEO
OncoSec Medical Incorporated
More details of the agreement can be found in OncoSec's filings with the U.S. Securities and Exchange Commission. This communication is being made in respect of the proposed transaction involving OncoSec Medical Incorporated (the "Company"), Grand Decade Developments Limited, a direct, wholly-owned subsidiary of China Grand Pharmaceutical and Healthcare Holdings Limited, and Sirtex Medical US Holding. In connection with the proposed transaction, the Company intends to file relevant materials with the Securities and Exchange Commission, including a proxy statement. Promptly after filing its definitive proxy statement with the SEC, the Company will mail the definitive proxy statement and a proxy card to each stockholder of the Company entitled to vote at the special meeting relating to the proposed transaction. This communication is not a substitute for the proxy statement or any other document that the Company may file with the SEC or send to its stockholders in connection with the proposed transaction. BEFORE MAKING ANY VOTING DECISION, COMPANY STOCKHOLDERS ARE URGED TO READ THESE MATERIALS (INCLUDING ANY AMENDMENTS OR SUPPLEMENTS THERETO) AND ANY OTHER RELEVANT DOCUMENTS IN CONNECTION WITH THE PROPOSED TRANSACTION THAT THE COMPANY WILL FILE WITH THE SEC WHEN THEY BECOME AVAILABLE BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION ABOUT THE COMPANY AND THE PROPOSED TRANSACTION. The Company's stockholders may obtain free copies of the proxy statement (when it becomes available) and other relevant documents filed with the SEC by the Company at the SEC's web site (http://www.sec.gov). Free copies of the proxy statement, when available, and other filings made by the Company with the SEC also may be obtained from the Investor Relations section of the Company's web site (www.oncosec.com) or by directing a request to the Company, Attn: Investor Relations, 24 North Main Street, Pennington, NJ 08534-2218.
The initial announcement of the strategic transaction can be accessed via OncoSec's website at https://ir.oncosec.com/press-releases/detail/2009/oncosec-announces-30-million-usd-strategic-investment-at-a.
About CGP
CGP is a public company listed on the Hong Kong stock exchange with a market capitalization of approximately $1.8 billion USD. CGP develops, manufactures and distributes pharmaceutical products and medical devices to retailers and medical organisations. CGP currently distributes its products to approximately 6,000 hospitals and approximately 30,000 pharmacies and has a sales team of more than 2,000 employees. CGP also has significant experience in R&D and product commercialisation in China. Such experience dealing with the relevant Chinese regulatory bodies makes CGP an ideal strategic partner for OncoSec as it looks to gain regulatory approval to introduce TAVO™ to the Chinese market. For more information, visit www.chinagrandpharm.com.
About Sirtex
Sirtex Medical is a global healthcare business company with offices in the U.S., Australia, Europe and Asia, working to improve outcomes in people with cancer. The Company's current lead product is a targeted radiation therapy for liver cancer called SIR-Spheres® Y-90 resin microspheres. More than 100,000 doses have been supplied to treat patients with liver cancer at more than 1,000 medical centers in over 40 countries. For more information, visit www.sirtex.com.
About OncoSec Medical Incorporated
OncoSec is a late-stage biotechnology company focused on developing cytokine-based intratumoral immunotherapies to stimulate the body's immune system to target and attack cancer. OncoSec's lead immunotherapy investigational product candidate – TAVO™ (tavokinogene telseplasmid) – enables the intratumoral delivery of DNA-based interleukin-12 (IL-12), a naturally occurring protein with immune-stimulating functions. The technology, which employs electroporation, is designed to produce a controlled, localized expression of IL-12 in the tumor microenvironment, enabling the immune system to target and attack tumors throughout the body. OncoSec has built a deep and diverse clinical pipeline utilizing TAVO as a potential treatment for multiple cancer indications either as a monotherapy or in combination with leading checkpoint inhibitors; with the latter potentially enabling OncoSec to address a great unmet medical need in oncology: anti-PD-1 non-responders. Results from recently completed clinical studies of TAVO have demonstrated a local immune response, and subsequently, a systemic effect as either a monotherapy or combination treatment approach. In addition to TAVO, OncoSec is identifying and developing new DNA-encoded therapeutic candidates and tumor indications for use with its new Visceral Lesion Applicator (VLA), to target deep visceral lesions, such as liver, lung or pancreatic lesions. For more information, please visit www.oncosec.com.
TAVO™ trademark of OncoSec Medical Incorporated.
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
SIR-Spheres® is a registered trademark of Sirtex Medical US Holdings, Inc.
Forward Looking Statements
Some of the statements included in this press release may be forward-looking statements that involve a number of risks and uncertainties. For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. The factors that could cause our actual results to differ materially include: the status, progress and results of our clinical programs; our ability to obtain regulatory approvals for, and the level of market opportunity for our product candidates; our business plans, strategies and objectives, including plans to pursue collaboration, licensing or other similar arrangements or transactions; expectations regarding our liquidity and performance, including expense levels, sources of capital and ability to maintain operations as a going concern; the competitive landscape of our industry; and general market, economic and political conditions; and other risk factors identified from time to time in our reports filed with the Securities and Exchange Commission. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not intend to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof.
Contact:
Gem Hopkins
Head of Corporate Communications
858-210-7334
ghopkins@oncosec.com
1 Details of the transaction can be found in OncoSec's filings with the U.S. Securities and Exchange Commission.
Cision View original content to download multimedia:http://www.prnewswire.com/news-releases/oncosec-provides-letter-to-shareholders-regarding-recently-announced-30-million-usd-strategic-investment-at-a-premium-to-market-300941969.html
SOURCE OncoSec Medical Incorporated
Released October 21, 2019
Email Alerts
exicure
here is the link to the Ladenburg report
https://ladenburg.bluematrix.com/sellside/EmailDocViewer?encrypt=a62dec4f-410e-4c35-b0c3-6c09a45d7a49&mime=pdf&co=Ladenburg&id=AllInvestmentBanking@ladenburg.com&source=mail
Exicure undervalued company in the RNA space
Exicure is the only company that can deliver RNA outside of the liver.
As you review the slide deck from the link below, please pay special attention to slide 25, which shows the valuation of Exicure compared to other companies in the RNA delivery space. So besides the fact that it can deliver RNA to more organs, it is also has a much lower valuation. Some of the companies on the list have no human data. On page 21 of the deck, you can see from the time that Exicure chose TNF alpha as a drug target, they were able to obtain human data in 18 months, for under 4 million dollars. This is unheard of in the pharmaceutical business.
https://exicuretxcom.ipage.com/assets/PDFs/Exicure_Corporate_Presentation.pdf
Below is a link to a press release discussing a pre clinical trial performed by Ohio State. These are the researchers that did the pre-clinical work for IONIS on Nusinersen. For the Ohio State researchers to successfully repeat and validate externally, the results that demonstrate the survival benefit of Ionis’ nusinersen was improved 4 fold, with less toxicity, by using Exicure’s SNA technology, is a profound differentiation from any of the other RNA companies.
http://investors.exicuretx.com/phoenix.zhtml?c=254193&p=irol-newsArticle&ID=2354533
Click on the pdf on the report below and you will see a chart showing the potency of Exicure's technology targeting TLR9, a major target in immune oncology.
<c65f1dab-a49a-48a5-9e55-2307de0dce6e@bluematrix.png> September 20, 2018
EXICURE, INC.
AST-008 TLR9 Agonist Preliminary Data Indicates Superiority vs Linear ODN; Buy
Please click here for full report.
AST-008 Phase 1 data in healthy volunteers showed preliminary but encouraging data indicating superiority over its parent linear oligonucleotide TLR9 agonist CpG 7909 from Pfizer (PFE, $43.26, Not Rated). AST-008 uses the similar oligonucleotide sequence as CpG 7909 but presents in a spherical structure using XCUR's proprietary SNA (spherical nucleic acid) platform. In the FIH data released this morning, AST-008 was tested in a single ascending subcutaneous dose trial comprised of 16 healthy volunteers. AST-008 was shown to be safe and tolerable in all subjects, with no serious adverse events and no dose limiting toxicity. AST-008 was well tolerated and all AST-008-related adverse events were of short duration, reversible and consistent with TLR9 activation.
Importantly, for the 4 subjects receiving the trial’s top dose of ~20 µg/kg of AST-008, AST-008 was shown to elicit 9.5 fold and 3.5 fold increases in the fraction of activated T cells and NK cells, respectively, compared to baseline. There were also an increase of multiple TH1 type cytokines vs baseline: IFN-gamma: 3 fold; IL-12: 2 fold; IL-6: 57 fold; IP-10: 32 fold; and MCP-1: 4 fold. In contrast, its linear parent CpG 7909 didn't show T cell or NK cell activation, and no increase of IFN-gamma and IL-12 at the same Sub-Q dose in 6 healthy volunteers (Exhibit 1). CpG 7909 did also induce IL-6, IP-10 and MCP-1, but at a much lower magnitude of 8 fold, 9 fold and 3 fold, respectively. Similarly, in 13 healthy volunteer Phase 1 data reported for another linear TLR9 agonist Lefitolimod from Mologen (MGN, £ 5.25, Not Rated), no T cell or NK activation was reported and no increase of IFN-gamma, IL-12, IL-6 and MCP-1 was reported (only a 7-fold increase of IP-10 reported) at a much higher dose of 60 mg (923 ug/kg for a 60 kg subject) (Exhibit 1).
We see these preliminary data show a more potent immune activation profile of spherical AST-008 vs its linear parent oligonucleotide CpG 7909 as well as Lefitolimod, providing initial clinical evidence of higher potency of XCUR's SNA drug vs linear oligonucleotide counterparts, with the caveat of cross trial comparison and small pts number. Preclinically, XCUR's SNA version of another marketed linear oligonucleotide drug Nusinersen (Spinraza) also showed superior efficacy in SMA mouse models vs linear Spinraza (up to 35x higher potency and 4-fold increase of survival).
XCUR to start Phase 1b/2 trial of intra-tumorally dosed AST-008 + checkpoint inhibitor combo in 4Q18 with data expected in late 2019.The trial will begin with an AST-008 dose finding Phase 1b stage, followed by a Phase 2 expansion stage. In the Phase 1b phase, XCUR will enroll patients with superficial injectable tumors and will prioritize those with Merkel cell carcinoma, cutaneous squamous cell carcinoma, melanoma, and squamous cell carcinoma of the head and neck. Preliminary data from the Phase 1b stage are expected in late 2019. Maturing TLR9 agonists data of SD-101 from Dynavax (DVAX, $11.95, Not Rated), Tilsotolimod from Idera (IDRA, $8.28, Not Rated) and CMP-001 from Checkmate (Private) are showing promising synergy with anti-PD-1/CTLA4 checkpoint inhibitors by turning cold tumors to hot tumors. AST-008’s potential higher potency and subQ administration option may present competitive differentiation from these current linear TLR9 agonists.
Reiterate Buy rating. We are encouraged by the preliminary AST-008 Phase 1 data showing higher potency of XCUR's SNA drug vs linear oligonucleotide counterparts and providing initial clinical evidence for superiority of SNA platform vs linear oligonucleotide drugs.
Risks
In addition to normal economic and market risk factors that impact most all equities, XCUR is uniquely subject to risks typical for small- to mid-cap biotech companies: The products the company is developing may not work, may prove to be unsafe, may never win approval and may never generate meaningful revenues. Changing medical practices, a changing reimbursement environment and/or products introduced by others could shrink the market for the company’s products. The company may not be able to enforce its own patents or may find itself infringing on patents held by others.
The company has incurred substantial operating losses since inception. This trend may continue and the company may never become profitable. The company has not yet commercialized any of its drug candidates and cannot be sure if it will ever be able to do so. If it is unable to successfully complete clinical trial programs, or if such clinical trials take longer to complete than expected, its ability to execute on its current business strategy will be adversely affected. Pre-clinical testing and clinical development are long, expensive and uncertain processes. If drug candidates do not receive the necessary regulatory approvals, the company will be unable to commercialize its drug candidates. XCUR currently relies on third parties for GMP manufacturing of its products. If these third parties do not successfully manufacture and test the products, the company’s business will be harmed.
For a full review of XCUR specific risk factors investors should refer to the company’s most recent filings with the SEC.
Wangzhi Li, Ph.D.
Managing Director
Equity Research--Biotechnology
Ladenburg Thalmann & Co., Inc.
277 Park Avenue - 26th Floor
New York, NY 10172
Direct: 212.409.2051
wli@ladenburg.com
Ladenburg Thalmann & Co. Inc. reviews and archives outgoing and incoming e-mail. Such may be produced at the request of regulators and/or in connection with judicial/arbitral proceedings. Sender accepts no liability for any errors or omissions arising as a result of transmission. Use by other than intended recipients is prohibited. This transmission is neither an offer nor a solicitation of an offer to buy or sell securities. Opinions or estimates constitute Ladenburg Thalmann & Co. Inc.'s best judgment at this time and are subject to change without notice. Information upon which the material contained in this transmission is based was obtained from sources believed to be reliable but has not been verified. Additional information is available upon request. Ladenburg Thalmann & Co. Inc., its affiliates and respective directors, officers and employees may buy or sell securities mentioned herein as agent or principal. Ladenburg does not give any representation or warranty as to the reliability, accuracy or completeness of any third party material, nor does Ladenburg Thalmann & Co. Inc. accept any responsibility arising in anyway (including negligence) for errors in, or omissions from such third party material. The fact that third party information was provided through Ladenburg does not constitute an endorsement, authorization, sponsorship, or affiliation by Ladenburg Thalmann & Co. Inc., its owners, or its employees.
Sharon Begley
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Say what you will about $NTRP 's #Alzheimers drug, they're about the only company aiming for patients w/moderate-severe AD, who no other company will touch. At #AAIC18, sustained cognitive improvement: http://www.neurotropebioscience.com/wp-content/assets/NTRP%20Presentation%20AAIC%202018.pdf …
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From: Josh Schimmer <Josh.Schimmer@Evercoreisi.com<mailto:Josh.Schimmer@Evercoreisi.com>>
Date: June 18, 2018 at 4:30:21 PM EDT
Subject: Emerging SMA programs
Reply-To: Josh Schimmer <Josh.Schimmer@Evercoreisi.com<mailto:Josh.Schimmer@Evercoreisi.com>>
For our tidbit today, we wanted to highlight emerging therapies in Type 1 spinal muscular atrophy (SMA) given the risdiplam (PTCT/Roche) data this weekend. Risdiplam’s early CHOP intend results at 6 months seems fairly strong and comparable to AVXS-101 and Spinraza (IONS/BIIB), causing the negative IONS/BIIB stock reaction. However, we do caution the sample size is still fairly small (n=11 who have reached 6 mo). The oral delivery of risdiplam is a clear cost and convenience advantage relative to the intrathecal administration of Spinraza. A detailed chart comparing SMA Type 1 trials is highlight at the end.
We also wanted to highlight Exicure’s novel approach to targeting SMA using spherical nucleic acids (SNA). Key advantages of SNA include increased cell uptake, extra-hepatic delivery, and increased half-life. In pre-clinical SMA mice models, SNA has shown 4x increased survival compared to Spinraza (nusinersen) as well as highly increased SMN2 full length mRNA. Data shown below.
Risdiplam (PTCT/Roche) CHOP-INTEND scores
[https://evercore.na.bdvision.ipreo.com/NSightWeb_v2.00/Downloads/Files/31251a48-1949-4a64- a51d-6ab36ffb869e.jpg]
Source: PTCT/Roche Presentation
Spinraza (IONS/BIIB) CHOP-INTEND scores in ENDEAR/SHINE
[https://evercore.na.bdvision.ipreo.com/NSightWeb_v2.00/Downloads/Files/770ac0c9-fa5c-4a63- be39-16bec7c4c562.jpg]
Source: IONS/BIIB Presentation
AVXS-101 CHOP-INTEND scores
[https://evercore.na.bdvision.ipreo.com/NSightWeb_v2.00/Downloads/Files/5b979dbb-7ed8-4a4b- 9ccc-f40ab0772750.jpg]
Source: NVS Poster
Exicure Pre-clinical SMA Program
[https://evercore.na.bdvision.ipreo.com/NSightWeb_v2.00/Downloads/Files/e567edda-6a17-405b- b9d9-57196083c21e.jpg]
[https://evercore.na.bdvision.ipreo.com/NSightWeb_v2.00/Downloads/Files/ebc6da19-f0d2-4109- bf15-a09dd0aad125.jpg]
[https://evercore.na.bdvision.ipreo.com/NSightWeb_v2.00/Downloads/Files/4af7c9f3-7895-4e88- 800a-c61c6756b114.jpg]
Source: Exicure Presentation
Detailed Comparison between Spinraza, AVXS-101, and Risdiplam
[https://evercore.na.bdvision.ipreo.com/NSightWeb_v2.00/Downloads/Files/6b451280-4866-447f- 8908-b5c9e11886e1.png]
Source: Spinraza, AVXS-101, Risdiplam Publications and Presentations
IONS: SMA Competitors Have A Long Way To Go
Ionis Pharmaceuticals, Inc.
Biotechnology
Jim Birchenough, MD, Senior Analyst (415) 947-5470 jim.birchenough@wellsfargo.com
Chuck Whitesell, Associate Analyst (212) 214-5067 chuck.whitesell@wellsfargo.com
Nick Abbott, Associate Analyst (206) 542-2492 nick.abbott@wellsfargo.com
Yanan Zhu, Associate Analyst (415) 396-3194 yanan.zhu@wellsfargo.com
Wells Fargo Securities, LLC.
We are reiterating our OUTPERFORM rating on shares of Ionis Pharmaceuticals (IONS) following review of competitive data in Spinal Muscular Atrophy (SMA) from both an oral splice modulator from PTC Therapeutics (PTCT) and an alternate spherical nucleic acid format of SPINRAZA from Exicure (XCUR). While clinical data from PTCT appear promising we believe that cross trial comparisons are difficult with potential differences in baseline characteristics and see timelines to approval extending several years with some risk to safety data based on experience with other splice modulators.
Pre-clinical data for Exicure (XCUR) is even further removed as a potential commercial challenge to SPINRAZA, in our opinion, as we would want to see clinical safety data before assessing relative therapeutic index differences with SPINRAZA.
PTC Therapeutics (PTCT), a competitor for Ionis Pharmaceuticals (IONS) and partner Biogen (BIIB) in SMA, reported data from the FIREFISH study of its oral SMN2 RNA splicing modulator, risdiplam (RG7916), partnered with Roche, in babies with Type 1 SMA over the weekend at the Cure SMA meeting.
FIREFISH is a two-part pivotal study in infants with SMA. Data reported at the meeting were from Part 1 of the study, which is a dose escalation study (planned enrollment of 21 infants). Part 2 of study is a single-arm open label study currently ongoing, with planned enrollment of 40 infants.
In Part 1 of FIREFISH, the median increases in CHOP-INTEND were 5.5 points (n=20) at day 56, 12.5 points (n=16) at day 119, and 14 points (n=11) at day 182. The proportion of patients achieving greater than 4-point increase from baseline in CHOP-INTEND was 75% at day 56, 94% at day 119, and 91% at day 182. No babies required a tracheostomy or permanent ventilation since study initiation and no baby lost the ability to swallow. The principal investigator of the study also presented video footage demonstrating the ability of study participants to control their head, roll or sit. The median age at first dose was 6.7 months (mostly after 5 months). The oldest patient on trial is currently 23.8 months of age. Risdiplam is described as well tolerated, with no study withdrawal due to AEs.
Recall that in SPINRAZA?s phase 3 ENDEAR study in infants with SMA, 71% of patients in the SPINRAZA group achieved greater than 4 point increase from baseline in CHOP-INTEND vs. 3% in the control group at the end-of-trial visit (6, 10 or 13 months).
Also at the Cure SMA meeting,
Exicure (XCUR) presented preclinical data demonstrating that SPINRAZA in the company?s spherical nucleic acid (SNA) format prolonged survival by 4-fold compared with SPINRAZA in the delta-7 SMA mouse model, and also mitigated toxicity of SPINRAZA at the highest dose tested.
Ionis Pharmaceuticals, Inc. (IONS-NASDAQ) --OUTPERFORM (1)
Price as of 6/18/2018: $43.1
FY 18 EPS: $0.48
FY 19 EPS: $2.61
Shares Out.: 125.3 MM
Market Cap.: $5,441.78 MM
Sector Rating: Biotechnology, Overweight
See attached PDF for additional information, current pricing and disclosures.
Exicure to Present Data at the Cure Spinal Muscular Atrophy Annual Conference in Dallas
Exicure’s three-dimensional spherical nucleic acid containing the nusinersen sequence prolongs survival and reduces toxicity compared to nusinersen in a spinal muscular atrophy mouse model
SKOKIE, Ill. – June 14, 2018 – Exicure, Inc. (OTCQB:XCUR), the pioneer in gene regulatory and immunotherapeutic drugs utilizing three-dimensional, spherical nucleic acid (SNA™) constructs, announced today that Exicure and its collaborators at The Ohio State University Wexner Medical Center will show preclinical data demonstrating the performance of Exicure’s SNA compound designed for use in spinal muscular atrophy (SMA). These data will be presented at the Cure SMA Annual Conference in Dallas, Texas on June 14, 2018.
“Exicure’s spherical nucleic acid version of nusinersen demonstrates increased survival and decreased toxicity in the translationally-relevant SMA mouse model,” said David Giljohann, PhD, CEO of Exicure. “We believe these results are important for developing improved treatments for patients with SMA. These data also suggest that Exicure’s technology platform could potentially create more potent therapies for other disorders of the central nervous system, including Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease.”
At the meeting, Arthur Burghes, PhD, from Ohio State’s Wexner Medical Center, and Exicure will present data from preclinical studies in a SMA mouse model. The poster is titled “Nusinersen in spherical nucleic acid (SNA) format improves efficacy both in vitro in SMA patient fibroblasts and in ?7 SMA mice and reduces toxicity in mice.” The presentation will highlight that Exicure’s proprietary technology:
Prolonged survival by four-fold (maximal survival of 115 days compared to 28 days for nusinersen-treated mice);
Doubled the levels of healthy full-length SMN2 mRNA and protein in SMA patient fibroblasts when compared to nusinersen;
Doubled the quantity of healthy full-length SMN mRNA levels in spinal cord tissue compared to untreated mice;
Mitigated toxicity of nusinersen at the highest dose tested in mice.
In August 2017, Exicure and The Ohio State University established a collaboration to further validate and characterize the pharmacology of Exicure’s nusinersen-SNA compound in mouse models. This collaboration’s ongoing in vivo research is conducted by Dr. Burghes, an internationally known researcher, leading basic and clinical research on SMA and other genetic neuromuscular disorders.
About Exicure, Inc.
Exicure, Inc. is a clinical stage biotechnology company developing a new class of immunomodulatory and gene regulating drugs against validated targets. Exicure's proprietary 3-dimensional, spherical nucleic acid (SNA™) architecture unlocks the potential of therapeutic oligonucleotides in a wide range of cells and tissues. Exicure's lead programs address oncology, inflammatory diseases and genetic disorders. Exicure is based outside of Chicago, IL. For more information, please visit www.exicuretx.com
About Spinal Muscular Atrophy (SMA)
SMA is the most common genetic cause of death for infants. SMA results from the loss of the SMN1 gene and an inability of SMN2 to produce sufficient full-length protein to make up for the loss of SMN1. The SMN1 gene, in a healthy person, produces a full-length protein that is essential to the function of the nerves that control muscles. Without sufficient SMN protein, the nerve cells cannot properly function and eventually die. This leads to debilitating and even fatal muscle weakness.
About Nusinersen
Nusinersen, marketed as Spinraza® by Biogen, is a modified antisense oligonucleotide. In December of 2016, nusinersen was approved by the US FDA for the treatment of SMA in pediatric and adult patients.
