Alnylam and Collaborators Publish Pre-clinical Study Results on ALN-AT3; Update On Tekmira's Ebola Research Development Print E-mail
By William Kent   
Monday, 13 April 2015 19:07
Below is a look at some of the headlines for companies that made news in the healthcare sector on April 13, 2015.   
Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY), announced the publication in Nature Medicine of pre-clinical results with ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD). The paper, titled "An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia" (Sehgal et al., Nat Med, doi:10.1038/nm.3847), documents a broad set of pre-clinical data supporting the clinical advancement of ALN-AT3. Among the many findings reported, subcutaneous administration of ALN-AT3 led to potent, dose-dependent, and durable knockdown of AT in wild-type mice, hemophilia A mice, and non-human primates (NHPs). In addition, ALN-AT3 treatment improved hemostasis in hemophilia mice and normalized thrombin generation in a non-human primate "inhibitor" model of hemophilia A (HA). Furthermore, long-term ALN-AT3 administration – even at highly exaggerated doses – was shown to be well tolerated in hemophilia mice, supporting a wide therapeutic index in the disease setting.
"ALN-AT3 is a key program in our RNAi therapeutics pipeline, and is aimed at re-balancing the coagulation cascade as a potential disease modifying therapy for people with hemophilia and rare bleeding disorders. Indeed, we believe that once-monthly subcutaneous administration of ALN-AT3 could provide a functional correction of the bleeding phenotype in hemophilia, representing a significant advance in the field. Our pre-clinical research findings demonstrate robust efficacy, safety, and durability for ALN-AT3 in mouse and NHP models of hemophilia, and we are pleased to be publishing these peer-reviewed data in Nature Medicine. Amongst other study results, safety data in hemophilia mice suggest that ALN-AT3 administration – even at highly exaggerated doses – should be well tolerated in the disease condition," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "Meanwhile, we are continuing to advance ALN-AT3 in an ongoing Phase 1 clinical trial in subjects with hemophilia. Recent results from this trial presented earlier this year provided clinical evidence for the first time suggesting that AT knockdown with ALN-AT3 has the potential to correct the hemophilia phenotype. While early and based on a limited number of subjects, we believe that these data support further development of ALN-AT3, a potentially promising and innovative strategy for the treatment of hemophilia and rare bleeding disorders as a once-monthly subcutaneous injection. We look forward to the continued data from our Phase 1 study and expect to present additional results in mid-2015 and then again later in the year."
As documented in the new publication, single and multiple subcutaneous doses of ALN-AT3 led to dose-dependent and durable knockdown of serum AT in wild-type and HA mice and in NHPs. In microvessel laser injury and saphenous vein bleeding models in HA mice, subcutaneous administration of ALN-AT3 provided hemostatic protection that was comparable to or better than that achieved with intravenously administered factor VIII replacement therapy. Furthermore, in wild type NHPs, repeat dosing with ALN-AT3 resulted in potent, titratable, and reversible knockdown of plasma AT. Studies were also performed in an NHP hemophilia "inhibitor" model, in which a hemophilia phenotype was induced via administration of a polyclonal anti-factor VIII antibody. ALN-AT3 treated animals showed robust AT knockdown as well as dose-dependent increases in thrombin generation, restoring this hemostatic parameter back to normal levels. These results demonstrate that ALN-AT3 can normalize thrombin generation in the absence of functional levels of factor VIII and/or in the presence of anti-factor VIII antibodies in a large animal model, providing key pre-clinical proof of concept for the program.
In addition, the new paper documents the results of tolerability studies that suggest a wide therapeutic index for ALN-AT3 in the hemophilia setting. Specifically, highly exaggerated doses of ALN-AT3 resulting in essentially complete ablation of AT were evaluated in wild-type and hemophilia mice. Weekly administration of ALN-AT3 in HA mice for 7 weeks at 10, 30, or 100 mg/kg was well tolerated across all dose levels, with no toxicologically significant findings in clinical or anatomic pathology exams, including the absence of any evidence for thrombosis. Finally, a 26-week toxicity study was performed in HA mice to evaluate long-term safety. As in the 7-week study, ALN-AT3 was well tolerated across all dose levels, with no adverse clinical signs. Further, compared to placebo treatment, ALN-AT3 administration was shown to confer a statistically significant survival benefit (p <0.0001; log-rank, Mantel-Cox test), consistent with the hypothesis that a reduction in AT levels leads to disease modification. In aggregate, these results suggest a wide therapeutic index for AT knockdown in the hemophilia setting.
