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Alnylam and The Alpha-1 Project TAP Form Collaboration for Advancement of ALN-AAT, an RNAi Therapeutic in Development for the Treatment of Alpha-1...

July 2, 2014

Alnylam and The Alpha-1 Project TAP Form Collaboration for Advancement of ALN-AAT, an RNAi Therapeutic in Development for the Treatment of Alpha-1 Antitrypsin AAT Deficiency-Associated Liver Disease

By a News Reporter-Staff News Editor at Biotech Week -- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, and The Alpha-1 Project (TAP), the venture philanthropy subsidiary of the Alpha-1 Foundation, announced that they have entered into a collaboration agreement for the continued advancement of ALN-AAT, a subcutaneously administrated RNAi therapeutic in development for the treatment of alpha-1 antitrypsin (AAT) deficiency-associated liver disease. TAP's mission is to work with patients, academia, pharmaceutical and biotech companies, and public health organizations in the pursuit of cures and therapies for chronic obstructive pulmonary disease (COPD) and liver disease caused by AAT deficiency. TAP is partially funding research activities for ALN-AAT. Detailed financial terms of the research agreement were not disclosed. Alnylam remains on track to file an investigational new drug (IND) application for this program in mid-2015 (see also Alnylam Pharmaceuticals, Inc.).

"We have assembled what we believe to be the industry's most robust pre-clinical data package supporting advancement of ALN-AAT - an 'Enhanced Stabilization Chemistry' or 'ESC'-GalNAc-siRNA conjugate targeting AAT - including results in rodent models that demonstrate knockdown of the disease-causing Z-allele and significant lowering of the mutant protein (Z-AAT) burden in the liver, with associated improvements in liver function, as seen by normalization of the proliferative index, improved liver pathology, attenuated tissue fibrosis, and decreased incidence of liver tumor formation. In addition, we believe we have confirmed the activity of ALN-AAT in non-human primate models and expect our Development Candidate to achieve human target gene knockdown at doses less than 1 mg/kg with a once-monthly dose regimen or better. Since our GalNAc-siRNA platform is clinically validated based on results from other Alnylam RNAi therapeutic programs, we have a high level of confidence that ALN-AAT can achieve potent knockdown of the disease-causing Z-allele protein with subcutaneous dose administration and a favorable safety profile," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "Accordingly, we are fully committed to the continued advancement of our RNAi therapeutic to patients with AAT deficiency with associated liver disease. This new recognition from TAP, part of the leading patient advocacy group for people afflicted with AAT deficiency, brings our efforts closer to patients in need and to their caregivers. We continue to expect that we will file our IND or IND equivalent for ALN-AAT in mid-2015."

ALN-AAT is one of Alnylam's genetic medicine programs, which are RNAi therapeutics directed toward genetically defined targets for the treatment of diseases with high unmet medical need. Alnylam pioneered the application of RNAi therapeutics toward genetically defined targets expressed in the liver as part of the company's "Alnylam 5x15" product strategy. AAT deficiency-associated liver disease is caused by accumulation of mutant AAT protein ("Z-allele" or "Z-AAT") in liver tissue with subsequent liver injury, fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma. It is estimated that approximately 10,000 to 20,000 people with AAT deficiency in the U.S. and E.U. have associated liver pathology.

"I applaud Alnylam for its efforts to develop a therapeutic for Alphas with liver disease, as there are few options available for them today. The Alpha-1 community is in desperate need of a treatment to improve the quality of life for both pediatric and adult liver patients," said John Walsh, CEO and co-founder of the Alpha-1 Foundation.

Pre-clinical data from Alnylam's ALN-AAT program were first presented at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD, "The Liver Meeting") in November 2013 and were most recently updated at Digestive Disease Week (DDW) in May 2014. Amongst other results presented, these data in rodent studies showed that administration of ALN-AAT was associated with a potent and dose-dependent knockdown of serum AAT (a surrogate for AAT knockdown in the liver) with a single-dose ED50 of 0.5 mg/kg. In multi-dose rodent experiments, subcutaneous administration at 0.5 mg/kg resulted in approximately 90% knockdown of serum AAT. In addition, initial single-dose NHP results were performed showing dose-dependent knockdown of serum AAT with an ED50 of less than 3 mg/kg; these results are expected to support a multi-dose ED50 of less than 0.3 mg/kg. ALN-AAT employs Alnylam's ESC-GalNAc-conjugate technology, enabling subcutaneous administration with a wide therapeutic index. Alnylam's GalNAc-siRNA conjugate platform has been clinically validated for both activity and tolerability through the company's ALN-TTRsc (an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR cardiac amyloidosis; currently in Phase 2) and ALN-AT3 (an RNAi therapeutic targeting antithrombin for the treatment of hemophilia and rare bleeding disorders; currently in Phase 1) programs.

Keywords for this news article include: Alnylam Pharmaceuticals Inc., Therapeutics, Liver Diseases, Digestive System Diseases.

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Source: Biotech Week

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