Forward Looking Statements
This press release contains forward-looking statements (including within the meaning of Section 21E of the United States Securities Exchange Act of 1934, as amended, and Section 27A of the United States Securities Act of 1933, as amended) concerning the Company, the Company's technology, potential therapies, pre-clinical results, and other matters. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as "may," "will," "should," "would," "expect," "plan," "believe," "intend," "look forward," and other similar expressions among others. Statements that are not historical facts are forward-looking statements. Forward-looking statements are based on current beliefs and assumptions that are subject to risks and uncertainties and are not guarantees of future performance. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including, without limitation: that Exicure's pre-clinical programs do not advance into the clinic or result in approved products on a timely or cost effective basis or at all; regulatory developments; and the ability of Exicure to obtain sufficient funding for its programs and to protect its intellectual property rights. Exicure's pipeline programs are in various stages of pre-clinical and clinical development, and the process by which such pre-clinical or clinical therapeutic candidates could potentially lead to an approved therapeutic is long and subject to significant risks and uncertainties. Risks facing the Company and its programs are set forth in the Company's filings with the SEC. Except as required by applicable law, the Company undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise.
Media Contact
Karen Sharma
ksharma@macbiocom.com
781-235-3060
Yasmeen Rahimi, Ph.D., yrahimi@roth.com
(646) 616-2787
Sales (800) 933-6830, Trading (800) 933-6820
COMPANY NOTE | EQUITY RESEARCH | November 28, 2017
Healthcare: Biotechnology
For full report in pdf, please click here
Ohr Pharmaceutical, Inc. | OHRP - $0.86 - NASDAQ | Buy
Company Update
Stock Data
52-Week Low - High
$0.56 - $2.90
Shares Out. (mil)
56.21
Mkt. Cap.(mil)
$48.3
3-Mo. Avg. Vol.
278,859
12-Mo.Price Target
$7.00
Cash (mil)
$18.1
Tot. Debt (mil)
$0.1
OHRP: Squalamine Remains Strong Wet-AMD Combo Player; Affirm Buy
With the announcement from Regeneron Pharmaceuticals (REGN-NC) yesterday that it will discontinue development of its REGN910 and Eylea combination therapy, we become more confident in the potential of squalamine. Squalamine is an easy to use non-invasive eye drop and has a novel mechanism of action that helps address a subgroup of patients largely ignored by anti-VEGF therapy alone. With that said, we affirm our Buy rating of OHRP.
Another combo trial bites the dust. Yesterday, Regeneron Pharmaceuticals Inc. (REGN-NC) announced its discontinuation of REGN910, an angiopoetin-2 antibody implicated in tumor and vascular endothelial anti-angiogenesis, and Eylea combo therapy for the treatment of diabetic macular edema (DME) and wet AMD. REGN explained it did not exhibit convincing efficacy over Eylea monotherapy in two Phase 2 trials, ONYX and RUBY. ONYX was a 365 wet-AMD subject trial and RUBY was a 304 DME subject trial, both testing for visual acuity baseline change measured by ETDRS score at 12 weeks. While the company did not reveal trial result details, it announced it will present them at an upcoming medical conference.
Squalamine: Non-invasive with novel MOA. Recall that the predominant method to treat wet AMD currently is anti VEGF-A, a monoclonal antibody that inhibits anti-vascular endothelial growth factor (VEGF). In our view, anti-VEGF therapy can carry significant burden because: it requires monthly injections, involving a regulated schedule difficult for both patients and physicians to maintain; it can be financially burdensome; and patients with occult CNV are often resistant to anti-VEGF. In our opinion, squalamine by OHRP, intended as a combination therapy with anti-VEGF injections, addresses these points. It is a simple non-invasive eye drop that can help reduce the number of required doctor visits by increasing treatment efficacy per visit, and it has shown most profound benefits in occult CNV <10mm2 patients. Squalamine has a novel MOA upstream of the VEGF pathway and modulates anti-angiogenic activity intra- and extra-cellularly by calmodulin-binding. Thus, Squalamine plus anti-VEGF presents a two-pronged approach to better address the subgroup of patients largely left out with anti-VEGF therapy alone.
Key binary event is MAKO Phase 3 top-line results in early January. OHRP's Phase 3 MAKO study tests for squalamine and Lucentis combo therapy in 200 wet-AMD subjects. Primary endpoint is BCVA at nine months in classic or occult CNV <10mm2. We believe the results will be positive, due to the strategic identification of the patient subgroup most likely to gain greatest therapeutic advantages, based upon its Phase 2 results.
Ohr Pharmaceutical’s 2018 Binary Event
by Sherli Looi
Aug. 16, 2017 4:33 PM ET
Summary
Ohr's phase 3 clinical trial will have a data readout in early 2018
If the data is positive, the stock price can jump multiple times
If the data is negative, the stock gets crushed
We are taking a look at the probabilities of these binary events
Ohr Pharmaceutical (OHRP) is a clinical stage company with a lead drug, Squalamine Lactate Ophthalmic solution, which is currently in a Phase 3 trial called “MAKO”. Ohr’s Squalamine is used as a combination therapy to the FDA approved Lucentis to treat patients with wet age-related macular degeneration (wet AMD).
OHR’s Squalamine drug may be a potential winner. Here are the reasons why:
A clinical need still exists.
Phase 3 trial has been substantially derisked by Phase 2 data
As a topical application, Ohr’s Squalamine has a great advantage against the current delivery system of intravitreal injections.
The market size will be substantial since the 2016 global sales from current FDA approved drugs is already at $8 billion.
With $18 million cash, and a burn rate of $4 million per quarter, Ohr has enough cash to its data read out in early 2018.
Wet AMD is the #1 cause of blindness in Americans over the age of 65. It occurs when there is abnormal growth of blood vessels in the choroid layer, under the macula, and these vessels have started to leak or bleed, eventually robbing the victim of sight.
Avastin, Eylea and Lucentis are currently the standard of care for wet AMD. These drugs are delivered via intravitreal injections. Although they are relatively “effective”, only about 25% of wet AMD patients gain at least 3 lines (15 letters) of visual acuity at nine months, a clinically meaningful endpoint for patients and for regulatory purposes. In addition, only 40% of patients achieve 20/40 vision outcomes, a key level of visual function indicating the ability to perform daily tasks and an improved quality of life. Hence, there is still a clinical need to develop more optimal treatments.
The most significant difference amongst these three drugs is cost. Lucentis and Eylea cost $2000 and $1850 per injection. Avastin costs only $50. Lucentis, Avastin and Eylea are injected at approximately 4 to 8 weeks intervals. Avastin is used off label as it was never FDA approved for wet AMD. Instead, it was approved for various cancers, but given its price and efficacy, it is the drug of choice for the insurers and Medicare. As a topical solution, Ohr’s Squalamine solution would offer ease of use for patients, increasing compliance and hopefully, improving visual outcomes.
Furthermore, retinal specialists have no drugs to delay the onset of this condition to a patient’s remaining good eye. For sufferers of wet AMD, the probability that their remaining good eye getting the condition is at 10-20% with each passing year. Given this situation, it is highly likely that the drug will be prescribed for “prevention” purposes as well, thereby increasing Ohr’s potential market size, if FDA approved. Also, since Lucentis and Eylea together generated a total of $8 billion in global sales in 2016, the sales outlook for Ohr’s Squalamine looks bright.
Stock Price
The stock is currently at $0.60, far from its highs of $17.85 in March 2014.
Investors crushed the stock on several major occasions, with good reasons.
March 27, 2015
The data from Ohr’s phase 2 trial, IMPACT was released. Ohr reported that “The mean number of injections between the treatment arms, the primary endpoint of the study, was not meaningfully different”. The stock had traded at $12 on March 6, 2015. It plunged to close at $2.54 on this news.
The positive aspects of IMPACT, which showed that the drug was safe and that there were significant improvements in visual acuity in the combination therapy, were completely ignored.
The point is that the company should not have stated its primary endpoint as a reduction in injections. Phase 2 trials are meant to evaluate safety and dosage specifications. And the point is Squalamine did improve visual acuity significantly. Oh well.
December 12, 2016
In May 2014, Ophthotech Corporation (OPHT) received an upfront fee of $330 million from Novartis Pharmaceutical for the commercial and licensing rights to Fovista in all non-US markets. Fovista was then in a Phase 3 trial, with primary endpoints of visual acuity improvements in wet AMD patients, when used as a combination therapy with Lucentis. The deal, if Fovista was successful, could be as much as US$1billion, excluding royalties.
However, on December 12, 2016, it was announced that Fovista had failed in its phase 3 clinical trial. It did not add any discernible improvement in visual acuity over the monotherapy drug, Lucentis. The stock of Ophthotech, which had reached a high of $80 in 2015, closed that day at $5.95
Unfortunately for OHRP, the failure of Fovista cast huge doubts over the benefits of combination therapies, and eliminated any chances of sponsorship or partnership from the big pharmaceutical companies.
Additionally, some media reporters, analysts and investors thought that both Ophthotech and Ohr were attacking the same cells to generate improvement. They were misinformed. Ophthotech/Fovista sought improvement using anti-PDGF which works on the pericyte cells. Ohr/Squalamine sought benefits using multiple angiogenic targets, including anti-VEGF which works directly on the endothelial cells. But, the damage was done.
April 10, 2017
Ohr announced that they would stop enrolling patients for its phase 3, MAKO trial. The investing world interpreted this as a bad omen. The press release which states that this was a “strategic decision”, did not dispel this feeling of gloom and the stock, OHRP, continues to languish in the $0.56 – $0.74 zone.
And of course, there had been several rounds of secondary offerings. We all know the plight of early investors.
Is OHRP buyable now?
Ohr is heading towards a binary event in early 2018.
The phase 3 trial, MAKO, will have its data released.
The WIN EVENT is defined as MAKO's data being as good as phase 2 IMPACT's positive results, as in table 1 below.
If that happens, then the stock price of OHRP can jump from $0.60 to $5.87. The $5.87 number is estimated from the $330 million upfront payment received by Ophthotech from Novartis AG for the marketing license of its Fovista drug, if FDA approved, to all non-US markets. If MAKO delivers positive data, then cash rich pharmaceutical companies would similarly want to partner with Ohr. At $0.60 per share, Ohr’s market capitalization is only $33.7 million. If the market cap is $330 million, it implies a stock price of $5.87.
The LOSE EVENT is when MAKO's data shows that the combination therapy does not meaningfully improve the visual acuity when compared to the Lucentis only therapy. The stock would most likely be crushed to zero.
What is the probability associated with these win/lose events?
According to a 2006-2015 study done on 9,985 clinical trials of varying phases, a phase 3 trial in Ophthalmology has a 58% probability of success. This is not to imply that Ohr will enjoy this probability. However, it is important to note that Ohr’s management has derisked its phase 3 trial by using data from its phase 2 by selecting a patient population with higher responses to Ohr’s Squalamine, as explained below.
The phase 2 trial, IMPACT, had already proved that Ohr’s Squalamine in combination with Lucentis delivered superior results in patients with occult CNV sizes of less than 10 mm², please see table 1 below:
Table 1. IMPACT Results
Ohr’s Phase 2, IMPACT Data for Patients with occult CNV sizes < 10mm²
Improvement combo lucentis alone diff
Change in Visual Acuity 11 letters 5.7 letters 5.3 letters = 92%
Proportion of Patients with
visual gains of at least 3 lines 40% 26% 54%
Better Final Visual Outcomes
at week 36 72 letters 67 letters
Note: 72 letters of vision is equivalent to 20/40 = Driving Vision
Thus, the MAKO trial enrolled only patients with occult CNV sizes of less than 10 mm² with the hope that MAKO can deliver IMPACT’s positive data.
Also, the fact that Dr. Jason Slakter, a successful retina specialist, academic and consultant, took over the stewardship of Ohr as its CEO, and according to FactSet, is its second largest shareholder, does reduce some of the anxiety over the MAKO trial results.
Given the above considerations, let us guess that the probability of winning to losing is 50/50. This means the expected return to a speculator buying OHRP at $0.60 is $2.94, resulting a ROI of 390%in 6 to 8 months' time frame.
Conclusion
Investing strategies based on clinical outcomes are risky propositions. Fovista has clearly illustrated this risk. It delivered promising phase 2 data but failed to meet its primary endpoint in phase 3. The same can happen to Ohr’s Squalamine, even though its management has tried to derisked the outcome somewhat.
Therein lies the risk. Buying the stock can generate absolute loss. Or, MAKO provides meaningful positive data and the stock could be a multi-bagger. This idea is best perceived as spending the $0.60 per share as a premium to a call option. One can sleep soundly, having delineated the risk dollars. And one may wake up to a good return in about 6 months’ time.
Disclosure: I am/we are long OHRP.
Arcturus,
Looking at their new items there was a story about them in 2015 with the story that they expected to have a drug in clinical trials in 2016. On the merger webcast they are saying they will not be in humans for another 18 months to 2 years.
If they have been so far off before why should I believe the new estimate.
Wet AMD call Ohrp featured prominently
Sam Slutsky, Research Analyst, LifeSci Capital
Dr. Peter Kaiser, Chaney Family Endowed Chair for Ophthalmology and Professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine
Dr. David Brown, Ophthalmologist and Ophthalmic Surgeon, Retina Consultants of Houston
P R E S E N T A T I O N
Operator:
Good day and welcome to the LifeSci Capital KOL Series on the topic of wet AMD conference call. Today’s conference is being recorded. At this time I would like to turn the conference over to Mr. Sam Slutsky. Please go ahead, sir.
Sam Slutsky:
Thank you. Good morning everyone and thank you for dialing in. I’m Sam Slutsky, one of the research analysts at LifeSci Capital. On today’s call we’ll be discussing the current treatment landscape for wet AMD, how it may change with the recent data from Novartis’s RTH258, and promising drugs in development for the disease.
We’re lucky to have with us today two distinguished experts in the field. They are Dr. Peter Kaiser and Dr. David Brown. Dr. Kaiser is the Chaney Family Endowed Chair for Ophthalmology Research and a Professor of Ophthalmology at the Cleveland Clinic Lerner College in Medicine. Dr. Brown is a practicing ophthalmologist and ophthalmic surgeon at Retina Consultants of Houston. He’s a thought leader in this space and is extensively published on the topic of Wet AMD.
After the discussion, there will be an opportunity for live Q&A, but questions may also be submitted any time during the call to questions@lifescicapital.com.
So, thank you Dr. Kaiser and Dr. Brown for joining us. To start the call I would like to ask both of you to give our audience some background on yourselves, your practices and your research interest, and then after that we can dive into some deeper questions. We’ll start off with you, Dr. Kaiser.
Dr. Peter Kaiser:
Good morning everyone. I’m a vitreoretinal specialist. I practice at the Cole Eye Institute at the Cleveland Clinic. I’ve been very involved with clinical trial research for many years, having been one of the lead investigators on the Lucentis studies, the Eylea studies and some of the studies that are in current clinical trials, so I look forward to speaking with you.
Sam Slutsky:
Great, and you, Dr. Brown?
Dr. David Brown:
I’m David Brown. We’ve got a 12 retina surgeon group in Houston, Texas. That’s the largest on the Gulf Coast. We also have the largest clinical research center in the United States and we’re part of most of the major trials, if not all, and we take care of a lot of macular degeneration and give a lot of injections every day, so we’d love to have something that helps our patients.
Sam Slutsky:
Great. We’ll start off the call by discussing the current treatment landscape for wet AMD. Dr. Brown, can you give us an overview of how you are currently using the three main VEGF inhibitors, Avastin, Lucentis and Eylea for wet AMD, and if there are any changing trends that you’ve noticed?
Dr. David Brown:
Basically we’ve got three good options; they’re not equal but they’re good options. Avastin tends to be the drug of choice for all the Medicare Advantage plans, all the managed care plans. More and more, they’re pushing us or incentivizing us into giving Avastin, if not first line, exclusively. That being said, our main treatment paradigm is to treat until dry and then treat and extend, and so the best drying agent appears to be Eylea, and so patients that have persistent fluid on either Lucentis or Avastin get switched to Eylea. Typically they’re extended until the point where they have a fixed dosing regimen.
To be honest, we’re about a third of each drug. We would not use much Avastin if it wasn’t for the insurance incentives or pressures, but it’d be nice to have something that had better duration or better drying agents.
Sam Slutsky:
Got it. Are there any specific patient types that you prefer one of the VEGF inhibitors for over the others?
Dr. David Brown:
Not necessarily. I mean, it’s sort of an equal opportunity. You know, the drugs are all pretty darned good, which is amazing. Patients with large PEDs, pigment epithelial detachments, patients who for whatever reason can’t last as long on an anti-VEGF inhibitor, certainly we go with the longer agent or the more drying agent, which is typically Eylea.
Sam Slutsky:
Got it. Dr. Kaiser, is your experience consistent with that of Dr. Brown?
Dr. Peter Kaiser:
Yes, I agree. I think in macular degeneration there hasn’t been a study that shows a huge difference in efficacy between these drugs. They’ve all behaved (inaudible) very similarly, the difference being in longevity, and as David mentioned drying ability, but at the end of the day in all the studies, the visual results were all pretty similar. That’s not the same in all diseases but certainly in macular degeneration it is.
As such, we also start most patients, if not all patients on Avastin. Remember, my boss is Dan Martin who ran the C.A.T. study, and so we have a reason that we’re told everyday why we should use Avastin first, and I think it’s very reasonable because if we can find the patients who do well on Avastin, we’re certainly saving the healthcare system quite a bit of money. But, if they don’t—if they fail Avastin or if we’re trying to extend them for a period of time longer than we can go usually with Avastin, then I agree with Dave that many of our patients are switched to Eylea.
Sam Slutsky:
Okay, great. Thanks for that overview. Now, I wanted to turn to the recent data of RTH258. Novartis recently reported positive data from its Phase 3 studies using RTH258. This is a VEGF inhibitor for neovascular AMD. The study achieved the primary endpoint of non-inferiority compared to Eylea, however a little more than half the patients maintained dosing every 12 weeks which compares favorably to Eylea’s 8-week dosing regimen and Lucentis’s 4-week regimen.
Dr. Kaiser, I first wanted to get your impression of the data they presented so far.
Dr. Peter Kaiser:
So, on the face of it, it certainly looks exciting. Eylea is what we consider the gold standard drug in macular degeneration. It’s certainly in terms of efficacy being equal to Lucentis but having a longer duration. Now we have another drug in brolucizumab which is the generic name for RTH. In brolucizumab’s case, about half the patients were able to extend the interval to 12 weeks.
Now, what’s going to be important, because this is based on study design, is sort of how those patients did between the 12-weekers and the 8-weekers because the way the study was designed, once you switched from 12 weeks to 8 weeks, you couldn’t go back. Even if you were doing well at 8 weeks, it wasn’t like you were going back and forth and it wasn’t an average either. So, that means that there were patients who were dry after a certain number of injections and were able to then be put into the 12-week group and remain in that 12-week group doing very, very well. That means about half the patients were doing really, really well, and that doesn’t mean the other half weren’t doing well, it’s just the press release doesn’t really tell us how that other group, the more aggressive lesions required a little more aggressive treatment, how they did and if they were similar to the Eylea group, better or worse. So, there’s certainly a lot of data that we still need to see come out of the study. The top line results are encouraging but not the end-all.
Sam Slutsky:
Okay. In terms of the additional data that could be presented at an upcoming conference, which data points were you most focused on?
Dr. Peter Kaiser:
Myself? I really would like to know first of all if the 12-week data did better than Eylea and the 8-week data did worse, and so on average they did the same. That would be a very interesting finding. Alternatively, you know, whenever we have an average visual acuity difference, you want to know how many are winners and how many are losers, so what’s the range of the visual distribution? In other words, are you more likely to have a winner but just as likely have a loser with brolucizumab? With Eylea (inaudible) we know what it looks like, so is brolucizumab different?
Finally, I’d want to know if there were particular subsets of lesions that the patients will do better with one drug versus the other. Safety is going to be a big area that we’re all going to be looking at, and finally, we know that Eylea is the best drying agent so far. How exactly did brolucizumab match up in terms of its drying capability? Was it similar, better or worse?
Sam Slutsky:
Got it. Thanks for that. Dr. Brown, are there any additional data points that you’d like to see?
Dr. David Brown:
Yes, I think to us, I think in a treatment naïve population like we said, even Avastin, the weakest horse in this race does pretty good. In a treatment naïve population, I think you really—like Peter alluded to, the last comment, I think it’s really drying ability. I mean, if you’re drying out a higher percentage of Eylea, I think that is in the hearts and minds of retina surgeons, will think it’s a better drug.
Because the Eylea arm didn’t have a chance to extend to 12 weeks, it’s a little hard to make that comparison that says, “Hey, 52% or 53% can go to 12 weeks with brolucizumab.” They didn’t test and see how many of those Eylea patients could have done that, so to me it’s mainly drying ability.
In the clinic, once we get it in the clinic, it’s really these recalcitrant patients that don’t dry out on monthly Eylea, do they dry out on brolucizumab and can they be extended longer?
So, it’s drying ability to me until it gets in the clinic, and then it’s tough because we put new drugs against our toughest cases, and if this drug can really outperform, it’ll have a definite place in the market.
Sam Slutsky:
Okay. Dr. Brown, how do you …
Dr. Peter Kaiser:
I just wanted to add something to what Dave said, which is very, very important. The study being a non-inferiority study, the Eylea patients had to be dosed on label, which in this case was every other month, but recall that in the VIEW study second year, the patients were dosed with a capped prn dosing scheme and almost half the patients in the Eylea group were actually able to get out to three-month intervals. So, had the study been done differently, the results may have been different also.
This is also a criticism of VIEW where had the second year been done differently, maybe Lucentis would have been able to go longer than a month also.
Sam Slutsky:
Interesting. Thanks for that. Dr. Brown, how do you anticipate RTH258 will be used, assuming there’s nothing negatively surprising in the data when they present full data?
Dr. David Brown:
You know, a lot of it depends on the finances and how good the data is. Eylea, Regeneron has not been able to convince the Aetnas and the Blue Crosses of the world that they’re better, and so it’s not like they tier them and say, “You should use Eylea over Lucentis because we’re a better drying agent.” If the data is strong enough and they can convince payers and retina physicians that it’s better than Eylea, I think it will be the go-to drug after Avastin in those insurances, and potentially first line because why not—in our practice we have a lot of patients with really good insurance who have done well for themselves and they don’t want to start with generic corn flakes; they want to start with the branded drug. The question is how does it compare against what’s currently deemed to be the best drug, which is Eylea. If they win that in the hearts and minds of retina surgeons and even better in the hearts and minds of insurance providers, I think it’ll be used as either first line or as your go-to drug, as your clean-up batter.
Part of it’s going to be how they price it. If they come out and price this thing at double the price of Eylea, I think they’re going to have a much harder time convincing those insurance companies that they’re the go-to drug. If they price it comparatively better or perhaps even a discount, they might win more of that market. It’s different than every other field of medicine because nothing else has a 50 buck drug or a 75 buck drug that’s pretty good. So, the economics and the rationale of how you price the drug is very challenging when you have Avastin as your—lurking in the horse race.
Sam Slutsky:
Got it. In terms of first line use, too, you touched on this briefly but it seems like RTH258 won’t be launched possibly until 2019. So, in terms of the emergence of Avastin biosimilars, how do you think that will play in in terms of uptake?
Dr. David Brown:
I think it really depends on how those biosimilars are priced. If you look biosimilars, other biosimilars are typically priced 20%, 30% less than the branded drug. I don’t think that’s going to play well in this market. When you have 75 buck alternatives, I think they’re going to have to have a 50% discount or more to really chip away at the branded drug.
If the biosimilars come out at $1000 and really takes over a large part of the market, I think insurers may start to do more tiers where they say, “You got to use Avastin, and if not you use biosimilar this or that,” and then the third line would be that drug, and that’s certainly where RTH doesn’t want to be. You don’t want to be the third line drug in a drug tier.