Alnylam is currently evaluating ALN-AT3 in a Phase 1 clinical trial in subjects with hemophilia. The ongoing study is being conducted in Bulgaria, Switzerland and the U.K. as a single- and multi-dose, dose-escalation study comprised of two parts. Part A – which is complete – was a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study (n=4 per cohort; 3:1 randomization of ALN-AT3:placebo) in healthy volunteer subjects. This part of the study was completed after the first dose cohort that received a single subcutaneous dose of ALN-AT3 at 30 micrograms/kilogram (mcg/kg). Part B of the study – which is ongoing – is an open-label, multi-dose, dose-escalation study enrolling up to 18 subjects with moderate or severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3. In addition, the study is recording potential effects of ALN-AT3 on the incidence of bleeding.
At the Goring Coagulation Conference, held January 11 – 12, 2015, Alnylam presented initial positive results from the ongoing Phase 1 trial. Specifically, in the study's second dose cohort in hemophilia subjects (n=3), subcutaneous administration of ALN-AT3 at a dose of 45 mcg/kg administered once weekly for 3 weeks resulted in an up to 70% knockdown of AT. Furthermore, ALN-AT3 administration resulted in a statistically significant increase in thrombin generation of up to 334% and a marked improvement in whole blood clotting. In addition, the most advanced severe hemophilia A subject in the cohort was shown to be bleed-free for 47 days without replacement factor prophylaxis as of the data cut-off date of January 6, 2015. Finally, ALN-AT3 administration was generally well tolerated. Alnylam believes that, collectively, these results provide initial evidence for potential correction of the hemophilia phenotype associated with ALN-AT3 administration and AT knockdown. The company intends to provide additional results from the ongoing Phase 1 study in mid-2015 and then again in late 2015.
"New therapeutic options are needed to manage bleeding in hemophilia and other rare bleeding disorders, particularly for patients who experience multiple annual bleeds when receiving replacement factor ‘on demand' and for patients who have developed inhibitory antibodies. The availability of a safe and effective, subcutaneously administered therapeutic with a long duration of action has the potential to provide significant benefits over currently available approaches for prophylaxis," said David Lillicrap, M.D., FRCPC, Professor, Department of Pathology and Molecular Medicine at Queen's University, and Canada Research Chair in Molecular Hemostasis. "The clinical advancement of ALN-AT3 is supported by a broad pre-clinical data package that is now published in Nature Medicine. Of particular interest is the correlation of antithrombin knockdown with thrombin generation, since thrombin generation has been shown to be predictive of disease severity. In addition, I believe that the long-term safety of the drug in the mouse model of hemophilia is an important finding, suggesting that ALN-AT3 may have a wide therapeutic index in people with hemophilia. Finally, I am encouraged by the initial data emerging from Alnylam's Phase 1 trial and I look forward to seeing further progress in the coming months."
In a report published Monday, Maxim Group analyst Jason Kolbert commented on Tekmira Pharmaceuticals Corp. (NASDAQ: TKMR) ongoing research into the Ebola virus. Tekmira is part of an international consortium known as the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) to produce TKM-Ebola for clinical trials in West Africa.
Kolbert noted that the FDA has modified the partial clinical hold on TKM-Ebola to permit repeat dosing up to 0.24 mg/kg/day in healthy volunteers, but the hold remains in place for higher doses. In addition, a phase I study is expected to resume in several weeks with final data set for the second half of 2014.
TKM-Ebola has been on a clinical hold as the FDA previously requested safety data on ascending doses and appears that they are now comfortable in allowing the higher doses.
"What does this mean?" Kolbert wrote. "It's good news, TKM-Ebola so far appears to be safe with repeat and ascending dosing. RNAi therapy is likely not going to be a one-shot cure for acute infections like Ebola. Much like an oral anti-viral, RNAi may need to be given multiple times to achieve viral clearance."
Kolbert concluded that the Ebola disease is highly infectious with a short incubation period and a high mortality rate. As such, TKM-Ebola should qualify to progress through the Animal Rule pathway (an FDA regulatory rule in which it marketing approval can be granted upon animal testing) just like similar products were approved to combat the bubonic plague and anthrax.
Shares remain Buy rated with a $27 price target.
Also Monday:
3D Systems (NYSE:DDD) announced today a new range of breakthrough virtual modules and simulators designed to enhance the training of surgeons and ultimately to improve patient outcomes. 
ACETO Corporation (Nasdaq:ACET), a global leader in the marketing, sale and distribution of products for Human Health, Pharmaceutical Ingredients and Performance Chemicals, today announced that Sal Guccione, President and CEO, will present at the Needham 14th Annual Healthcare Conference on Tuesday, April 14 at 5:00 p.m. ET. 
Allscripts Healthcare Solutions, Inc. (Nasdaq:MDRX) will report its financial results for the three months ended March 31, 2015, after the close of regular stock market hours on Thursday, May 7, 2015. 
American CareSource Holdings, Inc. (Nasdaq:ANCI) sadly announced today that Richard W. Turner, PhD, its President, Chief Executive Officer and Chairman of the Board of Directors, died unexpectedly on April 12, 2015 after a brief illness. 