Dr. Peter Kaiser:
I agree with Dave. This is one of those things where the price of the drug (inaudible).
Sam Slutsky:
Dr. Kaiser, we’re losing you. You’re breaking up a little. Are you there? All right, we’ll come back. Oh yes, yes. Now it’s good.
Dr. Peter Kaiser:
Sorry about that. I said the price is really going to play a large role, and I agree fully with what David said that these companies are not going to be able to (inaudible) this drug (inaudible). Can you hear me now?
Sam Slutsky:
Yes, yes, yes.
Dr. Peter Kaiser:
So, I’m saying that the $50 drug that we have really limits the biosimilar’s ability to (inaudible) have a high number. The biosimilars that are out there aren’t Avastin, they’re Lucentis. (Inaudible) Avastin biosimilar too.
Sam Slutsky:
You’re still breaking up a little bit but we’ll jump to the next question and come back. I wanted to now turn to other drugs in development and discuss programs targeting Ang2 calmodulin and VEGF. So, we know that there’s a lot of interest in Ang2 inhibitors such as Roche’s RG7716 and Regeneron’s nesvacumab which is in Phase 2 development. So, Dr. Brown, what do you see as the value of Ang2 inhibition and what are your expectations for this drug classes’ effect.
Dr. David Brown:
Ang2 is very interesting. It’s particularly interesting in the vascular diseases, retinal vein occlusion in diabetes because it looks to be a lot of Ang2 there and blocking of totally separate targets.
Wow, I’m getting a lot of feedback.
Blocking a totally separate target you hope would get better efficacy. In the early Phase 1s and 2s, it looked like we saw a duration effect. That’s what excited everybody. You’re going to have your data at the end of the year. If you really get a duration effect and hopefully can convince the FDA a way to prove on duration effect, that’d be great. Currently, the agency has only said they would approve a add-on drug if it improved visual acuity. For macular degeneration, we may be close to the top of where we can get with just an add-on drug with the one-time shot. Certainly if we get a sustained release device or a drug like Ohr’s that may potentially give you a steady state anti-VEGF by taking a pill every day or a drop every day, you may get more efficacy, but the devil’s in the—I guess we’re all waiting for the results and we should have that by the end of the year. We’re constantly optimistic.
Dr. Peter Kaiser:
(Inaudible).
Sam Slutsky:
You see its potential use though in some of the other neovascular indications such as DME and things like that moreso than AMD?
Dr. David Brown:
I think from a target perspective, yes. If you just look at the science, it makes more sense to me that those diseases have more Ang2 in the disease pathophysiology. That being said, we really didn’t think there was a whole lot of VEGF in macular degeneration and look how good it does with a VEGF blocker. So, there’s a distinct possibility that it could really help in macular degeneration, and we’ll see. We’ve got two major companies with two good drugs and we should have the data from both by the end of the year.
Sam Slutsky:
Okay, great. Dr. Kaiser, do you have anything to add to what Dr. Brown said?
Dr. Peter Kaiser:
Yes. Ang2 inhibition is something we’re all pretty excited about. We know that the tide 2 pathway which Ang2 works on is very involved in all these diseases, but I agree with David that it’s moreso in the retinal vascular diseases than macular degeneration. While it is involved in macular degeneration, we do expect the difference to be greater in diabetes.
The other interesting thing for me is the regulatory path that these two drugs are going to have to take are very different because the Regeneron product, which is used in combination with Eylea, has to show superiority in its Phase 3, if it gets there, whereas the Roche product being a biospecific molecule is actually a new drug. It’s not Lucentis-plus so its regulatory path is through a non-inferiority study, so that’ll definitely change the clinical trial design between the two drugs. It’ll be interesting.
Sam Slutsky:
Wow. Interesting. Thanks for that. Dr. Brown, you had touched on Ohr so we can discuss them right now. So, you’re both familiar with Ohr Pharmaceutical’s program of Squalamine, which his an antiangiogenic agent delivered as an eyedrop, inhibits a VEGF, PDGF and basic FGF through the inhibition of calmodulin, and its Phase 2 trial results from a prespecified analysis of patients within the (inaudible) CNB area of less than 10 millimeters squared, had particularly encouraging activity compared to Lucentis. The use of Squalamine led to a 5.3 letter improvement over Lucentis and mean change in visual acuity. The p value here is 0.03. Also that 40% of patients gained three or more lines of visual acuity versus around 25% for control, and based on the data and learnings of the drug’s mechanism of action or is enrolling the described patient population in its current large ongoing study.
So, Dr. Kaiser, can you discuss your impression on the company’s Phase 2 data and your thoughts on the rationale behind using the described enrollment criteria for the ongoing study?
Dr. Peter Kaiser:
Sure. I think one of the issues for Ohr was that many people, particularly people on Wall Street, bunched Ohr together with Fovista and other PDGF inhibitors because it does inhibit PDGF as one of its mechanisms of action, but what everybody—what all those people failed to realize is that as the molecule Squalamine doesn’t have any effect whatsoever on parasites. It’s effect is 100% on activated endothelial cells which is where the problem really lies, and so the Fovista drug and Regeneron’s PDGF inhibitor, both of which failed, were working an entirely different cell type, basically, than on parasites. That’s number one.
Number two, not only does it decrease these growth factors, it also specifically acts on these new endothelial cells. It changes the actin and filament within the cells which changes the structure of these new vessels, causing the vessels to block off, and that’s exactly what we want.
So, when you look at the Phase 2 data, unfortunately in the past everybody hoofed that horse, using Dave’s analogy, up to the buggy of all PDGF inhibitors and it was bunched together with them. Now, interestingly enough, the results of the study was actually very similar, however the similarity was not because it was working on PDGF; the similarity was that the combination of Squalamine as an eye drop together with Lucentis appeared to be working very well in Phase 2.
What I like about what Ohr did in Phase 3, unlike what Fovista did in its Phase 3 is that it basically Ohr took the patients who did well in Phase 2 and designed their Phase 3 clinical program on that, whereas Fovista and Ophthotech basically took their Phase 2 data where they did well and they changed it to include patients where their drug wouldn’t do well. So, one of the reasons why I think Fovista actually failed is they basically changed the study design between Phase 2 and Phase 3, which is a clinical trial no-no, and what Ohr did was the way that anybody who designs clinical trials would want to do which is take the learnings from Phase 2 and use that to design a rational Phase 3 that has an even higher chance of success than the Phase 2.
Sam Slutsky:
Got it. Thanks for that overview. Dr. Brown, wanted to get your view on the data and rationale for the patient enrollment in the current study.
Dr. David Brown:
First of all, on selecting patients that did better, I think it’s always good to enrich your effect. Certainly we do that in every clinical trial where we try to give a dose, you know, the month before the endpoint. It sounds like you wouldn’t want to restrict your label, but in today’s times where every optometrist has an OCT, most of the lesions we are catching are small lesions and most lesions are occult, and so this is the largest percentage of the lesions we get in the clinic these days.
I’m more excited about a continuous, ongoing anti-VEGF suppression. We basically give now pulsatile treatment where you give a big dose and most of the PK curves are linear, so when patients re-leak it’s typically when we think they get below a level of VEGF inhibition that would decrease leakage. If you could have ongoing VEGF suppression with something like an eyedrop, I think patients would love it. They’d definitely take their eyedrop and extend longer, and potentially get where they don’t have to have injections. I think that’s the most exciting part of this is a continuous anti-VEGF suppression along with some of the other cytokines that are blocked that we know from the Squalamine preclinical data.
Sam Slutsky:
Great. Thanks for that. Dr. Kaiser, in terms of the efficacy data for the control arm in Ohr’s study with Lucentis, do you think it was an accurate representation of what you would see in the real world?
Dr. Peter Kaiser:
Yes, it was. Obviously comparing across trials is an effort that you—fraught with error, however if you kind of look at the average of clinical studies where patients were enrolled all-comers, for instance the C.A.T. study or the IVAN study, the control group of Lucentis in the study performed almost identically to C.A.T., so it wasn’t that the control group was doing poorer and the combo group was doing normal. No, the monotherapy group was doing normal and the combo group was doing definitively better.
Sam Slutsky:
Okay, great. This question is for both doctors, but based on your extensive experience with clinical trials in the past and with Squalamine, what probability of success would you give this program in the current wet AMD trial? Dr. Brown, we can start with you.
Dr. David Brown:
I think that because of the continuous steady state suppression in multiple cytokines, I am on record as saying I thought the Fovista trial had a 10% chance of success and I think this one is much closer to 50/50.
It’s a well designed trial. They’ve got quite a bit of numbers. It seems like we’ve got quite a few patients in this trial and they’re not complaining that the eyedrop stings and it looks like their compliance is good. So, I’m optimistic that we got a horse race here. I hope we get visual acuity benefits. I think, to be honest, we may be close to the top of the curve, and so it may be that this is a drug that it does give you more duration or longer time between injections. We won’t see that in this first trial but hopefully there’s enough of a signal that they can go to a Phase 3. We’re in the second year. They’ve got where they stretch out the injections and you see duration. If we get visual acuity, that’s great, and I think that chance is about 50/50.
Sam Slutsky:
Great. Thanks for that. Dr. Kaiser, your thoughts?
Dr. Peter Kaiser:
Yes, I agree with Dave. I think when we look at some of the other combination studies, our probability of success that we were giving out was pretty low. Most companies will be pretty happy with 50/50; in fact, they would greenlight anything above probably about 30%.
I thinking maybe it’s a little higher. I’m going to go out on record and say 60% chance of success because I really think what the company has done in terms of honing in on the patients who did well in Phase 2 is going to bode well. They’ve eliminated the patients who may not do as well with the combination therapy from the enrollment, and to me this usually means that the success rate goes up from Phase 2.
So, you know, I’m pretty optimistic about this one. If it works, there’s a lot of other areas that an eyedrop can be used because remember now, the bar for a combo drop from a patient/physician standpoint—not from the FDA standpoint but from a patient/physician standpoint to add a drop is incredibly low versus another injection. The FDA, when you say combo to them, it doesn’t matter if it’s a drop or another injection, the bar is the same, but from a patient and a physician standpoint it’s a huge difference. An eyedrop, I don’t have to deliver it myself. I can write a prescription, the patient goes and gets it. The patient doesn’t mind taking an eyedrop, whereas if it’s another injection, here’s a whole nother worry about reimbursement, what’s going to happen with insurance companies’ coverage of that other injection. So, to me there’s a lot of reasons why I’m actually very bullish on this product and I’m optimistic to see the results in the future.
Dr. David Brown:
Yes, a lot of physicians that currently use Avastin, use Avastin because they’re worried about the financial implications, and what I mean by that is in a buy and bill scenario, when you give a $2,000 drug that you have to purchase from a drug distributor, you got to pay for that drug in 60 days. If your insurance company stiffs you once, and the margin’s 3%, 4% at the most, you got to do another 200 injections to make up for that one lost drug.
For this, physicians don’t have any financial risk by adding on the eyedrop with the prescription because it’s not a Part B drug.
Sam Slutsky:
Interesting. That’s going to be helpful for understanding the reimbursement landscape. Okay.
So, Dr. Brown, Dr. Kaiser had mentioned this briefly, but when thinking of some of the recent wet AMD failure’s such Ophthotech’s, Fovista, which had positive Phase 2 results, what do you think are the main contributors to the Phase 3 failing?
Dr. David Brown:
I think it’s the target. I mean, you had a very good study from Regeneron with potentially a better PDGF blocker that totally busted as well; the monotherapy did better than the combination therapy. If you look at Fovista’s Phase 2 data on lesion regression, which was the first thought, you strip the parasites, you get the anti-VEGF in there and it regresses more. If you go to the SEC (phon) filing, you see that monotherapy Lucentis caused more lesion regression than did combination therapy. So, if you’re premise is wrong, and I think it was tested well in both studies, both the Regeneron and the Fovista, and you put it up there and it loses, it loses.
Ang2 we hope has more of a potential of the combination, and again, anything that gives a steady state suppression like the sustained release device, like a gene therapy, if you can get enough product development, like an eyedrop from Ohr, I think that has the best chance of winning versus our paradigm of single injection high dose and then steady state linear decrease in PK.
Sam Slutsky:
Got it. Okay, thanks. Dr. Kaiser, in terms of combination approaches for wet AMD, do you think add-on therapies will be a one size fits all kind of like anti-VEGF, or do you think patient selection will be a key to truly recognizing the benefits of add-ons?
Dr. Peter Kaiser:
I think like everything, patient selection is going to be important. Certainly, for instance, with the Ohr product, very large occult lesions, probably not a good idea to be using the product unless we hear something differently. So yes, we are going to be using different add-ons for different reasons. The only other add-on that we probably will have is Ang2 in the near future—I should say anti-Ang2 in the form of Regeneron’s product which would be an add-on, but in that study we don’t know yet are there certain lesions that it works better on or is it a work on all comers? We don’t know yet.
Sam Slutsky:
Okay. In terms of the clinical pipeline, a bunch of companies are going after combination approaches on top of a VEGF inhibitor. So, Dr. Kaiser, in add-on works with one VEGF inhibitor in its study, do you think that can be extrapolated to use on top of the other anti-VEGF inhibitors as well?
Dr. Peter Kaiser:
As long as the mechanism of action is distinct, the answer should be yes. So, any add-on should work with any anti-VEGF agent, whether it be say a gene therapy anti-VEGF or a sustained release in the form of say an implant like the LADDER study from Genentech. It wouldn’t matter how the anti-VEGF is performed.
Now, if that add-on is another injection then the patient acceptance of it may be lower. If it’s an eyedrop like Squalamine, for instance, then that’s no big deal to add that on, and so it will be probably more likely for us to add on the ones that are easy to add on than the ones that are a little more difficult.
Dr. David Brown:
Yes, and that being said in an eyedrop, even if you have the world’s best injection—say RTH just kills it—there’s going to be very little uptake to that drug that’s a J code and that’s because of that buy and bill scenario I gave you. In other words, if I buy a $2,000, or a who knows, $3,000 RTH drug and there is no J code, you use an undefined code when you code it, which means that insurers always delay your payments. So that’s a six to eight-month delay typically after the drug comes out to get that J code.
With a prescription, I don’t care. I mean, it’s their problem if the patient’s insurance doesn’t cover it at the pharmacy. I think it’s much more likely to uptake an eyedrop quickly than it is another biologic injection.
Sam Slutsky:
Got it. Dr. Brown, can you discuss the potential challenges of combination therapy from a compliance and reimbursement standpoint when we have two products that are administered both as injection at different intervals?
Dr. David Brown:
Yes. So, even though the—Peter made a good point that the drugs are different, the Novartis and the Regeneron drug, but they’re still given as a single injection, so I think that’s okay. I think what would have been very challenging is something like Fovista where you had two injections, potentially the same day or close to each other. Currently we have both CMS Medicare and private insurers that do these overall big audits looking for an injection within 28 days of another, and that’s to say they don’t want me to give Avastin in between an Eylea injection. Anything within 28 days gets flagged. They typically deny the expensive drug; they’re not stupid. So, any time you have to give two injections that are expensive biologics within a similar time I think would be incredibly challenging unless you got the insurance companies to buy on that it was really that much better.
The two combinations, one, the BiFab from Novartis and the sort of like Tide where you’ve got the white little soaps and the blue little soaps together in the same injection, I don’t think is going to be as big of a deal for us because it’s just one injection code along with the price of the drug.
Sam Slutsky:
Interesting. Dr. Kaiser, you feel the same way about this or is there any differences from your practice?
Dr. Peter Kaiser:
I think David said it right, you know? What many on Wall Street don’t get is sort of the insurance aspects of what we do and how it guides so much of our practice of medicine, unfortunately, and the idea of having to do, like Fovista would have been, two injections, was really not going to be all that palatable to us with reimbursement. We’ll see what happens with the Ang2 inhibitors, where that plays out. It’s still an injection at the end of the day and when you have a new drug and a new injection, it’ll be a long uptake for us because of the worry about reimbursement.
Sam Slutsky:
(Inaudible). Got it. Thanks for that. I now wanted to turn to Regenxbio which is developing an AAV gene therapy technology that leads to the local production of an anti-VEGF antibody fragment. Dr. Kaiser, I wanted to get your view on the potential overall application of this technology and if it did work, how could it potentially interrupt the anti-VEGF market?
Dr. Peter Kaiser:
Well, let’s assume many things. One is that the vector that Regenxbio is using, so it’s its AAV vector, is correct to infect the cells we want and infect it in the retina. Let’s just assume that. Let’s also assume that the plasma they have packaged within the vector is correct also and will produce the anti-VEGF protein that will work. So, those are two big assumptions already. Then let’s assume that it actually transfects enough cells to produce enough protein for this to work in the eye.
Now, theoretically, it should, right? The Regenxbio IP is much stronger than say Avalanche’s old IP or some of the other gene therapy companies IP. It’s very strong and particular in the delivery of drug to the eye by an AAV vector. So, that part of the equation they’re at least as good as anybody else out there.
Let’s just assume that the drug completely works and produces long-term anti-VEGF protein within an eye. This is obviously an exciting thing, but it wouldn’t change any sort of the combo drugs that are individual. For instance, if Ohr worked, there’d be no reason to not combine that with a Regenxbio product because all you’re adding is an eyedrop. If there was another add-on that would require say an additional injection, then they’d be maybe a little less likely to be added on to a Regenxbio type situation.
So, I’m bullish on Regenxbio but it’s really early so there’s not too much to read into it because we have basically no data that really can guide us how that company is going to do just yet.
Sam Slutsky:
Okay. Great for that, thanks for that overview. Dr. Brown, just wanted to get your thoughts as well on the potential role of a gene therapy for wet AMD.
Dr. David Brown:
We’re excited about gene therapy. The difficulty is just as Peter alluded to, can you get enough product through your vector and your gene construct to actually give you a steady state drug? If you can, I think it would take over—it would be second line because you’d give injections for a while, and then people that knew they had to have injections more frequently than whatever it is, 8 weeks, 12 weeks, would say, “Hey, I’d love to have this operation.” There’s been two, I think, maybe three patients dosed in the U.S., so we’re going to have some data soon of whether it looks like this thing gives biologic activity. If it does, it will interrupt the landscape. Part of it’s going to be you’re going to have a surgery with a surgery center and a drug that’s probably got to be priced at 20 grand or more, so it’s going to take a while for insurance companies to swallow that, but I think it will be a major disruptor if, like Peter says, all the pieces fall into place and it really works.
Sam Slutsky:
Okay, thanks. Overall, Dr. Brown, from a prescribing standpoint, do you have any concerns with recommending gene therapy technologies for ophthalmology?
Dr. David Brown:
You know, we’re—AAV vector, the current vectors are not self-replicating. In other words, it’s not like something that can get in your system and go crazy and take over. That’s also a problem because those cells probably have less production of protein over time, which could limit potentially the use of this thing. Like it may not be a treatment that lasts 20 years, but we don’t know that. But, from a gene therapy perspective I think it’s a pretty safe bet with the current vectors.
Better vectors like the lentiviruses, the herpes, the AIDS viruses, etc., are much better at actually transfecting cells and turning your cells into doing what they want to do, but again, much scarier. A lentivirus is a much scarier virus that has much more potential for trouble, but yet it’s a better vector to actually do what you want to do. So, we hope that the AAV vectors work. If not, I think they’ll be pushing to stronger and potentially riskier vectors.
Sam Slutsky:
Oh, interesting. Thanks for that. Dr. Kaiser, do you have any additional potential concerns or thoughts on the overall application?
Dr. Peter Kaiser:
I don’t have a huge concern. One is more of a theoretical concern which is when we’re treating macular degeneration with anti-VEGF agents, there has been a suggestion that macular atrophy can occur. I’m on the camp that says I don’t really believe in it, but let’s just assume that there are some people who really believe in it and they’re right. In that situation, having chronic VEGF suppression for a disease like macular degeneration may not be a good idea.
Now, I say may not because all these things are theoretical and I’m still in the camp that says GA or macular atrophy is really not occurring in these patients; at least I haven’t seen it, so I think it’s more of a theoretical concern than a true concern at this point. Because once you turn on the gene production, you really can’t turn it off. Some of these gene therapy companies are saying you could turn it off by doing laser to the transfected cells. Well, that’s all said and good except you don’t know what the transfected cells are. So you can’t see it, so how are you supposed to laser it?
Sam Slutsky:
Got it. Got it, okay. Are there any other treatments in development that either of you are excited about for wet AMD that we haven’t discussed? Dr. Kaiser, we can start with you.
Dr. Peter Kaiser:
I think the other AMD product that has very strong data to date are the integrin inhibitors, in particular the one from Allegro Pharmaceuticals. That one has shown very good results in DME and some early results in AMD, and just by its mechanism of action would be distinct from anti-VEGF agents. What excites me is its possibility of it going—being used as monotherapy as well as combo therapy, but not having to do combo for the registration study, because I hate doing combo for registration if I can avoid it. It’s always easier to do monotherapy.
Sam Slutsky:
Got it. Do you think it’s magnitude of effect could go against VEGF?
Dr. Peter Kaiser:
It’s probably not going to be as strong as VEGF. It may last a little longer than anti-VEGFs, so that’s a plus, but because of its mechanism of action, it would be complementary to anti-VEGF. So, because of that, once we actually have it in market we would be able to use it in combo. Sort of like a lot of chemotherapy drugs are used now; they get approved mono but it turns out they work better together and they do that sort of post approval.
Sam Slutsky:
Okay, got it. Dr. Brown, are there any additional drugs in development that you want to discuss that we haven’t touched on?
Dr. David Brown:
It’s interesting. For years they kept looking for this magical factor, Factor X that became VEGF, and the VEGF blocker is amazing. We have equal scientific data on a bunch of other targets. CC3 chemokine receptors, tide agonists, Ang2 blockers, all of these things are a long ways away but potentially could be an additive agent or the magic bullet that really makes it where you turn off angiogenesis, neovascularization, and turn off the production of VEGF. Fortunately, there’s a lot of money in early drugs and so a lot of basic science been going on and preclinical data.
I don’t think we’ve found insulin. One of my partners keeps saying, “This is insulin, Dave. We’ll never have anything else. They’ve been using insulin since the ‘50s. They don’t have a second drug,” and they sort of do, but I’m hopeful that we will have something to decrease the treatment burden of the many, many, many patients I have that need injections every month to control their AMD, their DME or their RVO.
Sam Slutsky:
Okay.
Dr. Peter Kaiser:
I think the interesting thing about drug development in AMD is that many of the large pharma companies have offloaded the development onto the smaller companies. None of the large pharma companies—Regeneron excluded from that statement—really go out and develop in-house drugs and then take those drugs all the way throughout. They basically let somebody else do the development and then they buy them for large sums of money where it’s better to have a bird in hand than one in the bush, in other words. So, to me, companies like Allegro and like Ohr and some of these other smaller companies, once they show positive results in Phase 2, it’s very unlikely they’re going to stay alone at doing this. The pharma partner should be coming in very rapidly at that point.
I really wish also that these large pharma companies would spend some of that huge amounts of money they have on developing products because they have certainly much deeper pockets than the smaller companies.
Sam Slutsky:
Great. Yes, it seems like we’re seeing that approach throughout drug development overall in terms of partnerships and a lot of stuff being dumped onto the biotechs to do just because of the efficiency.
All right. I guess at this time, Operator, we’d like to open the line for questions. As a reminder, questions can also be submitted to questions@lifescicapital.com.
Operator:
Thank you. If you’d like to ask a question, please signal by pressing star, one on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, press star, one to ask a question. We’ll pause for just a moment to allow everyone an opportunity to signal for questions.
Sam Slutsky:
Great. While we wait for the queue to fill up, Dr. Brown, overall, could you provide us with a quick overview of the upcoming catalyst for wet AMD that you’re most excited about?
Dr. David Brown:
Like I said, end of the year we’re going to have our Ang2 combo results; we’re going to have some Ohr results here shortly thereafter. I think both are exciting.
Sam Slutsky:
Okay. Dr. Kaiser, any additional ones?
Dr. Peter Kaiser:
Those are the big ones. I think we’re all very excited about both these study results.
Dr. David Brown:
The RTH details obviously.
Dr. Peter Kaiser:
Yes, that’s for sure. We expect that probably like third quarter, around the AAO would be my guess. I’m actually surprised that you said that they’re not looking for approval for it until 2019. I would have thought they would be going earlier but you may be right.
Dr. David Brown:
Yes.
Operator:
Once again, if you’d like to ask a question, please press star, one.
Dr. David Brown:
Did they say why the delay? Is it production? That’s hard to believe. You would think that the second largest pharmaceutical company in the world could produce it.
Sam Slutsky:
Yes. I’m unclear (phon).
Dr. Peter Kaiser:
You would hope.
Sam Slutsky:
All right. At this time, it doesn’t seem like there are any questions in the queue, so wanted to thank both Dr. Kaiser and Dr. Brown for your time. Definitely a very insightful call, and thank you to everyone who tuned in.
Dr. Peter Kaiser:
Great.
Dr. David Brown:
Thanks, gentlemen.
Operator:
This conclude today’s call. Thank you for your participation. You may now disconnect.
David Brown who is on the call also is mentioned in the article you sited.
They are both top docs in the field so their discussing Squalamine in a positive way I think means something.
Wet AMD call Ohrp featured prominently
Sam Slutsky, Research Analyst, LifeSci Capital
Dr. Peter Kaiser, Chaney Family Endowed Chair for Ophthalmology and Professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine
Dr. David Brown, Ophthalmologist and Ophthalmic Surgeon, Retina Consultants of Houston
P R E S E N T A T I O N
Operator:
Good day and welcome to the LifeSci Capital KOL Series on the topic of wet AMD conference call. Today’s conference is being recorded. At this time I would like to turn the conference over to Mr. Sam Slutsky. Please go ahead, sir.
Sam Slutsky:
Thank you. Good morning everyone and thank you for dialing in. I’m Sam Slutsky, one of the research analysts at LifeSci Capital. On today’s call we’ll be discussing the current treatment landscape for wet AMD, how it may change with the recent data from Novartis’s RTH258, and promising drugs in development for the disease.
We’re lucky to have with us today two distinguished experts in the field. They are Dr. Peter Kaiser and Dr. David Brown. Dr. Kaiser is the Chaney Family Endowed Chair for Ophthalmology Research and a Professor of Ophthalmology at the Cleveland Clinic Lerner College in Medicine. Dr. Brown is a practicing ophthalmologist and ophthalmic surgeon at Retina Consultants of Houston. He’s a thought leader in this space and is extensively published on the topic of Wet AMD.
After the discussion, there will be an opportunity for live Q&A, but questions may also be submitted any time during the call to questions@lifescicapital.com.
So, thank you Dr. Kaiser and Dr. Brown for joining us. To start the call I would like to ask both of you to give our audience some background on yourselves, your practices and your research interest, and then after that we can dive into some deeper questions. We’ll start off with you, Dr. Kaiser.
Dr. Peter Kaiser:
Good morning everyone. I’m a vitreoretinal specialist. I practice at the Cole Eye Institute at the Cleveland Clinic. I’ve been very involved with clinical trial research for many years, having been one of the lead investigators on the Lucentis studies, the Eylea studies and some of the studies that are in current clinical trials, so I look forward to speaking with you.
Sam Slutsky:
Great, and you, Dr. Brown?
Dr. David Brown:
I’m David Brown. We’ve got a 12 retina surgeon group in Houston, Texas. That’s the largest on the Gulf Coast. We also have the largest clinical research center in the United States and we’re part of most of the major trials, if not all, and we take care of a lot of macular degeneration and give a lot of injections every day, so we’d love to have something that helps our patients.
Sam Slutsky:
Great. We’ll start off the call by discussing the current treatment landscape for wet AMD. Dr. Brown, can you give us an overview of how you are currently using the three main VEGF inhibitors, Avastin, Lucentis and Eylea for wet AMD, and if there are any changing trends that you’ve noticed?
Dr. David Brown:
Basically we’ve got three good options; they’re not equal but they’re good options. Avastin tends to be the drug of choice for all the Medicare Advantage plans, all the managed care plans. More and more, they’re pushing us or incentivizing us into giving Avastin, if not first line, exclusively. That being said, our main treatment paradigm is to treat until dry and then treat and extend, and so the best drying agent appears to be Eylea, and so patients that have persistent fluid on either Lucentis or Avastin get switched to Eylea. Typically they’re extended until the point where they have a fixed dosing regimen.
To be honest, we’re about a third of each drug. We would not use much Avastin if it wasn’t for the insurance incentives or pressures, but it’d be nice to have something that had better duration or better drying agents.
Sam Slutsky:
Got it. Are there any specific patient types that you prefer one of the VEGF inhibitors for over the others?
Dr. David Brown:
Not necessarily. I mean, it’s sort of an equal opportunity. You know, the drugs are all pretty darned good, which is amazing. Patients with large PEDs, pigment epithelial detachments, patients who for whatever reason can’t last as long on an anti-VEGF inhibitor, certainly we go with the longer agent or the more drying agent, which is typically Eylea.
Sam Slutsky:
Got it. Dr. Kaiser, is your experience consistent with that of Dr. Brown?
Dr. Peter Kaiser:
Yes, I agree. I think in macular degeneration there hasn’t been a study that shows a huge difference in efficacy between these drugs. They’ve all behaved (inaudible) very similarly, the difference being in longevity, and as David mentioned drying ability, but at the end of the day in all the studies, the visual results were all pretty similar. That’s not the same in all diseases but certainly in macular degeneration it is.
As such, we also start most patients, if not all patients on Avastin. Remember, my boss is Dan Martin who ran the C.A.T. study, and so we have a reason that we’re told everyday why we should use Avastin first, and I think it’s very reasonable because if we can find the patients who do well on Avastin, we’re certainly saving the healthcare system quite a bit of money. But, if they don’t—if they fail Avastin or if we’re trying to extend them for a period of time longer than we can go usually with Avastin, then I agree with Dave that many of our patients are switched to Eylea.
Sam Slutsky:
Okay, great. Thanks for that overview. Now, I wanted to turn to the recent data of RTH258. Novartis recently reported positive data from its Phase 3 studies using RTH258. This is a VEGF inhibitor for neovascular AMD. The study achieved the primary endpoint of non-inferiority compared to Eylea, however a little more than half the patients maintained dosing every 12 weeks which compares favorably to Eylea’s 8-week dosing regimen and Lucentis’s 4-week regimen.
Dr. Kaiser, I first wanted to get your impression of the data they presented so far.
Dr. Peter Kaiser:
So, on the face of it, it certainly looks exciting. Eylea is what we consider the gold standard drug in macular degeneration. It’s certainly in terms of efficacy being equal to Lucentis but having a longer duration. Now we have another drug in brolucizumab which is the generic name for RTH. In brolucizumab’s case, about half the patients were able to extend the interval to 12 weeks.
Now, what’s going to be important, because this is based on study design, is sort of how those patients did between the 12-weekers and the 8-weekers because the way the study was designed, once you switched from 12 weeks to 8 weeks, you couldn’t go back. Even if you were doing well at 8 weeks, it wasn’t like you were going back and forth and it wasn’t an average either. So, that means that there were patients who were dry after a certain number of injections and were able to then be put into the 12-week group and remain in that 12-week group doing very, very well. That means about half the patients were doing really, really well, and that doesn’t mean the other half weren’t doing well, it’s just the press release doesn’t really tell us how that other group, the more aggressive lesions required a little more aggressive treatment, how they did and if they were similar to the Eylea group, better or worse. So, there’s certainly a lot of data that we still need to see come out of the study. The top line results are encouraging but not the end-all.
Sam Slutsky:
Okay. In terms of the additional data that could be presented at an upcoming conference, which data points were you most focused on?
Dr. Peter Kaiser:
Myself? I really would like to know first of all if the 12-week data did better than Eylea and the 8-week data did worse, and so on average they did the same. That would be a very interesting finding. Alternatively, you know, whenever we have an average visual acuity difference, you want to know how many are winners and how many are losers, so what’s the range of the visual distribution? In other words, are you more likely to have a winner but just as likely have a loser with brolucizumab? With Eylea (inaudible) we know what it looks like, so is brolucizumab different?
Finally, I’d want to know if there were particular subsets of lesions that the patients will do better with one drug versus the other. Safety is going to be a big area that we’re all going to be looking at, and finally, we know that Eylea is the best drying agent so far. How exactly did brolucizumab match up in terms of its drying capability? Was it similar, better or worse?
Sam Slutsky:
Got it. Thanks for that. Dr. Brown, are there any additional data points that you’d like to see?
Dr. David Brown:
Yes, I think to us, I think in a treatment naïve population like we said, even Avastin, the weakest horse in this race does pretty good. In a treatment naïve population, I think you really—like Peter alluded to, the last comment, I think it’s really drying ability. I mean, if you’re drying out a higher percentage of Eylea, I think that is in the hearts and minds of retina surgeons, will think it’s a better drug.
Because the Eylea arm didn’t have a chance to extend to 12 weeks, it’s a little hard to make that comparison that says, “Hey, 52% or 53% can go to 12 weeks with brolucizumab.” They didn’t test and see how many of those Eylea patients could have done that, so to me it’s mainly drying ability.
In the clinic, once we get it in the clinic, it’s really these recalcitrant patients that don’t dry out on monthly Eylea, do they dry out on brolucizumab and can they be extended longer?
So, it’s drying ability to me until it gets in the clinic, and then it’s tough because we put new drugs against our toughest cases, and if this drug can really outperform, it’ll have a definite place in the market.
Sam Slutsky:
Okay. Dr. Brown, how do you …
Dr. Peter Kaiser:
I just wanted to add something to what Dave said, which is very, very important. The study being a non-inferiority study, the Eylea patients had to be dosed on label, which in this case was every other month, but recall that in the VIEW study second year, the patients were dosed with a capped prn dosing scheme and almost half the patients in the Eylea group were actually able to get out to three-month intervals. So, had the study been done differently, the results may have been different also.
This is also a criticism of VIEW where had the second year been done differently, maybe Lucentis would have been able to go longer than a month also.
Sam Slutsky:
Interesting. Thanks for that. Dr. Brown, how do you anticipate RTH258 will be used, assuming there’s nothing negatively surprising in the data when they present full data?
Dr. David Brown:
You know, a lot of it depends on the finances and how good the data is. Eylea, Regeneron has not been able to convince the Aetnas and the Blue Crosses of the world that they’re better, and so it’s not like they tier them and say, “You should use Eylea over Lucentis because we’re a better drying agent.” If the data is strong enough and they can convince payers and retina physicians that it’s better than Eylea, I think it will be the go-to drug after Avastin in those insurances, and potentially first line because why not—in our practice we have a lot of patients with really good insurance who have done well for themselves and they don’t want to start with generic corn flakes; they want to start with the branded drug. The question is how does it compare against what’s currently deemed to be the best drug, which is Eylea. If they win that in the hearts and minds of retina surgeons and even better in the hearts and minds of insurance providers, I think it’ll be used as either first line or as your go-to drug, as your clean-up batter.
Part of it’s going to be how they price it. If they come out and price this thing at double the price of Eylea, I think they’re going to have a much harder time convincing those insurance companies that they’re the go-to drug. If they price it comparatively better or perhaps even a discount, they might win more of that market. It’s different than every other field of medicine because nothing else has a 50 buck drug or a 75 buck drug that’s pretty good. So, the economics and the rationale of how you price the drug is very challenging when you have Avastin as your—lurking in the horse race.
Sam Slutsky:
Got it. In terms of first line use, too, you touched on this briefly but it seems like RTH258 won’t be launched possibly until 2019. So, in terms of the emergence of Avastin biosimilars, how do you think that will play in in terms of uptake?
Dr. David Brown:
I think it really depends on how those biosimilars are priced. If you look biosimilars, other biosimilars are typically priced 20%, 30% less than the branded drug. I don’t think that’s going to play well in this market. When you have 75 buck alternatives, I think they’re going to have to have a 50% discount or more to really chip away at the branded drug.
If the biosimilars come out at $1000 and really takes over a large part of the market, I think insurers may start to do more tiers where they say, “You got to use Avastin, and if not you use biosimilar this or that,” and then the third line would be that drug, and that’s certainly where RTH doesn’t want to be. You don’t want to be the third line drug in a drug tier.
Dr. Peter Kaiser:
I agree with Dave. This is one of those things where the price of the drug (inaudible).
Sam Slutsky:
Dr. Kaiser, we’re losing you. You’re breaking up a little. Are you there? All right, we’ll come back. Oh yes, yes. Now it’s good.
Dr. Peter Kaiser:
Sorry about that. I said the price is really going to play a large role, and I agree fully with what David said that these companies are not going to be able to (inaudible) this drug (inaudible). Can you hear me now?
Sam Slutsky:
Yes, yes, yes.
Dr. Peter Kaiser:
So, I’m saying that the $50 drug that we have really limits the biosimilar’s ability to (inaudible) have a high number. The biosimilars that are out there aren’t Avastin, they’re Lucentis. (Inaudible) Avastin biosimilar too.
Sam Slutsky:
You’re still breaking up a little bit but we’ll jump to the next question and come back. I wanted to now turn to other drugs in development and discuss programs targeting Ang2 calmodulin and VEGF. So, we know that there’s a lot of interest in Ang2 inhibitors such as Roche’s RG7716 and Regeneron’s nesvacumab which is in Phase 2 development. So, Dr. Brown, what do you see as the value of Ang2 inhibition and what are your expectations for this drug classes’ effect.
Dr. David Brown:
Ang2 is very interesting. It’s particularly interesting in the vascular diseases, retinal vein occlusion in diabetes because it looks to be a lot of Ang2 there and blocking of totally separate targets.
Wow, I’m getting a lot of feedback.
Blocking a totally separate target you hope would get better efficacy. In the early Phase 1s and 2s, it looked like we saw a duration effect. That’s what excited everybody. You’re going to have your data at the end of the year. If you really get a duration effect and hopefully can convince the FDA a way to prove on duration effect, that’d be great. Currently, the agency has only said they would approve a add-on drug if it improved visual acuity. For macular degeneration, we may be close to the top of where we can get with just an add-on drug with the one-time shot. Certainly if we get a sustained release device or a drug like Ohr’s that may potentially give you a steady state anti-VEGF by taking a pill every day or a drop every day, you may get more efficacy, but the devil’s in the—I guess we’re all waiting for the results and we should have that by the end of the year. We’re constantly optimistic.
Dr. Peter Kaiser:
(Inaudible).
Sam Slutsky:
You see its potential use though in some of the other neovascular indications such as DME and things like that moreso than AMD?
Dr. David Brown:
I think from a target perspective, yes. If you just look at the science, it makes more sense to me that those diseases have more Ang2 in the disease pathophysiology. That being said, we really didn’t think there was a whole lot of VEGF in macular degeneration and look how good it does with a VEGF blocker. So, there’s a distinct possibility that it could really help in macular degeneration, and we’ll see. We’ve got two major companies with two good drugs and we should have the data from both by the end of the year.
Sam Slutsky:
Okay, great. Dr. Kaiser, do you have anything to add to what Dr. Brown said?
Dr. Peter Kaiser:
Yes. Ang2 inhibition is something we’re all pretty excited about. We know that the tide 2 pathway which Ang2 works on is very involved in all these diseases, but I agree with David that it’s moreso in the retinal vascular diseases than macular degeneration. While it is involved in macular degeneration, we do expect the difference to be greater in diabetes.
The other interesting thing for me is the regulatory path that these two drugs are going to have to take are very different because the Regeneron product, which is used in combination with Eylea, has to show superiority in its Phase 3, if it gets there, whereas the Roche product being a biospecific molecule is actually a new drug. It’s not Lucentis-plus so its regulatory path is through a non-inferiority study, so that’ll definitely change the clinical trial design between the two drugs. It’ll be interesting.
Sam Slutsky:
Wow. Interesting. Thanks for that. Dr. Brown, you had touched on Ohr so we can discuss them right now. So, you’re both familiar with Ohr Pharmaceutical’s program of Squalamine, which his an antiangiogenic agent delivered as an eyedrop, inhibits a VEGF, PDGF and basic FGF through the inhibition of calmodulin, and its Phase 2 trial results from a prespecified analysis of patients within the (inaudible) CNB area of less than 10 millimeters squared, had particularly encouraging activity compared to Lucentis. The use of Squalamine led to a 5.3 letter improvement over Lucentis and mean change in visual acuity. The p value here is 0.03. Also that 40% of patients gained three or more lines of visual acuity versus around 25% for control, and based on the data and learnings of the drug’s mechanism of action or is enrolling the described patient population in its current large ongoing study.
So, Dr. Kaiser, can you discuss your impression on the company’s Phase 2 data and your thoughts on the rationale behind using the described enrollment criteria for the ongoing study?
Dr. Peter Kaiser:
Sure. I think one of the issues for Ohr was that many people, particularly people on Wall Street, bunched Ohr together with Fovista and other PDGF inhibitors because it does inhibit PDGF as one of its mechanisms of action, but what everybody—what all those people failed to realize is that as the molecule Squalamine doesn’t have any effect whatsoever on parasites. It’s effect is 100% on activated endothelial cells which is where the problem really lies, and so the Fovista drug and Regeneron’s PDGF inhibitor, both of which failed, were working an entirely different cell type, basically, than on parasites. That’s number one.
Number two, not only does it decrease these growth factors, it also specifically acts on these new endothelial cells. It changes the actin and filament within the cells which changes the structure of these new vessels, causing the vessels to block off, and that’s exactly what we want.
So, when you look at the Phase 2 data, unfortunately in the past everybody hoofed that horse, using Dave’s analogy, up to the buggy of all PDGF inhibitors and it was bunched together with them. Now, interestingly enough, the results of the study was actually very similar, however the similarity was not because it was working on PDGF; the similarity was that the combination of Squalamine as an eye drop together with Lucentis appeared to be working very well in Phase 2.
What I like about what Ohr did in Phase 3, unlike what Fovista did in its Phase 3 is that it basically Ohr took the patients who did well in Phase 2 and designed their Phase 3 clinical program on that, whereas Fovista and Ophthotech basically took their Phase 2 data where they did well and they changed it to include patients where their drug wouldn’t do well. So, one of the reasons why I think Fovista actually failed is they basically changed the study design between Phase 2 and Phase 3, which is a clinical trial no-no, and what Ohr did was the way that anybody who designs clinical trials would want to do which is take the learnings from Phase 2 and use that to design a rational Phase 3 that has an even higher chance of success than the Phase 2.
Sam Slutsky:
Got it. Thanks for that overview. Dr. Brown, wanted to get your view on the data and rationale for the patient enrollment in the current study.
Dr. David Brown:
First of all, on selecting patients that did better, I think it’s always good to enrich your effect. Certainly we do that in every clinical trial where we try to give a dose, you know, the month before the endpoint. It sounds like you wouldn’t want to restrict your label, but in today’s times where every optometrist has an OCT, most of the lesions we are catching are small lesions and most lesions are occult, and so this is the largest percentage of the lesions we get in the clinic these days.
I’m more excited about a continuous, ongoing anti-VEGF suppression. We basically give now pulsatile treatment where you give a big dose and most of the PK curves are linear, so when patients re-leak it’s typically when we think they get below a level of VEGF inhibition that would decrease leakage. If you could have ongoing VEGF suppression with something like an eyedrop, I think patients would love it. They’d definitely take their eyedrop and extend longer, and potentially get where they don’t have to have injections. I think that’s the most exciting part of this is a continuous anti-VEGF suppression along with some of the other cytokines that are blocked that we know from the Squalamine preclinical data.
Sam Slutsky:
Great. Thanks for that. Dr. Kaiser, in terms of the efficacy data for the control arm in Ohr’s study with Lucentis, do you think it was an accurate representation of what you would see in the real world?
Dr. Peter Kaiser:
Yes, it was. Obviously comparing across trials is an effort that you—fraught with error, however if you kind of look at the average of clinical studies where patients were enrolled all-comers, for instance the C.A.T. study or the IVAN study, the control group of Lucentis in the study performed almost identically to C.A.T., so it wasn’t that the control group was doing poorer and the combo group was doing normal. No, the monotherapy group was doing normal and the combo group was doing definitively better.
Sam Slutsky:
Okay, great. This question is for both doctors, but based on your extensive experience with clinical trials in the past and with Squalamine, what probability of success would you give this program in the current wet AMD trial? Dr. Brown, we can start with you.
Dr. David Brown:
I think that because of the continuous steady state suppression in multiple cytokines, I am on record as saying I thought the Fovista trial had a 10% chance of success and I think this one is much closer to 50/50.
It’s a well designed trial. They’ve got quite a bit of numbers. It seems like we’ve got quite a few patients in this trial and they’re not complaining that the eyedrop stings and it looks like their compliance is good. So, I’m optimistic that we got a horse race here. I hope we get visual acuity benefits. I think, to be honest, we may be close to the top of the curve, and so it may be that this is a drug that it does give you more duration or longer time between injections. We won’t see that in this first trial but hopefully there’s enough of a signal that they can go to a Phase 3. We’re in the second year. They’ve got where they stretch out the injections and you see duration. If we get visual acuity, that’s great, and I think that chance is about 50/50.
Sam Slutsky:
Great. Thanks for that. Dr. Kaiser, your thoughts?
Dr. Peter Kaiser:
Yes, I agree with Dave. I think when we look at some of the other combination studies, our probability of success that we were giving out was pretty low. Most companies will be pretty happy with 50/50; in fact, they would greenlight anything above probably about 30%.
I thinking maybe it’s a little higher. I’m going to go out on record and say 60% chance of success because I really think what the company has done in terms of honing in on the patients who did well in Phase 2 is going to bode well. They’ve eliminated the patients who may not do as well with the combination therapy from the enrollment, and to me this usually means that the success rate goes up from Phase 2.
So, you know, I’m pretty optimistic about this one. If it works, there’s a lot of other areas that an eyedrop can be used because remember now, the bar for a combo drop from a patient/physician standpoint—not from the FDA standpoint but from a patient/physician standpoint to add a drop is incredibly low versus another injection. The FDA, when you say combo to them, it doesn’t matter if it’s a drop or another injection, the bar is the same, but from a patient and a physician standpoint it’s a huge difference. An eyedrop, I don’t have to deliver it myself. I can write a prescription, the patient goes and gets it. The patient doesn’t mind taking an eyedrop, whereas if it’s another injection, here’s a whole nother worry about reimbursement, what’s going to happen with insurance companies’ coverage of that other injection. So, to me there’s a lot of reasons why I’m actually very bullish on this product and I’m optimistic to see the results in the future.
Dr. David Brown:
Yes, a lot of physicians that currently use Avastin, use Avastin because they’re worried about the financial implications, and what I mean by that is in a buy and bill scenario, when you give a $2,000 drug that you have to purchase from a drug distributor, you got to pay for that drug in 60 days. If your insurance company stiffs you once, and the margin’s 3%, 4% at the most, you got to do another 200 injections to make up for that one lost drug.
For this, physicians don’t have any financial risk by adding on the eyedrop with the prescription because it’s not a Part B drug.
Sam Slutsky:
Interesting. That’s going to be helpful for understanding the reimbursement landscape. Okay.
So, Dr. Brown, Dr. Kaiser had mentioned this briefly, but when thinking of some of the recent wet AMD failure’s such Ophthotech’s, Fovista, which had positive Phase 2 results, what do you think are the main contributors to the Phase 3 failing?