Arno Therapeutics, Inc. (OTCQB:ARNI), a clinical stage biopharmaceutical company primarily focused on the development of therapeutics for cancer and other life threatening diseases, today announced the upcoming presentation of three posters supporting the ongoing clinical development program for lead compound onapristone at the American Association for Cancer Research (AACR) Annual Meeting 2015, being held April 18-22 in Philadelphia, PA.  
athenahealth, Inc. (Nasdaq:ATHN), a leading provider of cloud-based services and mobile applications for medical groups and health systems, today announced that it will hold a conference call for investors on Friday, May 1, 2015, at 8:00 a.m. ET. 
In a release issued earlier today by athenahealth (Nasdaq:ATHN), the company is updating the infographic.
Cerner (Nasdaq:CERN) today announced it will release its first quarter 2015 earnings results after the market closes on May 7. There will be a conference call at 3:30 p.m. CT that can be accessed via dial-in or webcast.
Endologix, Inc. (Nasdaq:ELGX), developer and marketer of minimally invasive treatments for aortic disorders, announced today details relating to the release of its first quarter 2015 financial results, which will take place on Wednesday, April 29, 2015 after the close of the market.
GW Pharmaceuticals plc (Nasdaq:GWPH) (AIM:GWP), a biopharmaceutical company focused on discovering, developing and commercializing novel therapeutics from its proprietary cannabinoid product platform, today noted that the American Academy of Neurology (AAN) issued a press release today on GW's investigational medicine, Epidiolex® (pure cannabidiol, or CBD).
IRADIMED CORPORATION (Nasdaq:IRMD) announced today that the Company will release its 2015 first quarter financial results before the market opens on Thursday, April 30th. 
Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, today announced the issuance of U.S. Patent No. 8,999,996 entitled "Hydrazide Containing Nuclear Transport Modulators and Uses Thereof." 
Macrocure Ltd. (Nasdaq:MCUR), a clinical-stage biotechnology company focused on developing a novel therapeutic platform to address chronic and hard-to-heal wounds, today announced that it will participate in the upcoming Symposium on Advanced Wound Care from April 29 – May 3, 2015 in San Antonio, Texas.
Neothetics, Inc. (Nasdaq:NEOT), a clinical-stage specialty pharmaceutical company developing therapeutics for the aesthetic market, today announced the initiation of two pivotal U.S. Phase 3 trials titled AbCONTOUR1 and AbCONTOUR2 of LIPO-202, the first non-invasive injectable drug candidate for reduction of central abdominal bulging due to subcutaneous fat in non-obese subjects.
Nearly 60 percent of the health system members that attended the national summit for Premier, Inc.'s (Nasdaq:PINC) population health collaborative plan to tie at least half their reimbursement to risk-based programs such as bundled payment, shared savings or global payment by 2018 (Figure 1).
Rexahn Pharmaceuticals, Inc. (NYSE MKT:RNN), a clinical stage biopharmaceutical company developing best-in-class therapeutics for the treatment of cancer, today announced that it will have two poster presentations at the 2015 American Association for Cancer Research (AACR) Annual Meeting. 
SAGE Therapeutics (Nasdaq:SAGE) today announced that it has commenced an underwritten public offering of $100 million of shares of its common stock. 
TRACON Pharmaceuticals (Nasdaq:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted therapeutics for cancer, age-related macular degeneration and fibrotic diseases, today announced presentations for both TRC105 and TRC102 at the upcoming American Association for Cancer Research (AACR) annual meeting to be held April 18-22, 2015, in Philadelphia, PA.
Ultragenyx Pharmaceutical Inc. (Nasdaq:RARE), a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, today announced the appointment of Daniel G. Welch to the company's Board of Directors effective April 8, 2015. 
VeriTeQ Corporation (OTC Markets:VTEQ), a provider of implantable medical device identification and radiation dose measurement technologies, announced today that it has expanded its intellectual property portfolio with a patent filing in Brazil for its high-temperature Q Inside Safety Technology micro-transponder.
Versartis, Inc. (Nasdaq:VSAR), an endocrine-focused biopharmaceutical company that is developing a novel, long-acting form of recombinant human growth hormone (rhGH), today announced the initiation of its Phase 2/3 study of VRS-317 in Japan for children with growth hormone deficiency (GHD).
WaferGen Bio-systems, Inc. (Nasdaq:WGBS) announced today that it will host a KOL Webinar on the topic of "Clinical NGS Testing Strategies for Oncology and Rare Disease" on Wednesday, April 15th.
Wellness Center USA, Inc. (OTCQB:WCUI) today announced that its wholly owned subsidiary, StealthCo, Inc. (SCI) dba Stealth Mark, has been accepted into MATTER, the nation's newest healthcare technology incubator, focused on next-generation health IT, medical device, bio/pharma and diagnostic innovation. 

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