Dr. David Brown:
I think it’s the target. I mean, you had a very good study from Regeneron with potentially a better PDGF blocker that totally busted as well; the monotherapy did better than the combination therapy. If you look at Fovista’s Phase 2 data on lesion regression, which was the first thought, you strip the parasites, you get the anti-VEGF in there and it regresses more. If you go to the SEC (phon) filing, you see that monotherapy Lucentis caused more lesion regression than did combination therapy. So, if you’re premise is wrong, and I think it was tested well in both studies, both the Regeneron and the Fovista, and you put it up there and it loses, it loses.
Ang2 we hope has more of a potential of the combination, and again, anything that gives a steady state suppression like the sustained release device, like a gene therapy, if you can get enough product development, like an eyedrop from Ohr, I think that has the best chance of winning versus our paradigm of single injection high dose and then steady state linear decrease in PK.
Sam Slutsky:
Got it. Okay, thanks. Dr. Kaiser, in terms of combination approaches for wet AMD, do you think add-on therapies will be a one size fits all kind of like anti-VEGF, or do you think patient selection will be a key to truly recognizing the benefits of add-ons?
Dr. Peter Kaiser:
I think like everything, patient selection is going to be important. Certainly, for instance, with the Ohr product, very large occult lesions, probably not a good idea to be using the product unless we hear something differently. So yes, we are going to be using different add-ons for different reasons. The only other add-on that we probably will have is Ang2 in the near future—I should say anti-Ang2 in the form of Regeneron’s product which would be an add-on, but in that study we don’t know yet are there certain lesions that it works better on or is it a work on all comers? We don’t know yet.
Sam Slutsky:
Okay. In terms of the clinical pipeline, a bunch of companies are going after combination approaches on top of a VEGF inhibitor. So, Dr. Kaiser, in add-on works with one VEGF inhibitor in its study, do you think that can be extrapolated to use on top of the other anti-VEGF inhibitors as well?
Dr. Peter Kaiser:
As long as the mechanism of action is distinct, the answer should be yes. So, any add-on should work with any anti-VEGF agent, whether it be say a gene therapy anti-VEGF or a sustained release in the form of say an implant like the LADDER study from Genentech. It wouldn’t matter how the anti-VEGF is performed.
Now, if that add-on is another injection then the patient acceptance of it may be lower. If it’s an eyedrop like Squalamine, for instance, then that’s no big deal to add that on, and so it will be probably more likely for us to add on the ones that are easy to add on than the ones that are a little more difficult.
Dr. David Brown:
Yes, and that being said in an eyedrop, even if you have the world’s best injection—say RTH just kills it—there’s going to be very little uptake to that drug that’s a J code and that’s because of that buy and bill scenario I gave you. In other words, if I buy a $2,000, or a who knows, $3,000 RTH drug and there is no J code, you use an undefined code when you code it, which means that insurers always delay your payments. So that’s a six to eight-month delay typically after the drug comes out to get that J code.
With a prescription, I don’t care. I mean, it’s their problem if the patient’s insurance doesn’t cover it at the pharmacy. I think it’s much more likely to uptake an eyedrop quickly than it is another biologic injection.
Sam Slutsky:
Got it. Dr. Brown, can you discuss the potential challenges of combination therapy from a compliance and reimbursement standpoint when we have two products that are administered both as injection at different intervals?
Dr. David Brown:
Yes. So, even though the—Peter made a good point that the drugs are different, the Novartis and the Regeneron drug, but they’re still given as a single injection, so I think that’s okay. I think what would have been very challenging is something like Fovista where you had two injections, potentially the same day or close to each other. Currently we have both CMS Medicare and private insurers that do these overall big audits looking for an injection within 28 days of another, and that’s to say they don’t want me to give Avastin in between an Eylea injection. Anything within 28 days gets flagged. They typically deny the expensive drug; they’re not stupid. So, any time you have to give two injections that are expensive biologics within a similar time I think would be incredibly challenging unless you got the insurance companies to buy on that it was really that much better.
The two combinations, one, the BiFab from Novartis and the sort of like Tide where you’ve got the white little soaps and the blue little soaps together in the same injection, I don’t think is going to be as big of a deal for us because it’s just one injection code along with the price of the drug.
Sam Slutsky:
Interesting. Dr. Kaiser, you feel the same way about this or is there any differences from your practice?
Dr. Peter Kaiser:
I think David said it right, you know? What many on Wall Street don’t get is sort of the insurance aspects of what we do and how it guides so much of our practice of medicine, unfortunately, and the idea of having to do, like Fovista would have been, two injections, was really not going to be all that palatable to us with reimbursement. We’ll see what happens with the Ang2 inhibitors, where that plays out. It’s still an injection at the end of the day and when you have a new drug and a new injection, it’ll be a long uptake for us because of the worry about reimbursement.
Sam Slutsky:
(Inaudible). Got it. Thanks for that. I now wanted to turn to Regenxbio which is developing an AAV gene therapy technology that leads to the local production of an anti-VEGF antibody fragment. Dr. Kaiser, I wanted to get your view on the potential overall application of this technology and if it did work, how could it potentially interrupt the anti-VEGF market?
Dr. Peter Kaiser:
Well, let’s assume many things. One is that the vector that Regenxbio is using, so it’s its AAV vector, is correct to infect the cells we want and infect it in the retina. Let’s just assume that. Let’s also assume that the plasma they have packaged within the vector is correct also and will produce the anti-VEGF protein that will work. So, those are two big assumptions already. Then let’s assume that it actually transfects enough cells to produce enough protein for this to work in the eye.
Now, theoretically, it should, right? The Regenxbio IP is much stronger than say Avalanche’s old IP or some of the other gene therapy companies IP. It’s very strong and particular in the delivery of drug to the eye by an AAV vector. So, that part of the equation they’re at least as good as anybody else out there.
Let’s just assume that the drug completely works and produces long-term anti-VEGF protein within an eye. This is obviously an exciting thing, but it wouldn’t change any sort of the combo drugs that are individual. For instance, if Ohr worked, there’d be no reason to not combine that with a Regenxbio product because all you’re adding is an eyedrop. If there was another add-on that would require say an additional injection, then they’d be maybe a little less likely to be added on to a Regenxbio type situation.
So, I’m bullish on Regenxbio but it’s really early so there’s not too much to read into it because we have basically no data that really can guide us how that company is going to do just yet.
Sam Slutsky:
Okay. Great for that, thanks for that overview. Dr. Brown, just wanted to get your thoughts as well on the potential role of a gene therapy for wet AMD.
Dr. David Brown:
We’re excited about gene therapy. The difficulty is just as Peter alluded to, can you get enough product through your vector and your gene construct to actually give you a steady state drug? If you can, I think it would take over—it would be second line because you’d give injections for a while, and then people that knew they had to have injections more frequently than whatever it is, 8 weeks, 12 weeks, would say, “Hey, I’d love to have this operation.” There’s been two, I think, maybe three patients dosed in the U.S., so we’re going to have some data soon of whether it looks like this thing gives biologic activity. If it does, it will interrupt the landscape. Part of it’s going to be you’re going to have a surgery with a surgery center and a drug that’s probably got to be priced at 20 grand or more, so it’s going to take a while for insurance companies to swallow that, but I think it will be a major disruptor if, like Peter says, all the pieces fall into place and it really works.
Sam Slutsky:
Okay, thanks. Overall, Dr. Brown, from a prescribing standpoint, do you have any concerns with recommending gene therapy technologies for ophthalmology?
Dr. David Brown:
You know, we’re—AAV vector, the current vectors are not self-replicating. In other words, it’s not like something that can get in your system and go crazy and take over. That’s also a problem because those cells probably have less production of protein over time, which could limit potentially the use of this thing. Like it may not be a treatment that lasts 20 years, but we don’t know that. But, from a gene therapy perspective I think it’s a pretty safe bet with the current vectors.
Better vectors like the lentiviruses, the herpes, the AIDS viruses, etc., are much better at actually transfecting cells and turning your cells into doing what they want to do, but again, much scarier. A lentivirus is a much scarier virus that has much more potential for trouble, but yet it’s a better vector to actually do what you want to do. So, we hope that the AAV vectors work. If not, I think they’ll be pushing to stronger and potentially riskier vectors.
Sam Slutsky:
Oh, interesting. Thanks for that. Dr. Kaiser, do you have any additional potential concerns or thoughts on the overall application?
Dr. Peter Kaiser:
I don’t have a huge concern. One is more of a theoretical concern which is when we’re treating macular degeneration with anti-VEGF agents, there has been a suggestion that macular atrophy can occur. I’m on the camp that says I don’t really believe in it, but let’s just assume that there are some people who really believe in it and they’re right. In that situation, having chronic VEGF suppression for a disease like macular degeneration may not be a good idea.
Now, I say may not because all these things are theoretical and I’m still in the camp that says GA or macular atrophy is really not occurring in these patients; at least I haven’t seen it, so I think it’s more of a theoretical concern than a true concern at this point. Because once you turn on the gene production, you really can’t turn it off. Some of these gene therapy companies are saying you could turn it off by doing laser to the transfected cells. Well, that’s all said and good except you don’t know what the transfected cells are. So you can’t see it, so how are you supposed to laser it?
Sam Slutsky:
Got it. Got it, okay. Are there any other treatments in development that either of you are excited about for wet AMD that we haven’t discussed? Dr. Kaiser, we can start with you.
Dr. Peter Kaiser:
I think the other AMD product that has very strong data to date are the integrin inhibitors, in particular the one from Allegro Pharmaceuticals. That one has shown very good results in DME and some early results in AMD, and just by its mechanism of action would be distinct from anti-VEGF agents. What excites me is its possibility of it going—being used as monotherapy as well as combo therapy, but not having to do combo for the registration study, because I hate doing combo for registration if I can avoid it. It’s always easier to do monotherapy.
Sam Slutsky:
Got it. Do you think it’s magnitude of effect could go against VEGF?
Dr. Peter Kaiser:
It’s probably not going to be as strong as VEGF. It may last a little longer than anti-VEGFs, so that’s a plus, but because of its mechanism of action, it would be complementary to anti-VEGF. So, because of that, once we actually have it in market we would be able to use it in combo. Sort of like a lot of chemotherapy drugs are used now; they get approved mono but it turns out they work better together and they do that sort of post approval.
Sam Slutsky:
Okay, got it. Dr. Brown, are there any additional drugs in development that you want to discuss that we haven’t touched on?
Dr. David Brown:
It’s interesting. For years they kept looking for this magical factor, Factor X that became VEGF, and the VEGF blocker is amazing. We have equal scientific data on a bunch of other targets. CC3 chemokine receptors, tide agonists, Ang2 blockers, all of these things are a long ways away but potentially could be an additive agent or the magic bullet that really makes it where you turn off angiogenesis, neovascularization, and turn off the production of VEGF. Fortunately, there’s a lot of money in early drugs and so a lot of basic science been going on and preclinical data.
I don’t think we’ve found insulin. One of my partners keeps saying, “This is insulin, Dave. We’ll never have anything else. They’ve been using insulin since the ‘50s. They don’t have a second drug,” and they sort of do, but I’m hopeful that we will have something to decrease the treatment burden of the many, many, many patients I have that need injections every month to control their AMD, their DME or their RVO.
Sam Slutsky:
Okay.
Dr. Peter Kaiser:
I think the interesting thing about drug development in AMD is that many of the large pharma companies have offloaded the development onto the smaller companies. None of the large pharma companies—Regeneron excluded from that statement—really go out and develop in-house drugs and then take those drugs all the way throughout. They basically let somebody else do the development and then they buy them for large sums of money where it’s better to have a bird in hand than one in the bush, in other words. So, to me, companies like Allegro and like Ohr and some of these other smaller companies, once they show positive results in Phase 2, it’s very unlikely they’re going to stay alone at doing this. The pharma partner should be coming in very rapidly at that point.
I really wish also that these large pharma companies would spend some of that huge amounts of money they have on developing products because they have certainly much deeper pockets than the smaller companies.
Sam Slutsky:
Great. Yes, it seems like we’re seeing that approach throughout drug development overall in terms of partnerships and a lot of stuff being dumped onto the biotechs to do just because of the efficiency.
All right. I guess at this time, Operator, we’d like to open the line for questions. As a reminder, questions can also be submitted to questions@lifescicapital.com.
Operator:
Thank you. If you’d like to ask a question, please signal by pressing star, one on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, press star, one to ask a question. We’ll pause for just a moment to allow everyone an opportunity to signal for questions.
Sam Slutsky:
Great. While we wait for the queue to fill up, Dr. Brown, overall, could you provide us with a quick overview of the upcoming catalyst for wet AMD that you’re most excited about?
Dr. David Brown:
Like I said, end of the year we’re going to have our Ang2 combo results; we’re going to have some Ohr results here shortly thereafter. I think both are exciting.
Sam Slutsky:
Okay. Dr. Kaiser, any additional ones?
Dr. Peter Kaiser:
Those are the big ones. I think we’re all very excited about both these study results.
Dr. David Brown:
The RTH details obviously.
Dr. Peter Kaiser:
Yes, that’s for sure. We expect that probably like third quarter, around the AAO would be my guess. I’m actually surprised that you said that they’re not looking for approval for it until 2019. I would have thought they would be going earlier but you may be right.
Dr. David Brown:
Yes.
Operator:
Once again, if you’d like to ask a question, please press star, one.
Dr. David Brown:
Did they say why the delay? Is it production? That’s hard to believe. You would think that the second largest pharmaceutical company in the world could produce it.
Sam Slutsky:
Yes. I’m unclear (phon).
Dr. Peter Kaiser:
You would hope.
Sam Slutsky:
All right. At this time, it doesn’t seem like there are any questions in the queue, so wanted to thank both Dr. Kaiser and Dr. Brown for your time. Definitely a very insightful call, and thank you to everyone who tuned in.
Dr. Peter Kaiser:
Great.
Dr. David Brown:
Thanks, gentlemen.
Operator:
This conclude today’s call. Thank you for your participation. You may now disconnect.
Wet AMD KOL call Ohrp featured prominently.
Sam Slutsky, Research Analyst, LifeSci Capital
Dr. Peter Kaiser, Chaney Family Endowed Chair for Ophthalmology and Professor of Ophthalmology, Cleveland Clinic Lerner College of Medicine
Dr. David Brown, Ophthalmologist and Ophthalmic Surgeon, Retina Consultants of Houston
P R E S E N T A T I O N
Operator:
Good day and welcome to the LifeSci Capital KOL Series on the topic of wet AMD conference call. Today’s conference is being recorded. At this time I would like to turn the conference over to Mr. Sam Slutsky. Please go ahead, sir.
Sam Slutsky:
Thank you. Good morning everyone and thank you for dialing in. I’m Sam Slutsky, one of the research analysts at LifeSci Capital. On today’s call we’ll be discussing the current treatment landscape for wet AMD, how it may change with the recent data from Novartis’s RTH258, and promising drugs in development for the disease.
We’re lucky to have with us today two distinguished experts in the field. They are Dr. Peter Kaiser and Dr. David Brown. Dr. Kaiser is the Chaney Family Endowed Chair for Ophthalmology Research and a Professor of Ophthalmology at the Cleveland Clinic Lerner College in Medicine. Dr. Brown is a practicing ophthalmologist and ophthalmic surgeon at Retina Consultants of Houston. He’s a thought leader in this space and is extensively published on the topic of Wet AMD.
After the discussion, there will be an opportunity for live Q&A, but questions may also be submitted any time during the call to questions@lifescicapital.com.
So, thank you Dr. Kaiser and Dr. Brown for joining us. To start the call I would like to ask both of you to give our audience some background on yourselves, your practices and your research interest, and then after that we can dive into some deeper questions. We’ll start off with you, Dr. Kaiser.
Dr. Peter Kaiser:
Good morning everyone. I’m a vitreoretinal specialist. I practice at the Cole Eye Institute at the Cleveland Clinic. I’ve been very involved with clinical trial research for many years, having been one of the lead investigators on the Lucentis studies, the Eylea studies and some of the studies that are in current clinical trials, so I look forward to speaking with you.
Sam Slutsky:
Great, and you, Dr. Brown?
Dr. David Brown:
I’m David Brown. We’ve got a 12 retina surgeon group in Houston, Texas. That’s the largest on the Gulf Coast. We also have the largest clinical research center in the United States and we’re part of most of the major trials, if not all, and we take care of a lot of macular degeneration and give a lot of injections every day, so we’d love to have something that helps our patients.
Sam Slutsky:
Great. We’ll start off the call by discussing the current treatment landscape for wet AMD. Dr. Brown, can you give us an overview of how you are currently using the three main VEGF inhibitors, Avastin, Lucentis and Eylea for wet AMD, and if there are any changing trends that you’ve noticed?
Dr. David Brown:
Basically we’ve got three good options; they’re not equal but they’re good options. Avastin tends to be the drug of choice for all the Medicare Advantage plans, all the managed care plans. More and more, they’re pushing us or incentivizing us into giving Avastin, if not first line, exclusively. That being said, our main treatment paradigm is to treat until dry and then treat and extend, and so the best drying agent appears to be Eylea, and so patients that have persistent fluid on either Lucentis or Avastin get switched to Eylea. Typically they’re extended until the point where they have a fixed dosing regimen.
To be honest, we’re about a third of each drug. We would not use much Avastin if it wasn’t for the insurance incentives or pressures, but it’d be nice to have something that had better duration or better drying agents.
Sam Slutsky:
Got it. Are there any specific patient types that you prefer one of the VEGF inhibitors for over the others?
Dr. David Brown:
Not necessarily. I mean, it’s sort of an equal opportunity. You know, the drugs are all pretty darned good, which is amazing. Patients with large PEDs, pigment epithelial detachments, patients who for whatever reason can’t last as long on an anti-VEGF inhibitor, certainly we go with the longer agent or the more drying agent, which is typically Eylea.
Sam Slutsky:
Got it. Dr. Kaiser, is your experience consistent with that of Dr. Brown?
Dr. Peter Kaiser:
Yes, I agree. I think in macular degeneration there hasn’t been a study that shows a huge difference in efficacy between these drugs. They’ve all behaved (inaudible) very similarly, the difference being in longevity, and as David mentioned drying ability, but at the end of the day in all the studies, the visual results were all pretty similar. That’s not the same in all diseases but certainly in macular degeneration it is.
As such, we also start most patients, if not all patients on Avastin. Remember, my boss is Dan Martin who ran the C.A.T. study, and so we have a reason that we’re told everyday why we should use Avastin first, and I think it’s very reasonable because if we can find the patients who do well on Avastin, we’re certainly saving the healthcare system quite a bit of money. But, if they don’t—if they fail Avastin or if we’re trying to extend them for a period of time longer than we can go usually with Avastin, then I agree with Dave that many of our patients are switched to Eylea.
Sam Slutsky:
Okay, great. Thanks for that overview. Now, I wanted to turn to the recent data of RTH258. Novartis recently reported positive data from its Phase 3 studies using RTH258. This is a VEGF inhibitor for neovascular AMD. The study achieved the primary endpoint of non-inferiority compared to Eylea, however a little more than half the patients maintained dosing every 12 weeks which compares favorably to Eylea’s 8-week dosing regimen and Lucentis’s 4-week regimen.
Dr. Kaiser, I first wanted to get your impression of the data they presented so far.
Dr. Peter Kaiser:
So, on the face of it, it certainly looks exciting. Eylea is what we consider the gold standard drug in macular degeneration. It’s certainly in terms of efficacy being equal to Lucentis but having a longer duration. Now we have another drug in brolucizumab which is the generic name for RTH. In brolucizumab’s case, about half the patients were able to extend the interval to 12 weeks.
Now, what’s going to be important, because this is based on study design, is sort of how those patients did between the 12-weekers and the 8-weekers because the way the study was designed, once you switched from 12 weeks to 8 weeks, you couldn’t go back. Even if you were doing well at 8 weeks, it wasn’t like you were going back and forth and it wasn’t an average either. So, that means that there were patients who were dry after a certain number of injections and were able to then be put into the 12-week group and remain in that 12-week group doing very, very well. That means about half the patients were doing really, really well, and that doesn’t mean the other half weren’t doing well, it’s just the press release doesn’t really tell us how that other group, the more aggressive lesions required a little more aggressive treatment, how they did and if they were similar to the Eylea group, better or worse. So, there’s certainly a lot of data that we still need to see come out of the study. The top line results are encouraging but not the end-all.
Sam Slutsky:
Okay. In terms of the additional data that could be presented at an upcoming conference, which data points were you most focused on?
Dr. Peter Kaiser:
Myself? I really would like to know first of all if the 12-week data did better than Eylea and the 8-week data did worse, and so on average they did the same. That would be a very interesting finding. Alternatively, you know, whenever we have an average visual acuity difference, you want to know how many are winners and how many are losers, so what’s the range of the visual distribution? In other words, are you more likely to have a winner but just as likely have a loser with brolucizumab? With Eylea (inaudible) we know what it looks like, so is brolucizumab different?
Finally, I’d want to know if there were particular subsets of lesions that the patients will do better with one drug versus the other. Safety is going to be a big area that we’re all going to be looking at, and finally, we know that Eylea is the best drying agent so far. How exactly did brolucizumab match up in terms of its drying capability? Was it similar, better or worse?
Sam Slutsky:
Got it. Thanks for that. Dr. Brown, are there any additional data points that you’d like to see?
Dr. David Brown:
Yes, I think to us, I think in a treatment naïve population like we said, even Avastin, the weakest horse in this race does pretty good. In a treatment naïve population, I think you really—like Peter alluded to, the last comment, I think it’s really drying ability. I mean, if you’re drying out a higher percentage of Eylea, I think that is in the hearts and minds of retina surgeons, will think it’s a better drug.
Because the Eylea arm didn’t have a chance to extend to 12 weeks, it’s a little hard to make that comparison that says, “Hey, 52% or 53% can go to 12 weeks with brolucizumab.” They didn’t test and see how many of those Eylea patients could have done that, so to me it’s mainly drying ability.
In the clinic, once we get it in the clinic, it’s really these recalcitrant patients that don’t dry out on monthly Eylea, do they dry out on brolucizumab and can they be extended longer?
So, it’s drying ability to me until it gets in the clinic, and then it’s tough because we put new drugs against our toughest cases, and if this drug can really outperform, it’ll have a definite place in the market.
Sam Slutsky:
Okay. Dr. Brown, how do you …
Dr. Peter Kaiser:
I just wanted to add something to what Dave said, which is very, very important. The study being a non-inferiority study, the Eylea patients had to be dosed on label, which in this case was every other month, but recall that in the VIEW study second year, the patients were dosed with a capped prn dosing scheme and almost half the patients in the Eylea group were actually able to get out to three-month intervals. So, had the study been done differently, the results may have been different also.
This is also a criticism of VIEW where had the second year been done differently, maybe Lucentis would have been able to go longer than a month also.
Sam Slutsky:
Interesting. Thanks for that. Dr. Brown, how do you anticipate RTH258 will be used, assuming there’s nothing negatively surprising in the data when they present full data?
Dr. David Brown:
You know, a lot of it depends on the finances and how good the data is. Eylea, Regeneron has not been able to convince the Aetnas and the Blue Crosses of the world that they’re better, and so it’s not like they tier them and say, “You should use Eylea over Lucentis because we’re a better drying agent.” If the data is strong enough and they can convince payers and retina physicians that it’s better than Eylea, I think it will be the go-to drug after Avastin in those insurances, and potentially first line because why not—in our practice we have a lot of patients with really good insurance who have done well for themselves and they don’t want to start with generic corn flakes; they want to start with the branded drug. The question is how does it compare against what’s currently deemed to be the best drug, which is Eylea. If they win that in the hearts and minds of retina surgeons and even better in the hearts and minds of insurance providers, I think it’ll be used as either first line or as your go-to drug, as your clean-up batter.
Part of it’s going to be how they price it. If they come out and price this thing at double the price of Eylea, I think they’re going to have a much harder time convincing those insurance companies that they’re the go-to drug. If they price it comparatively better or perhaps even a discount, they might win more of that market. It’s different than every other field of medicine because nothing else has a 50 buck drug or a 75 buck drug that’s pretty good. So, the economics and the rationale of how you price the drug is very challenging when you have Avastin as your—lurking in the horse race.
Sam Slutsky:
Got it. In terms of first line use, too, you touched on this briefly but it seems like RTH258 won’t be launched possibly until 2019. So, in terms of the emergence of Avastin biosimilars, how do you think that will play in in terms of uptake?
Dr. David Brown:
I think it really depends on how those biosimilars are priced. If you look biosimilars, other biosimilars are typically priced 20%, 30% less than the branded drug. I don’t think that’s going to play well in this market. When you have 75 buck alternatives, I think they’re going to have to have a 50% discount or more to really chip away at the branded drug.
If the biosimilars come out at $1000 and really takes over a large part of the market, I think insurers may start to do more tiers where they say, “You got to use Avastin, and if not you use biosimilar this or that,” and then the third line would be that drug, and that’s certainly where RTH doesn’t want to be. You don’t want to be the third line drug in a drug tier.
Dr. Peter Kaiser:
I agree with Dave. This is one of those things where the price of the drug (inaudible).
Sam Slutsky:
Dr. Kaiser, we’re losing you. You’re breaking up a little. Are you there? All right, we’ll come back. Oh yes, yes. Now it’s good.
Dr. Peter Kaiser:
Sorry about that. I said the price is really going to play a large role, and I agree fully with what David said that these companies are not going to be able to (inaudible) this drug (inaudible). Can you hear me now?
Sam Slutsky:
Yes, yes, yes.
Dr. Peter Kaiser:
So, I’m saying that the $50 drug that we have really limits the biosimilar’s ability to (inaudible) have a high number. The biosimilars that are out there aren’t Avastin, they’re Lucentis. (Inaudible) Avastin biosimilar too.
Sam Slutsky:
You’re still breaking up a little bit but we’ll jump to the next question and come back. I wanted to now turn to other drugs in development and discuss programs targeting Ang2 calmodulin and VEGF. So, we know that there’s a lot of interest in Ang2 inhibitors such as Roche’s RG7716 and Regeneron’s nesvacumab which is in Phase 2 development. So, Dr. Brown, what do you see as the value of Ang2 inhibition and what are your expectations for this drug classes’ effect.
Dr. David Brown:
Ang2 is very interesting. It’s particularly interesting in the vascular diseases, retinal vein occlusion in diabetes because it looks to be a lot of Ang2 there and blocking of totally separate targets.
Wow, I’m getting a lot of feedback.
Blocking a totally separate target you hope would get better efficacy. In the early Phase 1s and 2s, it looked like we saw a duration effect. That’s what excited everybody. You’re going to have your data at the end of the year. If you really get a duration effect and hopefully can convince the FDA a way to prove on duration effect, that’d be great. Currently, the agency has only said they would approve a add-on drug if it improved visual acuity. For macular degeneration, we may be close to the top of where we can get with just an add-on drug with the one-time shot. Certainly if we get a sustained release device or a drug like Ohr’s that may potentially give you a steady state anti-VEGF by taking a pill every day or a drop every day, you may get more efficacy, but the devil’s in the—I guess we’re all waiting for the results and we should have that by the end of the year. We’re constantly optimistic.
Dr. Peter Kaiser:
(Inaudible).
Sam Slutsky:
You see its potential use though in some of the other neovascular indications such as DME and things like that moreso than AMD?
Dr. David Brown:
I think from a target perspective, yes. If you just look at the science, it makes more sense to me that those diseases have more Ang2 in the disease pathophysiology. That being said, we really didn’t think there was a whole lot of VEGF in macular degeneration and look how good it does with a VEGF blocker. So, there’s a distinct possibility that it could really help in macular degeneration, and we’ll see. We’ve got two major companies with two good drugs and we should have the data from both by the end of the year.
Sam Slutsky:
Okay, great. Dr. Kaiser, do you have anything to add to what Dr. Brown said?
Dr. Peter Kaiser:
Yes. Ang2 inhibition is something we’re all pretty excited about. We know that the tide 2 pathway which Ang2 works on is very involved in all these diseases, but I agree with David that it’s moreso in the retinal vascular diseases than macular degeneration. While it is involved in macular degeneration, we do expect the difference to be greater in diabetes.
The other interesting thing for me is the regulatory path that these two drugs are going to have to take are very different because the Regeneron product, which is used in combination with Eylea, has to show superiority in its Phase 3, if it gets there, whereas the Roche product being a biospecific molecule is actually a new drug. It’s not Lucentis-plus so its regulatory path is through a non-inferiority study, so that’ll definitely change the clinical trial design between the two drugs. It’ll be interesting.
Sam Slutsky:
Wow. Interesting. Thanks for that. Dr. Brown, you had touched on Ohr so we can discuss them right now. So, you’re both familiar with Ohr Pharmaceutical’s program of Squalamine, which his an antiangiogenic agent delivered as an eyedrop, inhibits a VEGF, PDGF and basic FGF through the inhibition of calmodulin, and its Phase 2 trial results from a prespecified analysis of patients within the (inaudible) CNB area of less than 10 millimeters squared, had particularly encouraging activity compared to Lucentis. The use of Squalamine led to a 5.3 letter improvement over Lucentis and mean change in visual acuity. The p value here is 0.03. Also that 40% of patients gained three or more lines of visual acuity versus around 25% for control, and based on the data and learnings of the drug’s mechanism of action or is enrolling the described patient population in its current large ongoing study.
So, Dr. Kaiser, can you discuss your impression on the company’s Phase 2 data and your thoughts on the rationale behind using the described enrollment criteria for the ongoing study?
Dr. Peter Kaiser:
Sure. I think one of the issues for Ohr was that many people, particularly people on Wall Street, bunched Ohr together with Fovista and other PDGF inhibitors because it does inhibit PDGF as one of its mechanisms of action, but what everybody—what all those people failed to realize is that as the molecule Squalamine doesn’t have any effect whatsoever on parasites. It’s effect is 100% on activated endothelial cells which is where the problem really lies, and so the Fovista drug and Regeneron’s PDGF inhibitor, both of which failed, were working an entirely different cell type, basically, than on parasites. That’s number one.
Number two, not only does it decrease these growth factors, it also specifically acts on these new endothelial cells. It changes the actin and filament within the cells which changes the structure of these new vessels, causing the vessels to block off, and that’s exactly what we want.
So, when you look at the Phase 2 data, unfortunately in the past everybody hoofed that horse, using Dave’s analogy, up to the buggy of all PDGF inhibitors and it was bunched together with them. Now, interestingly enough, the results of the study was actually very similar, however the similarity was not because it was working on PDGF; the similarity was that the combination of Squalamine as an eye drop together with Lucentis appeared to be working very well in Phase 2.
What I like about what Ohr did in Phase 3, unlike what Fovista did in its Phase 3 is that it basically Ohr took the patients who did well in Phase 2 and designed their Phase 3 clinical program on that, whereas Fovista and Ophthotech basically took their Phase 2 data where they did well and they changed it to include patients where their drug wouldn’t do well. So, one of the reasons why I think Fovista actually failed is they basically changed the study design between Phase 2 and Phase 3, which is a clinical trial no-no, and what Ohr did was the way that anybody who designs clinical trials would want to do which is take the learnings from Phase 2 and use that to design a rational Phase 3 that has an even higher chance of success than the Phase 2.
Sam Slutsky:
Got it. Thanks for that overview. Dr. Brown, wanted to get your view on the data and rationale for the patient enrollment in the current study.
Dr. David Brown:
First of all, on selecting patients that did better, I think it’s always good to enrich your effect. Certainly we do that in every clinical trial where we try to give a dose, you know, the month before the endpoint. It sounds like you wouldn’t want to restrict your label, but in today’s times where every optometrist has an OCT, most of the lesions we are catching are small lesions and most lesions are occult, and so this is the largest percentage of the lesions we get in the clinic these days.
I’m more excited about a continuous, ongoing anti-VEGF suppression. We basically give now pulsatile treatment where you give a big dose and most of the PK curves are linear, so when patients re-leak it’s typically when we think they get below a level of VEGF inhibition that would decrease leakage. If you could have ongoing VEGF suppression with something like an eyedrop, I think patients would love it. They’d definitely take their eyedrop and extend longer, and potentially get where they don’t have to have injections. I think that’s the most exciting part of this is a continuous anti-VEGF suppression along with some of the other cytokines that are blocked that we know from the Squalamine preclinical data.
Sam Slutsky:
Great. Thanks for that. Dr. Kaiser, in terms of the efficacy data for the control arm in Ohr’s study with Lucentis, do you think it was an accurate representation of what you would see in the real world?
Dr. Peter Kaiser:
Yes, it was. Obviously comparing across trials is an effort that you—fraught with error, however if you kind of look at the average of clinical studies where patients were enrolled all-comers, for instance the C.A.T. study or the IVAN study, the control group of Lucentis in the study performed almost identically to C.A.T., so it wasn’t that the control group was doing poorer and the combo group was doing normal. No, the monotherapy group was doing normal and the combo group was doing definitively better.
Sam Slutsky:
Okay, great. This question is for both doctors, but based on your extensive experience with clinical trials in the past and with Squalamine, what probability of success would you give this program in the current wet AMD trial? Dr. Brown, we can start with you.
Dr. David Brown:
I think that because of the continuous steady state suppression in multiple cytokines, I am on record as saying I thought the Fovista trial had a 10% chance of success and I think this one is much closer to 50/50.
It’s a well designed trial. They’ve got quite a bit of numbers. It seems like we’ve got quite a few patients in this trial and they’re not complaining that the eyedrop stings and it looks like their compliance is good. So, I’m optimistic that we got a horse race here. I hope we get visual acuity benefits. I think, to be honest, we may be close to the top of the curve, and so it may be that this is a drug that it does give you more duration or longer time between injections. We won’t see that in this first trial but hopefully there’s enough of a signal that they can go to a Phase 3. We’re in the second year. They’ve got where they stretch out the injections and you see duration. If we get visual acuity, that’s great, and I think that chance is about 50/50.
Sam Slutsky:
Great. Thanks for that. Dr. Kaiser, your thoughts?
Dr. Peter Kaiser:
Yes, I agree with Dave. I think when we look at some of the other combination studies, our probability of success that we were giving out was pretty low. Most companies will be pretty happy with 50/50; in fact, they would greenlight anything above probably about 30%.
I thinking maybe it’s a little higher. I’m going to go out on record and say 60% chance of success because I really think what the company has done in terms of honing in on the patients who did well in Phase 2 is going to bode well. They’ve eliminated the patients who may not do as well with the combination therapy from the enrollment, and to me this usually means that the success rate goes up from Phase 2.
So, you know, I’m pretty optimistic about this one. If it works, there’s a lot of other areas that an eyedrop can be used because remember now, the bar for a combo drop from a patient/physician standpoint—not from the FDA standpoint but from a patient/physician standpoint to add a drop is incredibly low versus another injection. The FDA, when you say combo to them, it doesn’t matter if it’s a drop or another injection, the bar is the same, but from a patient and a physician standpoint it’s a huge difference. An eyedrop, I don’t have to deliver it myself. I can write a prescription, the patient goes and gets it. The patient doesn’t mind taking an eyedrop, whereas if it’s another injection, here’s a whole nother worry about reimbursement, what’s going to happen with insurance companies’ coverage of that other injection. So, to me there’s a lot of reasons why I’m actually very bullish on this product and I’m optimistic to see the results in the future.
Dr. David Brown:
Yes, a lot of physicians that currently use Avastin, use Avastin because they’re worried about the financial implications, and what I mean by that is in a buy and bill scenario, when you give a $2,000 drug that you have to purchase from a drug distributor, you got to pay for that drug in 60 days. If your insurance company stiffs you once, and the margin’s 3%, 4% at the most, you got to do another 200 injections to make up for that one lost drug.
For this, physicians don’t have any financial risk by adding on the eyedrop with the prescription because it’s not a Part B drug.
Sam Slutsky:
Interesting. That’s going to be helpful for understanding the reimbursement landscape. Okay.
So, Dr. Brown, Dr. Kaiser had mentioned this briefly, but when thinking of some of the recent wet AMD failure’s such Ophthotech’s, Fovista, which had positive Phase 2 results, what do you think are the main contributors to the Phase 3 failing?
Dr. David Brown:
I think it’s the target. I mean, you had a very good study from Regeneron with potentially a better PDGF blocker that totally busted as well; the monotherapy did better than the combination therapy. If you look at Fovista’s Phase 2 data on lesion regression, which was the first thought, you strip the parasites, you get the anti-VEGF in there and it regresses more. If you go to the SEC (phon) filing, you see that monotherapy Lucentis caused more lesion regression than did combination therapy. So, if you’re premise is wrong, and I think it was tested well in both studies, both the Regeneron and the Fovista, and you put it up there and it loses, it loses.
Ang2 we hope has more of a potential of the combination, and again, anything that gives a steady state suppression like the sustained release device, like a gene therapy, if you can get enough product development, like an eyedrop from Ohr, I think that has the best chance of winning versus our paradigm of single injection high dose and then steady state linear decrease in PK.
Sam Slutsky:
Got it. Okay, thanks. Dr. Kaiser, in terms of combination approaches for wet AMD, do you think add-on therapies will be a one size fits all kind of like anti-VEGF, or do you think patient selection will be a key to truly recognizing the benefits of add-ons?
Dr. Peter Kaiser:
I think like everything, patient selection is going to be important. Certainly, for instance, with the Ohr product, very large occult lesions, probably not a good idea to be using the product unless we hear something differently. So yes, we are going to be using different add-ons for different reasons. The only other add-on that we probably will have is Ang2 in the near future—I should say anti-Ang2 in the form of Regeneron’s product which would be an add-on, but in that study we don’t know yet are there certain lesions that it works better on or is it a work on all comers? We don’t know yet.
Sam Slutsky:
Okay. In terms of the clinical pipeline, a bunch of companies are going after combination approaches on top of a VEGF inhibitor. So, Dr. Kaiser, in add-on works with one VEGF inhibitor in its study, do you think that can be extrapolated to use on top of the other anti-VEGF inhibitors as well?
Dr. Peter Kaiser:
As long as the mechanism of action is distinct, the answer should be yes. So, any add-on should work with any anti-VEGF agent, whether it be say a gene therapy anti-VEGF or a sustained release in the form of say an implant like the LADDER study from Genentech. It wouldn’t matter how the anti-VEGF is performed.
Now, if that add-on is another injection then the patient acceptance of it may be lower. If it’s an eyedrop like Squalamine, for instance, then that’s no big deal to add that on, and so it will be probably more likely for us to add on the ones that are easy to add on than the ones that are a little more difficult.
Dr. David Brown:
Yes, and that being said in an eyedrop, even if you have the world’s best injection—say RTH just kills it—there’s going to be very little uptake to that drug that’s a J code and that’s because of that buy and bill scenario I gave you. In other words, if I buy a $2,000, or a who knows, $3,000 RTH drug and there is no J code, you use an undefined code when you code it, which means that insurers always delay your payments. So that’s a six to eight-month delay typically after the drug comes out to get that J code.
With a prescription, I don’t care. I mean, it’s their problem if the patient’s insurance doesn’t cover it at the pharmacy. I think it’s much more likely to uptake an eyedrop quickly than it is another biologic injection.
Sam Slutsky:
Got it. Dr. Brown, can you discuss the potential challenges of combination therapy from a compliance and reimbursement standpoint when we have two products that are administered both as injection at different intervals?
Dr. David Brown:
Yes. So, even though the—Peter made a good point that the drugs are different, the Novartis and the Regeneron drug, but they’re still given as a single injection, so I think that’s okay. I think what would have been very challenging is something like Fovista where you had two injections, potentially the same day or close to each other. Currently we have both CMS Medicare and private insurers that do these overall big audits looking for an injection within 28 days of another, and that’s to say they don’t want me to give Avastin in between an Eylea injection. Anything within 28 days gets flagged. They typically deny the expensive drug; they’re not stupid. So, any time you have to give two injections that are expensive biologics within a similar time I think would be incredibly challenging unless you got the insurance companies to buy on that it was really that much better.
The two combinations, one, the BiFab from Novartis and the sort of like Tide where you’ve got the white little soaps and the blue little soaps together in the same injection, I don’t think is going to be as big of a deal for us because it’s just one injection code along with the price of the drug.
Sam Slutsky:
Interesting. Dr. Kaiser, you feel the same way about this or is there any differences from your practice?
Dr. Peter Kaiser:
I think David said it right, you know? What many on Wall Street don’t get is sort of the insurance aspects of what we do and how it guides so much of our practice of medicine, unfortunately, and the idea of having to do, like Fovista would have been, two injections, was really not going to be all that palatable to us with reimbursement. We’ll see what happens with the Ang2 inhibitors, where that plays out. It’s still an injection at the end of the day and when you have a new drug and a new injection, it’ll be a long uptake for us because of the worry about reimbursement.
Sam Slutsky:
(Inaudible). Got it. Thanks for that. I now wanted to turn to Regenxbio which is developing an AAV gene therapy technology that leads to the local production of an anti-VEGF antibody fragment. Dr. Kaiser, I wanted to get your view on the potential overall application of this technology and if it did work, how could it potentially interrupt the anti-VEGF market?
Dr. Peter Kaiser:
Well, let’s assume many things. One is that the vector that Regenxbio is using, so it’s its AAV vector, is correct to infect the cells we want and infect it in the retina. Let’s just assume that. Let’s also assume that the plasma they have packaged within the vector is correct also and will produce the anti-VEGF protein that will work. So, those are two big assumptions already. Then let’s assume that it actually transfects enough cells to produce enough protein for this to work in the eye.
Now, theoretically, it should, right? The Regenxbio IP is much stronger than say Avalanche’s old IP or some of the other gene therapy companies IP. It’s very strong and particular in the delivery of drug to the eye by an AAV vector. So, that part of the equation they’re at least as good as anybody else out there.
Let’s just assume that the drug completely works and produces long-term anti-VEGF protein within an eye. This is obviously an exciting thing, but it wouldn’t change any sort of the combo drugs that are individual. For instance, if Ohr worked, there’d be no reason to not combine that with a Regenxbio product because all you’re adding is an eyedrop. If there was another add-on that would require say an additional injection, then they’d be maybe a little less likely to be added on to a Regenxbio type situation.
So, I’m bullish on Regenxbio but it’s really early so there’s not too much to read into it because we have basically no data that really can guide us how that company is going to do just yet.
Sam Slutsky:
Okay. Great for that, thanks for that overview. Dr. Brown, just wanted to get your thoughts as well on the potential role of a gene therapy for wet AMD.
Dr. David Brown:
We’re excited about gene therapy. The difficulty is just as Peter alluded to, can you get enough product through your vector and your gene construct to actually give you a steady state drug? If you can, I think it would take over—it would be second line because you’d give injections for a while, and then people that knew they had to have injections more frequently than whatever it is, 8 weeks, 12 weeks, would say, “Hey, I’d love to have this operation.” There’s been two, I think, maybe three patients dosed in the U.S., so we’re going to have some data soon of whether it looks like this thing gives biologic activity. If it does, it will interrupt the landscape. Part of it’s going to be you’re going to have a surgery with a surgery center and a drug that’s probably got to be priced at 20 grand or more, so it’s going to take a while for insurance companies to swallow that, but I think it will be a major disruptor if, like Peter says, all the pieces fall into place and it really works.
Sam Slutsky:
Okay, thanks. Overall, Dr. Brown, from a prescribing standpoint, do you have any concerns with recommending gene therapy technologies for ophthalmology?
Dr. David Brown:
You know, we’re—AAV vector, the current vectors are not self-replicating. In other words, it’s not like something that can get in your system and go crazy and take over. That’s also a problem because those cells probably have less production of protein over time, which could limit potentially the use of this thing. Like it may not be a treatment that lasts 20 years, but we don’t know that. But, from a gene therapy perspective I think it’s a pretty safe bet with the current vectors.
Better vectors like the lentiviruses, the herpes, the AIDS viruses, etc., are much better at actually transfecting cells and turning your cells into doing what they want to do, but again, much scarier. A lentivirus is a much scarier virus that has much more potential for trouble, but yet it’s a better vector to actually do what you want to do. So, we hope that the AAV vectors work. If not, I think they’ll be pushing to stronger and potentially riskier vectors.
Sam Slutsky:
Oh, interesting. Thanks for that. Dr. Kaiser, do you have any additional potential concerns or thoughts on the overall application?
Dr. Peter Kaiser:
I don’t have a huge concern. One is more of a theoretical concern which is when we’re treating macular degeneration with anti-VEGF agents, there has been a suggestion that macular atrophy can occur. I’m on the camp that says I don’t really believe in it, but let’s just assume that there are some people who really believe in it and they’re right. In that situation, having chronic VEGF suppression for a disease like macular degeneration may not be a good idea.
Now, I say may not because all these things are theoretical and I’m still in the camp that says GA or macular atrophy is really not occurring in these patients; at least I haven’t seen it, so I think it’s more of a theoretical concern than a true concern at this point. Because once you turn on the gene production, you really can’t turn it off. Some of these gene therapy companies are saying you could turn it off by doing laser to the transfected cells. Well, that’s all said and good except you don’t know what the transfected cells are. So you can’t see it, so how are you supposed to laser it?
Sam Slutsky:
Got it. Got it, okay. Are there any other treatments in development that either of you are excited about for wet AMD that we haven’t discussed? Dr. Kaiser, we can start with you.
Dr. Peter Kaiser:
I think the other AMD product that has very strong data to date are the integrin inhibitors, in particular the one from Allegro Pharmaceuticals. That one has shown very good results in DME and some early results in AMD, and just by its mechanism of action would be distinct from anti-VEGF agents. What excites me is its possibility of it going—being used as monotherapy as well as combo therapy, but not having to do combo for the registration study, because I hate doing combo for registration if I can avoid it. It’s always easier to do monotherapy.
Sam Slutsky:
Got it. Do you think it’s magnitude of effect could go against VEGF?
Dr. Peter Kaiser:
It’s probably not going to be as strong as VEGF. It may last a little longer than anti-VEGFs, so that’s a plus, but because of its mechanism of action, it would be complementary to anti-VEGF. So, because of that, once we actually have it in market we would be able to use it in combo. Sort of like a lot of chemotherapy drugs are used now; they get approved mono but it turns out they work better together and they do that sort of post approval.
Sam Slutsky:
Okay, got it. Dr. Brown, are there any additional drugs in development that you want to discuss that we haven’t touched on?
Dr. David Brown:
It’s interesting. For years they kept looking for this magical factor, Factor X that became VEGF, and the VEGF blocker is amazing. We have equal scientific data on a bunch of other targets. CC3 chemokine receptors, tide agonists, Ang2 blockers, all of these things are a long ways away but potentially could be an additive agent or the magic bullet that really makes it where you turn off angiogenesis, neovascularization, and turn off the production of VEGF. Fortunately, there’s a lot of money in early drugs and so a lot of basic science been going on and preclinical data.
I don’t think we’ve found insulin. One of my partners keeps saying, “This is insulin, Dave. We’ll never have anything else. They’ve been using insulin since the ‘50s. They don’t have a second drug,” and they sort of do, but I’m hopeful that we will have something to decrease the treatment burden of the many, many, many patients I have that need injections every month to control their AMD, their DME or their RVO.
Sam Slutsky:
Okay.
Dr. Peter Kaiser:
I think the interesting thing about drug development in AMD is that many of the large pharma companies have offloaded the development onto the smaller companies. None of the large pharma companies—Regeneron excluded from that statement—really go out and develop in-house drugs and then take those drugs all the way throughout. They basically let somebody else do the development and then they buy them for large sums of money where it’s better to have a bird in hand than one in the bush, in other words. So, to me, companies like Allegro and like Ohr and some of these other smaller companies, once they show positive results in Phase 2, it’s very unlikely they’re going to stay alone at doing this. The pharma partner should be coming in very rapidly at that point.
I really wish also that these large pharma companies would spend some of that huge amounts of money they have on developing products because they have certainly much deeper pockets than the smaller companies.
Sam Slutsky:
Great. Yes, it seems like we’re seeing that approach throughout drug development overall in terms of partnerships and a lot of stuff being dumped onto the biotechs to do just because of the efficiency.
All right. I guess at this time, Operator, we’d like to open the line for questions. As a reminder, questions can also be submitted to questions@lifescicapital.com.
Operator:
Thank you. If you’d like to ask a question, please signal by pressing star, one on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, press star, one to ask a question. We’ll pause for just a moment to allow everyone an opportunity to signal for questions.
Sam Slutsky:
Great. While we wait for the queue to fill up, Dr. Brown, overall, could you provide us with a quick overview of the upcoming catalyst for wet AMD that you’re most excited about?
Dr. David Brown:
Like I said, end of the year we’re going to have our Ang2 combo results; we’re going to have some Ohr results here shortly thereafter. I think both are exciting.
Sam Slutsky:
Okay. Dr. Kaiser, any additional ones?
Dr. Peter Kaiser:
Those are the big ones. I think we’re all very excited about both these study results.
Dr. David Brown:
The RTH details obviously.
Dr. Peter Kaiser:
Yes, that’s for sure. We expect that probably like third quarter, around the AAO would be my guess. I’m actually surprised that you said that they’re not looking for approval for it until 2019. I would have thought they would be going earlier but you may be right.
Dr. David Brown:
Yes.
Operator:
Once again, if you’d like to ask a question, please press star, one.
Dr. David Brown:
Did they say why the delay? Is it production? That’s hard to believe. You would think that the second largest pharmaceutical company in the world could produce it.
Sam Slutsky:
Yes. I’m unclear (phon).
Dr. Peter Kaiser:
You would hope.
Sam Slutsky:
All right. At this time, it doesn’t seem like there are any questions in the queue, so wanted to thank both Dr. Kaiser and Dr. Brown for your time. Definitely a very insightful call, and thank you to everyone who tuned in.
Dr. Peter Kaiser:
Great.
Dr. David Brown:
Thanks, gentlemen.
Operator:
This conclude today’s call. Thank you for your participation. You may now disconnect.
Kite was probably going to charge 500 thousand a year for their drug
will Gilead be able to do that?
Spotlight – Putting a number on CAR-T deaths
http://epvantage.com/Universal/View.aspx?type=Story&id=716231&isEPVantage=yes
Spotlight – Putting a number on CAR-T deaths
Date June 26, 2017
The toxicity of CAR-T therapies took on fresh importance with the discontinuation of Juno’s Rocket study of JCAR015 owing to deaths from cerebral oedema. Little wonder that when Novartis presented its update of the Eliana trial of CTL019 one spotlight fell on safety.
The good news, according to Saturday’s update at the European Haematology Association meeting, is that there were no new unexpected deaths, and no cerebral oedema. How this plays out will be important: precise safety data are hard to pin down, but an exhaustive EP Vantagesearch of various sources has yielded a definitive list of CAR-T deaths not due to disease progression (see tables below).
This involves not just CTL019, but all of the three leading players’ CD19-targeted projects. One little-appreciated finding is there have been seven deaths – two from cerebral oedema – in trials of Juno’s JCAR014. This has resonated little with investors, likely because Juno has long maintained that it does not intend to pursue JCAR014 to registration.
However, the close similarity with Juno’s lead – JCAR017 differs from JCAR014 only in a manufacturing step – should push CAR-T followers to pay close attention to this issue. That said, reported deaths on JCAR017 have been substantially lower, the data show.
18 Juno study deaths not due to disease progression
Indication Study Trial ID Description of grade 5 event Due to CAR? Source
JCAR017 (Juno/Seattle Children's Hospital)
Lymphoma Transcend NCT02631044 Diffuse alveolar damage (subject refused mechanical ventilation) Yes Asco 2017
Lymphoma Transcend NCT02631044 Multiple organ failure No Asco 2017
JCAR015 (Juno/Memorial Sloan Kettering)
Adult ALL MSKCC study (Jae Park) NCT01044069 Severe hypotension, (ventricular arrhythmia?),CRS Yes Juno S-1, Dec 2014
Adult ALL MSKCC study (Jae Park) NCT01044069 Status epilepticus, CRS(history of neurotox w prior CAR-T)* Yes Juno S-1, Dec 2014
Paed/adult ALL MSKCC study (Kevin Curran) NCT01860937 Survived CRS, died 4mth later from multiviral pneumonia No Report to GTSAB
Adult ALL MSKCC study (Jae Park) NCT01044069 Sepsis, multi-organ failure Yes Ash 2015
Adult ALL Rocket NCT02535364 Neurotox, later specified as cererbral oedema Yes Juno Q3 2016 SEC filing
Adult ALL Rocket NCT02535364 Cerebral oedema Yes Juno 7 Jul 2016 call (revised)
Adult ALL Rocket NCT02535364 Cerebral oedema** Yes Juno 7 Jul 2016 call (revised)
Adult ALL Rocket NCT02535364 Cerebral oedema Yes Juno Q4 2016 SEC filing
Adult ALL Rocket NCT02535364 Cerebral oedema*** Yes Juno Q4 2016 SEC filing
JCAR014 (Juno/Fred Hutchinson)
Adult ALL Hutch study NCT01865617 CRS Yes Juno S-1, Dec 2014
Lymphoma Hutch study NCT01865617 Encephalopathy and pontine haemorrhage Yes Ash 2015
Adult ALL Hutch study NCT01865617 Cerebral oedema Yes 7 Jul 2016 call (revised)
CLL Hutch study NCT01865617 Pulmonary aspergillosisafter severe CRS No Ash 2015
Lymphoma Hutch study NCT01865617 CRS or neurotox Yes Juno Q4 2016 SEC filing
Adult ALL Hutch study NCT01865617 CRS or neurotox Yes Juno Q4 2016 SEC filing
CLL Hutch study NCT01865617 CRS, cerebral oedema Yes Juno Q4 2016 SEC filing
Note: patient exposure numbers are undisclosed for JCAR015, JCAR017 or JCAR014.CRS=cytokine release syndrome.*FDA-imposed clinical hold. **Second FDA-imposed clinical hold. ***Voluntary clinical hold, leading to discontinuation of JCAR015.
The toxicity of CAR-T therapies has been problematic ever since the first signs of truly robust activity were seen – it is known that cytokine release syndrome and neurotoxicities correlate with efficacy and tumour burden.
However, nurses have become very skilled at dealing with these types of toxicities, and several important centres have developed detailed plans to minimise their effects. Nonetheless, the specific finding of cerebral oedema posed very serious questions, and ultimately did forJCAR015, which until recently was Juno’s lead.
The issue also hit Kite’s KTE-C19, a construct very similar to JCAR015, and this group’s stock took a tumble last month when a patient died from cerebral oedema in a safety extensioncohort of the pivotal Zuma-1 lymphoma study (Kite investors see an uncomfortable parallel with Juno, May 8, 2017).
Nine KTE-C19 study deaths not due to disease progression
Indication Study Trial ID Description of grade 5 event Due to CAR? Source
Lymphoma NCI phase I-IIa trial, group 1 NCT00924326 Influenza pneumonia 18 days after receiving CAR No Kite S-1, Dec 2014
Lymphoma NCI phase I-IIa trial, group 2 NCT00924326 Unknown cause 16 days after receiving CAR, presumed heart arrhythmia No Kite S-1, Dec 2014
Lymphoma Zuma-1, phase I NCT02348216 Gr 4 encephalopathy & CRS, gr 5 intracranial hemorrhage& severe thrombocytopenia No Ash 2015
Lymphoma Zuma-1, phase II NCT02348216 Hemophagocytic lymphohistiocytosis Yes Ash 2016
Lymphoma Zuma-1, phase II NCT02348216 Cardiac arrest in setting ofCRS, later specified as anoxicbrain injury Yes Ash 2016, FR doc 2017-07800
Lymphoma Zuma-1, phase II NCT02348216 Pulmonary embolism No Ash 2016
Adult ALL Zuma-3 NCT02614066 Hypotension, heart failure, hypoxemia, acidosis in dose expansion, organ failure &CRS Yes Ash 2016
Paed ALL Zuma-4 NCT02625480 Fungal infection No Ash 2016
Lymphoma Zuma-1, safety expansioncohort NCT02348216 CRS, multi-organ failure, leading to cerebral oedema Yes Q1 2017 call
Note: ~300 subjects have been dosed KTE-C19, including NCI studies. CRS=cytokine release syndrome.
The data need to be seen in the context of several important caveats. Firstly, they comprise alldisclosed CD19-directed CAR-T trial deaths that were not due to disease progression, whether these were deemed to be due specifically to the CAR-T cells or not – a subjective decision made by the specialist in question.
Early deaths on trials of KTE-C19 and JCAR015 were in the academic setting, and will have involved academic rather than commercial manufacturing. In evaluating the frequency of deaths the total number of patients treated must be borne in mind – though this is a numberJuno has never disclosed.
And of course it must be remembered that subjects on CAR-T studies are very ill, so are already at high risk of death. While this does not reduce the need for clinical rigour, several sources have commented to EP Vantage off the record that Juno might – scientifically if not reputationally – have been rash to discontinue JCAR015.
Extreme care must also be taken in extrapolating JCAR014 deaths to JCAR017; the deaths caused Juno to continue its ALL trial only with the lowest JCAR014 dose (2x105 cells/kg), and to scrap two higher levels. Juno has yet to choose a dose of JCAR017 to take into its pivotal lymphoma trial.
All that said, taking into consideration the caveats the data should speak for themselves.
After EP Vantage compiled the lists Kite and Juno cooperated fully in confirming the data as accurate. Novartis, however, did not respond to requests for clarification; as such, it is possible that there have been more deaths on CTL019 trials, and the list comprises only the two that came to light in scientific presentations.
Two CTL019 study deaths not due to disease progression
Indication Study Trial ID Description of grade 5 event Due to CAR? Source
Lymphoma Penn study (Stephen Schuster) NCT02030834 Encephalitis Yes Ash 2015
Paed ALL Eliana NCT02435849 Cerebralhaemorrhage Yes Ash 2016
Note: 283 subjects have been dosed CTL019.
Across CAR-T projects, the cerebral oedema deaths tally with those reported at December’s meeting of the US Recombinant DNA Advisory Committee, which additionally detailed two non-fatal cerebral oedema cases, one in a multiple myeloma study of an anti-BCMA CAR.
Several of the other neurotoxicity-related deaths disclosed – brain haemorrhage, for instance – sound uncomfortably close to cerebral oedema. But it should be stressed that after theJCAR015 incident most groups went back and reanalysed all previous toxicities to ascertain whether cerebral oedema might have been involved, and to rule out such a possibility.
Mechanistic mystery
Meanwhile, it is one of the many mysteries of CAR-T therapy that there is still no agreement on what precise mechanism might be responsible for causing cerebral oedema, though it is largely accepted that, being a cytokine-mediated event, it is something that arises from cytokine release syndrome.
Some doctors have told EP Vantage that this likely involves activated CAR-T cells crossing the blood-brain barrier, and then undergoing some kind of secondary activation event in the cerebrospinal fluid. However, many dismiss the simple answer that this results from expression of CD19 in the CNS.
An even deeper mystery is what aspect of CAR-T therapy might give rise to this kind of stimulation. Some have suggested the role of the co-stimulatory domain that each construct uses, others the manufacturing process, others still the indication studied, but given that all the CAR constructs differ in multiple ways, and that the numbers are still small, there is no way to be sure.
The FDA is separately compiling its own database of CAR-T toxicities. The provisos notwithstanding, investors should at the very least be aware of the numbers as they emerge.
To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter
from Biocentury
9:38 PM EDT | MAY 12, 2017 | BIOCENTURY | POLITICS, POLICY & LAW
INNOVATION MANDATE
SCOTT GOTTLIEB’S BIPARTISAN MANDATE FOR INNOVATION
BY STEVE USDIN, WASHINGTON EDITOR
Scott Gottlieb was sworn in as FDA commissioner with a clear, bipartisan mandate to continue and accelerate regulatory innovations that speed the transformation of scientific progress into medical products and to intensify the participation of patients in regulatory decisions.
Gottlieb will start with a large measure of goodwill among career FDA staff and members of Congress who heaved massive sighs of relief when he was selected for the position over candidates who had denigrated the agency’s civil servants and ridiculed the basic premises of modern medical product regulation.
Even Democratic senators who did not vote for him decided not to stall confirmation because they want Gottlieb to help push reauthorization of medical product user fees onto President Donald Trump’s desk before FDA has to start notifying thousands of reviewers that they may be laid off.
Gottlieb arrived on FDA’s White Oak campus on May 12, a day after the Senate Health, Education, Labor and Pensions (HELP) Committee passed medical product user fee reauthorization legislation. The HELP vote set the stage for a vote by the full Senate.
Gottlieb will start with a large measure of goodwill among career FDA staff and members of Congress.
The House Energy & Commerce Committee’s health subcommittee is likely to discuss user fee reauthorization legislation on May 17, and the full committee could pass it the following week. This would put both the House and Senate on track to pass the bills well before the summer break starts at the end of July.
Although there is bipartisan agreement to get user fees reauthorized quickly, in the current political environment, surprises or controversies that would delay or derail legislation are always possible.
The user fee legislation, combined with the 21st Century Cures Act that was enacted in December, will give FDA a great deal of discretion about how it advances regulatory innovation. The two laws also will provide Gottlieb new tools to recruit and retain staff, and even more importantly, put Congress on record as supporting FDA’s use of its power to proactively advance medical product development.
The premise of the 996-page Cures Act is that increased government investment in and new ways of thinking about biomedical innovation and regulation can produce more “cures.” It promotes patient-focused drug regulation, along with pushing FDA to qualify more drug development tools including biomarkers and surrogate endpoints, and to facilitate the use of novel clinical trial designs.
The PDUFA VI agreement commits FDA to advance its engagement with patients from town hall-style meetings to the development of rigorous tools for the collection and assessment of patient preferences.
The new PDUFA deal also would provide resources for and commit FDA to moving forward on model-informed drug development, biomarker qualification and novel clinical trial designs.
Gottlieb is likely to layer new innovation initiatives on top of the measures mandated in PDUFA and 21st Century Cures.
GETTING USER FEES DONE
To get rolling on PDUFA VI and new user fee agreements for biosimilars, generic drugs and medical devices, one of Gottlieb’s most pressing tasks will be ushering the FDA Reauthorization Act of 2017 (S. 934) and a similar House bill through Congress and onto the president’s desk.
HELP Chairman Lamar Alexander (R-Tenn.) has cut a deal with Democrats on his committee that should make the Senate process relatively smooth.
Alexander secured cooperation from Democrats to quickly move the user fee bill out of the committee by agreeing to their demands to hold at least one, and possibly as many as three, hearings on prescription drug costs. Based on this commitment, HELP Democrats withdrew a number of contentious amendments and agreed to limited discussion before the full committee passed S. 934 in a 21-2 vote.
The deal both speeds the user fee reauthorization to the floor, and provides opportunities to separate drug price control proposals from FDA legislation.
The two laws put Congress on record as supporting FDA’s use of its power to proactively advance medical product development.
The committee approved an amendment sponsored by Sens. Susan Collins (R-Maine) and Al Franken (D-Minn.) that would fast-track ANDAs if there were three or fewer generic versions of a product on the market. The goals of the amendment are consistent with policies Gottlieb advocated prior to his nomination and in his confirmation hearing.
So far, Congress has backed away from entangling FDA and Gottlieb in controversies over commercial-scale prescription drug importation. Gottlieb has opposed importation in the past and declined to endorse it during his confirmation hearing, despite Trump’s public statements supporting importation.
The HELP Committee voted 13-10 against an amendment offered by Sen. Bernie Sanders (I-Vt.) to allow importation from Canada and possibly other countries.
Sanders is expected to introduce the amendment again when the full Senate considers S. 934, and the vote will almost certainly be close.
In January the Senate defeated a non-binding amendment that expressed support for importation in a 46-52 vote. After the vote, several of the Democrats who voted against importation said they would favor it in future votes, and President Trump has expressed strong support for importation.
Alexander submitted but did not request a vote on a poison pill amendment that would effectively neuter importation by making any attempt to bring drugs into the U.S. contingent on declarations by the HHS secretary that doing so would not create health or safety risks, increase exposure to counterfeit drugs or exacerbate the opioid crisis.
If the amendment is added to S. 934 it would strengthen current law enacted during the Clinton administration, which allows importation only if the HHS secretary certifies it can be done safely and would produce meaningful financial savings.
By piling on the requirements about counterfeits and opioids, Alexander’s proposal would make it even more difficult for any HHS secretary to honestly certify that importation met all of the legal criteria.
Congress is likely to continue to resist efforts to hurt biopharma companies by attaching price controls to user fee legislation, or to help them by including new market exclusivities or other incentives.
ADDRESSING ACCESS?
HELP green-lighted an amendment sponsored by Sens. Orrin Hatch (R-Utah), Michael Bennet (D-Colo.), Richard Burr (R-N.C.), and Bob Casey (D-Pa.) that addresses some of the concerns expressed by patient advocates who are seeking easier access to unapproved therapies.
The amendment would require FDA to create guidance about expanding clinical trial inclusion criteria to more accurately reflect populations who will receive drugs. The amendment specifically mentions expanding trials to include children, and patients with co-morbid conditions.
FDA and medical societies already have been pressuring drug developers to expand entry criteria for clinical studies so patients can access investigational drugs without resorting to compassionate use.
The Hatch amendment also would change the law to allow sponsors to publicize the availability of unapproved drugs through compassionate use, or expanded access, 15 days after receiving breakthrough therapy, Fast Track or regenerative medicine advanced therapy (RMAT) designations. Under the current law, companies cannot communicate about expanded access until products are in Phase II or III trials.
If enacted, the amendment could reduce pressure on Congress to pass right-to-try (RTT) legislation that Trump and Vice President Mike Pence have endorsed. For FDA, the most problematic part of right-to-try legislation that has been introduced in both houses of Congress is language prohibiting the agency from considering safety signals that emerge from use of unapproved drugs outside of a clinical trial.
In response to a question about RTT posed to him as part of the confirmation process, Gottlieb committed to policies that would “appropriately balance individual patients’ needs for access to investigational therapies while recognizing the importance of maintaining a rigorous clinical trial paradigm for testing investigational products and demonstrating safety and efficacy.”
TARGETING PEDIATRIC CANCER
Lobbyists will be working overtime to persuade the Senate leadership to slip additional provisions into S. 934 before the full Senate votes, and those who fail will be pressing senators to introduce amendments.
Some of the most intense lobbying and negotiations will involve the fate of an amendment Bennet withdrew at last week’s hearing.
The amendment was based on the Research to Accelerate Cures and Equity (RACE) for Children Act (S. 456, H.R. 1231), which seeks to modify the Pediatric Research Equity Act (PREA) to stimulate pediatric cancer trials.
PREA requires sponsors to conduct pediatric trials of drugs that are being developed for adults if the condition the drug is intended to treat occurs in children. It hasn’t led to more pediatric cancer trials, because under conventional definitions based on the site where tumors occur, children and adults rarely get the same kinds of cancer.
In addition, there is an exemption from PREA for Orphan drugs, and in recent years about 90% of cancer drugs have had Orphan status.
The RACE Act would modify PREA to make it apply to pediatric cancers that are driven by the same molecular or genetic targets as an adult cancer. It also would waive the Orphan exemption for cancer drugs.
Bennet said at the May 11 hearing that FDA agrees PREA should be updated to make it applicable to pediatric cancer. He secured a commitment from Alexander to have language reflecting FDA’s views inserted into S. 934 before it is brought to the Senate floor.
Biopharma lobbyists, pediatric cancer advocates and FDA are negotiating modifications of the RACE Act with Bennet. According to congressional staff, the final legislation is likely to make PREA pediatric study requirements apply to Orphan cancer drugs “for an indication for a pediatric cancer or adult cancer if such drug or biological product is intended for the treatment of an adult cancer and is determined by scientific evidence to be directed at a molecular target” likely to be relevant to a pediatric cancer.
FDA would be required to develop and publish a list of primary molecular targets for pediatric cancers after consulting with the pediatric oncology subcommittee of the Oncologic Drugs Advisory Committee and convening a public meeting.
ONGOING REGULATORY INNOVATIONS
New regulatory innovation policies Gottlieb rolls out will likely complement those spelled out in the 21st Century Cures Act and contained in PDUFA VI.
Under Cures, FDA must develop a plan by June 11 for the creation of guidance documents on how sponsors can collect patient experience data and integrate it into drug development. The agency will then have a year to release a draft of at least one of these guidance documents.
Cures also shines a spotlight on patient data by requiring that FDA include in drug approval announcements “a brief statement regarding the patient experience data and related information, if any, submitted and reviewed.”
The PDUFA VI agreement commits FDA to release draft guidance in FY19 “describing processes and methodological approaches to development of holistic sets of impacts that are most important to patients.”
The guidance will include FDA’s thinking about determining the factors that are most important to patients “in terms of burden of disease, burden of treatment, and other critical aspects.” It also will “address how patient input can inform drug development and review processes, and, as appropriate, regulatory decision making.”
Cures also requires the agency to develop plans for the integration of real-world evidence to support approvals of new indications of approved drugs.
Both Cures and PDUFA VI commit FDA to devote more resources to the review of biomarkers and surrogate endpoints and to the development and assessment of novel clinical trial designs. The user fee agreement commits FDA to start a pilot project in FY18 for “highly innovative trial designs for which analytically derived properties (e.g., Type I error) may not be feasible, and simulations are necessary to determine trial operating characteristics.”
FDA’s ability to implement regulatory science provisions of previous user fees has been undermined by its long-running inability to hire and recruit staff. PDUFA VI seeks to fix the agency’s human resources problems by requiring that it adopt practices common in the private sector, such as contracting with headhunters, and by setting hiring goals.
The 21st Century Cures Act complements these provisions by giving FDA the ability to offer salaries that are competitive with private sector pay.
COMPANIES AND INSTITUTIONS MENTIONED
U.S. Food and Drug Administration (FDA), Silver Spring, Md.
REFERENCES
Usdin, S. “Balancing act.” BioCentury (2017)
Usdin, S. “Beyond right to try.” BioCentury (2017)
Usdin, S. “Christmas in July.” BioCentury (2017)
htgm
went from 2 to 12 in two days because of a CE mark. doesn't make any sense
android 2-73 is posting that from an article that lee somonian has written on seeking alpha. he has avxl on the brain
he writes that bryostatin has downregulated pkc alpha so it won't work. bryostatin upregulates pkc epsilon. so he isn't even discussing the correct isoform
bryostatin restores the synaptic networks which is the cause of alzheimers
LUVOX or Fluvoxamine is an approved Sigma-1 Receptor Agonist. That is the target for Anavex's drug. Why hasn't LUVOX been tried in Alzheimer's?
Now all of a sudden IGF=1 is seen as being a potential side effect.
You are correct Taking external IGF-1 could be a problem espeicially to a person with normal amounts. In the case of bryostatin, PKC epsilon is activating the IGF-1 to be released naturally within the brain. It isn't from an external delivery. The reason why that is important is because Alzheimer's patients have low amounts of the growth factors which is what causes damage to the synapses, so the pkc epsilon is simply increasing something that is deficient.
There is nothing wrong with targeting plaques and tau, if you doing other things also
the problem with the BACE inhibitors and monoclonal antibodies target plaque is that is ALL they do.
Bryostatin activates the enzymes ECE, IDE and neprilysin, which inhibit plaque and inhibits GSK3 beta which inhibits tau formation, but in addition to that increases growth factors to restore synapses.
Multi modal mechanism, not one target
go on the website.
under publications you can take your pick, everything revolves around the restoration of synapses
it wouldn't work better for genetic causes because the company isn't downregulating the genes directly
late onset alzheimer's is also caused by damage to synaptic networks
Bryostatin by activating BDNF, Igf and NGF restores the synapses
Compassionate use patients were not based on genetic mutations.
The company is looking to treat Alzheimer's, if it works in moderate to severe it will work in mild to moderate
the Jenni Spencer was not a Apoe4 patient, she was PSEN1, those patients get it even earlier. The fact that it seemed to work in that patient with a genetic mutation exhibits the fact that the company can even treat diseases like fragile x and Rett sydrome which are caused by genetic mutations. So it isn't the genetic mutation that bryostatin treats, it is the synaptic networks, no matter the cause of the damage
Neurotrope’s Novel Therapy to Treat Alzheimer’s Disease
http://www.onemednews.com/2016/12/31/neurotrope-alzheimers/
Neurotrope BioScience, (OTCQB:NTRP), formed in 2012, is at the forefront of the biotech industry and is focused on developing new therapies with Bryostatin 1 for the treatment of neurodegenerative diseases and developmental disorders.
The company’s experience, capabilities, and passion for innovative and novel drug therapies have enabled it to build a development pipeline that includes various treatment approaches with Bryostatin 1 for serious and difficult-to-treat diseases such as Alzheimer’s dementia and the Orphan diseases, Fragile X Syndrome (FXS) and Niemann-Pick Type C (NPC).
Neurotrope’s molecular mechanisms of memory that were responsible for classical conditioning of the Mollusk Hermissenda. They then demonstrated that these molecular mechanisms were conserved across evolution, providing a basis for memory-specific changes for synaptic function in a variety of animal species and associative learning paradigms.
Subsequently, they have discovered a convergence of memory-specific molecular and synaptic functions with the pathophysiology of Alzheimer’s disease, particularly involving biochemical cascades in which the isozymes of PKC play a central role. PKC activators, for example, phosphorylate the mRNA stabilizing proteins (HuD, HuR) during associative learning.
The mRNA stabilizing proteins then move into the dendritic tree to stabilize and regulate an ensemble of synaptic remodeling proteins such as GAP43, BDNF, IGF, and NGF. Similarly, memory-specific activation of PKC isozymes activate additional pathways to control learning specific protein synthesis via the NFkB and CREB pathways.
These same pathways are targeted by toxic Beta elevated in Alzheimer’s tissues to cause the synaptic loss characteristically demonstrated at autopsy and that correlates with the dementia shown by patients clinically. Thus, the convergence of molecular pathways of memory and the pathologic pathways responsible for neuro-degeneration has provided a whole new strategy for treatment in our aging population.
Bryostatin, currently undergoing a 148 patient phase 2 trial, has shown remarkable efficacy inducing new synaptic growth in fully differentiated nervous systems, for rescuing dying neurons, and for the normalization of A Beta and amyloid plaques. These new findings on associative memory mechanisms are guiding development of drug discovery with the potential to treat the loss of synapses and to prevent neuronal death in neuro-degenerative disorders such as, Alzheimer’s disease, stroke, traumatic brain injury, fragile x, Neimann Pick type C, Rett Syndrome and attention-deficit disorders.
Neurotrope’s Novel Therapy to Treat Alzheimer’s Disease
http://www.onemednews.com/2016/12/31/neurotrope-alzheimers/
Neurotrope BioScience, (OTCQB:NTRP), formed in 2012, is at the forefront of the biotech industry and is focused on developing new therapies with Bryostatin 1 for the treatment of neurodegenerative diseases and developmental disorders.
The company’s experience, capabilities, and passion for innovative and novel drug therapies have enabled it to build a development pipeline that includes various treatment approaches with Bryostatin 1 for serious and difficult-to-treat diseases such as Alzheimer’s dementia and the Orphan diseases, Fragile X Syndrome (FXS) and Niemann-Pick Type C (NPC).
Neurotrope’s molecular mechanisms of memory that were responsible for classical conditioning of the Mollusk Hermissenda. They then demonstrated that these molecular mechanisms were conserved across evolution, providing a basis for memory-specific changes for synaptic function in a variety of animal species and associative learning paradigms.
Subsequently, they have discovered a convergence of memory-specific molecular and synaptic functions with the pathophysiology of Alzheimer’s disease, particularly involving biochemical cascades in which the isozymes of PKC play a central role. PKC activators, for example, phosphorylate the mRNA stabilizing proteins (HuD, HuR) during associative learning.
The mRNA stabilizing proteins then move into the dendritic tree to stabilize and regulate an ensemble of synaptic remodeling proteins such as GAP43, BDNF, IGF, and NGF. Similarly, memory-specific activation of PKC isozymes activate additional pathways to control learning specific protein synthesis via the NFkB and CREB pathways.
These same pathways are targeted by toxic Beta elevated in Alzheimer’s tissues to cause the synaptic loss characteristically demonstrated at autopsy and that correlates with the dementia shown by patients clinically. Thus, the convergence of molecular pathways of memory and the pathologic pathways responsible for neuro-degeneration has provided a whole new strategy for treatment in our aging population.
Bryostatin, currently undergoing a 148 patient phase 2 trial, has shown remarkable efficacy inducing new synaptic growth in fully differentiated nervous systems, for rescuing dying neurons, and for the normalization of A Beta and amyloid plaques. These new findings on associative memory mechanisms are guiding development of drug discovery with the potential to treat the loss of synapses and to prevent neuronal death in neuro-degenerative disorders such as, Alzheimer’s disease, stroke, traumatic brain injury, fragile x, Neimann Pick type C, Rett Syndrome and attention-deficit disorders.
The preferred has been converted to common
After the raise there is approximatly 240 million shares with 30 in cash
if the drug works the stock will go up it won't matter that there was dilution.
If it doesn't work the dilution wouldn't matter either
November 23, 2016
12:42 EDT
LLY
theflyonthewall.com:
10:44 EDT
LLY
theflyonthewall.com:
Analysts hold out hope for Biogen drug after Lilly's Alzheimer trial fails
Shares of Eli Lilly (LLY) are plunging after the drugmaker announced that a Phase 3 study showed that solanezumab failed to slow loss of cognitive ability in patients with mild Alzheimer's disease. The news is also dragging down competitor Biogen (BIIB), which is developing its own Alzheimer's drug. FAILED CLINICAL TRIAL: Eli Lilly announced that its solanezumab drug did not meet the primary endpoint in the EXPEDITION3 clinical trial, a phase 3 study in people with mild dementia due to Alzheimer's disease. Patients treated with the drug did not experience a statistically significant slowing in cognitive decline compared to patients treated with placebo. Lilly will not pursue U.S. regulatory submissions for solanezumab for the treatment of mild dementia due to Alzheimer's disease. During an interview on CNBC, the company's CEO John Lechleiter said Eli Lilly is disappointed with the results, but remains committed to Alzheimer's. SELLOFF AN ATTRACTIVE OPPORTUNITY: While viewing the clinical results as a "disappointing outcome," JPMorgan analyst Chris Schott told investors that Eli Lilly has a diverse range of new product and pipeline opportunities that support 5% sales growth and mid-teens earnings growth. Moreover, he sees the selloff as an "attractive opportunity." He reiterates an Overweight rating on the stock, but lowered his price target on the shares to $85 from $95. His peer at Jefferies also remains bullish on Eli Lilly, reiterating a Buy rating and $100 price target on the shares. Analyst Jeffrey Holford noted that the company's management still expects to grow revenue between 2015 and 2020, while expanding margins. Further, the co mpany is still pursuing the Alzheimer's indication through a number of other programs, Holford told investors in a research note of his own. BIOGEN DRUG CAN STILL WORK: Following the failure of Eli Lilly's solanezumab, Citi analyst Robyn Karnauska told investors that she sees four reasons why Biogen's Alzheimer's drug aducanumab can still work, namely the difference in mechanism of action, efficacy in an end-point-dependent manner, patient population and endpoints. Piper Jaffray analyst Joshua Schimmer voiced a similar opinion, arguing that the "amyloid hypothesis" is not dead. The amyloid cascade hypothesis to which he refers is the theory that the deposition of the amyloid-beta peptide in the brain is a central event in Alzheimer's disease pathology. The analyst pointed out that he sees Biogen and Eisai's aducanumab study as the most potent approach for amyloid lowering, adding that he was skeptical whether solanezumab's effect was adequate. The amyloid hypothesis for Alzh eimer's may have taken another step back, but will not be fully put to the test until Biogen reports Phase 3 results, he contended. Additionally, Schimmer believes that today's selloff in Biogen's shares creates "some breathing room." He reiterated an Overweight rating and $335 price target on Biogen's shares. PRICE ACTION: In morning trading, shares of Eli Lilly have dropped 12% to $66.88, while Biogen's stock has slipped about 5% to $302.37 per share. :theflyonthewall.com
09:35 EDT
LLY
theflyonthewall.com:
Neurotrope President says 'deeply regrets' news on Eli Lilly's solanezumab
Neurotrope (NTRP) issued a statement on Eli Lilly's (LLY) experimental drug solanezumab. Lilly stated that, based upon results from its recent Phase 3 clinical trial, solanezumab failed to improve cognition of patients with mild Alzheimer's disease. Dr. Daniel Alkon, Neurotrope's President and Chief Scientific Officer stated' "I deeply regret the news released today that Lilly's latest trial of its leading Alzheimer's drug candidate has failed. Lilly's dedication and persistence to finding a cure for this devastating affliction deserves everyone's admiration and gratitude. Repeated attempts to treat or even slow the relentless progression of Alzheimer's disease by ta rgeting the red flag in patient's brains called amyloid plaques have continued to lead to such disappointing outcomes. Neurotrope has focused all of its resources on regenerative medicine that would replace the lost synaptic networks that are so consistently associated with the breakdown of human cognitive functions. Bryostatin, a drug that induces growth of new networks to replace those that have degenerated while also degrading plaques and tau tangles, may also address the red flags of this scourge threatening increasing numbers of the world's aging populations. At Neurotrope, we believe that treating Alzheimer's disease is a daunting challenge that will need to be treated by a drug with multi modal efficacy. We believe that our drug bryotstatin may be the drug. The top line results of our Phase 2 study with 148 patients is expected to be announced in April 2017. We hope, at that time, that a new therapy will be viewed as a possible future treatment for this disease." :theflyonthewall.com
09:31 EDT
LLY
theflyonthewall.com:
Biogen selloff may be an overreaction, says Jefferies
Jefferies analyst Brian Abrahams believes selloff in shares of Biogen (BIIB) following Eli Lilly's (LLY) Alzheimer's failure may be an overreaction. Signals of activity seen for Lilly's sola "do maintain some possibility" that Biogen's aducanumab could "ultimately make it over the line," Abrahams tells investors in a research note. He keeps a Hold rating on Biogen with a $310 price target, however, viewing the risk/reward as balanced. :theflyonthewall.com
09:29 EDT
LLY
theflyonthewall.com:
Eli Lilly falls sharply after solanezumab trial did not meet endpoint
The stock was last down over 15.6% to $63.99 to a new 52-week low. At that price $62.19 is next support. Resistance is at $65.54. :theflyonthewall.com
09:25 EDT
LLY
theflyonthewall.com:
Citi sees four reasons why Biogen Alzheimer's drug can still work
Citi analyst Robyn Karnauska sees four reasons why Biogen's (BIIB) Alzheimer's drug aducanumab can still work following the failure of Eli Lilly's (LLY) solanezumab. The analyst lists difference in mechanism of action, efficacy in an end-point-dependent manner, patient population and endpoints as why she thinks Biogen's drug can have a different outcome than Lilly's. The analyst has a Neutral rating on Biogen with a $305 price target. :theflyonthewall.
November 23, 2016
12:42 EDT
LLY
theflyonthewall.com:
10:44 EDT
LLY
theflyonthewall.com:
Analysts hold out hope for Biogen drug after Lilly's Alzheimer trial fails
Shares of Eli Lilly (LLY) are plunging after the drugmaker announced that a Phase 3 study showed that solanezumab failed to slow loss of cognitive ability in patients with mild Alzheimer's disease. The news is also dragging down competitor Biogen (BIIB), which is developing its own Alzheimer's drug. FAILED CLINICAL TRIAL: Eli Lilly announced that its solanezumab drug did not meet the primary endpoint in the EXPEDITION3 clinical trial, a phase 3 study in people with mild dementia due to Alzheimer's disease. Patients treated with the drug did not experience a statistically significant slowing in cognitive decline compared to patients treated with placebo. Lilly will not pursue U.S. regulatory submissions for solanezumab for the treatment of mild dementia due to Alzheimer's disease. During an interview on CNBC, the company's CEO John Lechleiter said Eli Lilly is disappointed with the results, but remains committed to Alzheimer's. SELLOFF AN ATTRACTIVE OPPORTUNITY: While viewing the clinical results as a "disappointing outcome," JPMorgan analyst Chris Schott told investors that Eli Lilly has a diverse range of new product and pipeline opportunities that support 5% sales growth and mid-teens earnings growth. Moreover, he sees the selloff as an "attractive opportunity." He reiterates an Overweight rating on the stock, but lowered his price target on the shares to $85 from $95. His peer at Jefferies also remains bullish on Eli Lilly, reiterating a Buy rating and $100 price target on the shares. Analyst Jeffrey Holford noted that the company's management still expects to grow revenue between 2015 and 2020, while expanding margins. Further, the co mpany is still pursuing the Alzheimer's indication through a number of other programs, Holford told investors in a research note of his own. BIOGEN DRUG CAN STILL WORK: Following the failure of Eli Lilly's solanezumab, Citi analyst Robyn Karnauska told investors that she sees four reasons why Biogen's Alzheimer's drug aducanumab can still work, namely the difference in mechanism of action, efficacy in an end-point-dependent manner, patient population and endpoints. Piper Jaffray analyst Joshua Schimmer voiced a similar opinion, arguing that the "amyloid hypothesis" is not dead. The amyloid cascade hypothesis to which he refers is the theory that the deposition of the amyloid-beta peptide in the brain is a central event in Alzheimer's disease pathology. The analyst pointed out that he sees Biogen and Eisai's aducanumab study as the most potent approach for amyloid lowering, adding that he was skeptical whether solanezumab's effect was adequate. The amyloid hypothesis for Alzh eimer's may have taken another step back, but will not be fully put to the test until Biogen reports Phase 3 results, he contended. Additionally, Schimmer believes that today's selloff in Biogen's shares creates "some breathing room." He reiterated an Overweight rating and $335 price target on Biogen's shares. PRICE ACTION: In morning trading, shares of Eli Lilly have dropped 12% to $66.88, while Biogen's stock has slipped about 5% to $302.37 per share. :theflyonthewall.com
09:35 EDT
LLY
theflyonthewall.com:
Neurotrope President says 'deeply regrets' news on Eli Lilly's solanezumab
Neurotrope (NTRP) issued a statement on Eli Lilly's (LLY) experimental drug solanezumab. Lilly stated that, based upon results from its recent Phase 3 clinical trial, solanezumab failed to improve cognition of patients with mild Alzheimer's disease. Dr. Daniel Alkon, Neurotrope's President and Chief Scientific Officer stated' "I deeply regret the news released today that Lilly's latest trial of its leading Alzheimer's drug candidate has failed. Lilly's dedication and persistence to finding a cure for this devastating affliction deserves everyone's admiration and gratitude. Repeated attempts to treat or even slow the relentless progression of Alzheimer's disease by ta rgeting the red flag in patient's brains called amyloid plaques have continued to lead to such disappointing outcomes. Neurotrope has focused all of its resources on regenerative medicine that would replace the lost synaptic networks that are so consistently associated with the breakdown of human cognitive functions. Bryostatin, a drug that induces growth of new networks to replace those that have degenerated while also degrading plaques and tau tangles, may also address the red flags of this scourge threatening increasing numbers of the world's aging populations. At Neurotrope, we believe that treating Alzheimer's disease is a daunting challenge that will need to be treated by a drug with multi modal efficacy. We believe that our drug bryotstatin may be the drug. The top line results of our Phase 2 study with 148 patients is expected to be announced in April 2017. We hope, at that time, that a new therapy will be viewed as a possible future treatment for this disease." :theflyonthewall.com
09:31 EDT
LLY
theflyonthewall.com:
Biogen selloff may be an overreaction, says Jefferies
Jefferies analyst Brian Abrahams believes selloff in shares of Biogen (BIIB) following Eli Lilly's (LLY) Alzheimer's failure may be an overreaction. Signals of activity seen for Lilly's sola "do maintain some possibility" that Biogen's aducanumab could "ultimately make it over the line," Abrahams tells investors in a research note. He keeps a Hold rating on Biogen with a $310 price target, however, viewing the risk/reward as balanced. :theflyonthewall.com
09:29 EDT
LLY
theflyonthewall.com:
Eli Lilly falls sharply after solanezumab trial did not meet endpoint
The stock was last down over 15.6% to $63.99 to a new 52-week low. At that price $62.19 is next support. Resistance is at $65.54. :theflyonthewall.com
09:25 EDT
LLY
theflyonthewall.com:
Citi sees four reasons why Biogen Alzheimer's drug can still work
Citi analyst Robyn Karnauska sees four reasons why Biogen's (BIIB) Alzheimer's drug aducanumab can still work following the failure of Eli Lilly's (LLY) solanezumab. The analyst lists difference in mechanism of action, efficacy in an end-point-dependent manner, patient population and endpoints as why she thinks Biogen's drug can have a different outcome than Lilly's. The analyst has a Neutral rating on Biogen with a $305 price target. :theflyonthewall.
NEUROTROPE COMPLETES ENROLLMENT IN ITS RANDOMIZED, DOUBLE-BLINDED, PLACEBO-CONTROLLED PHASE 2 CLINICAL TRIAL OF BRYOSTATIN IN PATIENTS WITH MODERATE TO SEVERE ALZHEIMER'S DISEASE
Top line Phase 2 study results expected to be released in April 2017
The Company has also raised an additional $4.3 million in a final closing of its private placement for a total amount of $24.5 million
NEW YORK, November 22, 2016 /PRNewswire/ -- Neurotrope, Inc. (OTCQB:NTRP), a company focused on developing drugs to treat neurodegenerative diseases including Alzheimer's disease, today announced that it has initiated dosing in the final patient in its randomized, double-blinded, placebo-controlled, Phase 2 study in moderate to severe Alzheimer's disease patients. The primary endpoint of the trial is the Severe Impairment Battery (SIB) and the secondary endpoints are the Mini Mental State Exam (MMSE), Activity of Daily Living (ADL) and Neuropsychiatric Inventory scale (NPI). Top line results from the study are expected to be announced in April 2017. Patients meeting the MMSE enrollment criteria score of 4-15 were enrolled in the study. Two doses of bryostatin, 20ug and 40ug, vs. placebo for 12 weeks are being tested. A total of 148 patients were enrolled into the study.
The Company also announced that it has raised an additional $4.3 million in a final closing of its private placement in addition to the approximately $20.2 million raised and previously announced in a press release on Friday, November 18, 2016.
"Completion of enrollment in this study marks a significant milestone for Neurotrope, as well as the Alzheimer's community, as we take another step toward advancing what we believe could be the first potential new treatment for people with Alzheimer's disease in more than 15 years, and we believe would be the first one targeting causes of the symptoms, lost synaptic networks, and not just providing transient symptomatic relief,” said Dr. Daniel Alkon, MD, Neurotrope’s President and Chief Scientific Officer. “Other companies targeting this disease are enrolling mildly impaired patients. We targeted the more severe patient population because of our experience with severe patients through our compassionate use studies. Those studies suggested reversal of some of the manifestations of the disease."
"Bryostatin's multi-modal mechanism of action not only targets the neuronal deficits of AD but also synaptic deficits. This combined mechanism of action through PKC epsilon activation gave the Company the confidence to commit to these trials in moderate to severe patients," said Dr. Susanne Wilke, PhD., the Company’s Chief Executive Officer. We believe that we may have a breakthrough in Alzheimer’s disease and other neurological disorders. With the recently completed financing, we believe that we are in a strong position to negotiate terms with pharmaceutical partners."
Josh Silverman, Chairman of the Company, added "We are pleased with the investor response to our new management team and the excitement surrounding our upcoming clinical data. We raised more money than anticipated and plan on investing our capital efficiently in our continuing effort to increase shareholder value while making a difference in treating neurological disorders.”
Further details may be found in the Company's Form 8-K filing with the Securities and Exchange Commission (SEC).
The securities to be sold in the private placement will not have been registered under the Securities Act of 1933, as amended, or state securities laws as of the time of issuance and may not be offered or sold in the United States absent registration with the Securities and Exchange Commission (SEC) or an applicable exemption from such registration requirements. Neurotrope has agreed to file one or more registration statements with the SEC registering the resale of the shares of common stock underlying the warrants purchased in the private placement.
This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful.
About Neurotrope
Neurotrope BioScience, Inc., a wholly owned subsidiary of Neurotrope, Inc., is at the forefront of biotechnology companies having a focus on developing a novel therapy for the treatment of moderately severe to severe Alzheimer's disease. The scientific basis of our treatment is activation of Protein Kinase C isozymes e and a by bryostatin, a natural product, which in mouse AD models was demonstrated to result in repair of damaged synapses as well as synaptogenesis, the induction of new neuronal networks, reduction of toxic beta-amyloid generation, prevention of neuronal death, and enhancement of memory and learning, thus having the potential to improve cognition and behavior in Alzheimer's disease.
Neurotrope is also conducting preclinical studies of bryostatin-1 as a treatment for Fragile X Syndrome and Niemann-Pick Type C disease, two rare genetic diseases for which only symptomatic treatments are currently available. The FDA has granted Orphan Drug Designation to Neurotrope for bryostatin-1 as a treatment for Fragile X Syndrome. Bryostatin-1 has undergone testing in over 1,500 people establishing a large safety database.
Neurotrope has exclusively licensed technology from Cognitive Research Enterprises (formerly named the Blanchette Rockefeller Neurosciences Institute) for Alzheimer's disease therapeutics and Fragile X Syndrome and has a world-wide, exclusive license with the Icahn School of Medicine at Mt. Sinai for Niemann-Pick Type C disease.
Forward-Looking Statements
Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements. These forward-looking statements include statements regarding the proposed study and timing of initiation, and continued development of use of bryostatin for Alzheimer's disease and other cognitive diseases, and the Company's ability to list its common shares on a major stock exchange. Such forward-looking statements are subject to risks and uncertainties and other influences, many of which the Company has no control over. Actual results and the timing of certain events and circumstances may differ materially from those described by the forward-looking statements as a result of these risks and uncertainties. Factors that may influence or cause actual results to differ materially from expected or desired results may include, without limitation, the Company's inability to obtain adequate financing, the significant length of time associated with drug development and related insufficient cash flows and resulting illiquidity, the Company's patent portfolio, the Company's inability to expand the Company's business, the Company's inability to meet listing requirements for major stock exchanges, significant government regulation of pharmaceuticals and the healthcare industry, lack of product diversification, availability of the Company's raw materials, existing or increased competition, stock volatility and illiquidity, and the Company's failure to implement the Company's business plans or strategies. These and other factors are identified and described in more detail in the Company's filings with the SEC, including the Company's Annual Report on Form 10-K for the year ended December 31, 2015 and its Quarterly Report on Form 10-Q for the quarter ended September 30, 2016. The Company does not undertake to update these forward-looking statements.
I own it. the data released so far is excellent
Juniper learned that poking around with the vagina isn't always fun
BLUE’s CFO quits:
It is reported that he refuses to work for biotech companies with less than 900 million dollars on the balance sheet
Since October, Walgreens representatives have met a number of times with Theranos Chief Executive Elizabeth Holmes and her executive team but were dissatisfied with their responses, the people added.
They probably should have met with her board member Henry Kissinger. He could have straightened it all out