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PRESS RELEASE
Alnylam Presents Clinical and Non-Clinical Data Demonstrating Continued RNAi Platform Optimization and Leadership in the Development of RNA-Based Therapeutics at 12th Annual Meeting of the Oligonucleotide Therapeutics Society
Sept. 28, 2016 4:05 p.m. ET
-- Clinical Data from Phase 1/2 Study of ALN-AAT, an Investigational RNAi Therapeutic Targeting Alpha-1 Antitrypsin (AAT) for the Treatment of AAT Deficiency-Associated Liver Disease, Demonstrate Dose-Dependent and Durable AAT Knockdown --

-- Company to Pursue Follow-On Candidate with Improved Tolerability Profile; Expects to File Clinical Trial Application in 2017 --

-- In Addition, Alnylam Presents Non-Clinical Data on RNAi Therapeutics, Including Extensive Review of Toxicology Results of GalNAc Conjugates Demonstrating Wide Therapeutic Index, With Lack of Thrombocytopenia or Pro-Inflammatory Effects --


CAMBRIDGE, Mass.--(BUSINESS WIRE)--September 28, 2016--
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today new clinical and non-clinical research results demonstrating continued RNAi therapeutics platform innovation and optimization, including improved potency, durability, metabolic stability and tolerability with its GalNAc platform, as well as clinical translation across multiple pipeline programs. The research was presented at the 12th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held from September 25 - 28, 2016 in Montreal, Quebec. These data were presented in a series of 10 posters and oral presentations highlighting progress on the Company's GalNAc platform and its clinical translation. Among the presentations from Alnylam scientists and clinicians, clinical data were presented from the Phase 1/2 study of ALN-AAT, an investigational RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease, also known as alpha-1 liver disease. Results showed that ALN-AAT administration provided potent, dose-dependent, and durable knockdown of serum AAT, although three instances of asymptomatic, transient elevations of liver enzymes were detected in the highest dose groups. As a result, the Company is finalizing selection of a new Development Candidate with plans to rapidly advance this new RNAi therapeutic toward submission of a Clinical Trial Application (CTA) in 2017. In addition, new non-clinical platform data were presented, including an extensive review of data from toxicology studies with GalNAc conjugates.

"We continue to optimize Alnylam's RNAi therapeutics platform to achieve improved potency, durability, tolerability, and metabolic stability, and we're pleased to share this progress across 10 presentations at this year's OTS meeting," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer at Alnylam. "We also presented clinical results from our ALN-AAT program showing potent, dose-dependent, and durable knockdown of the target protein, just as we've seen in clinical data presented from all of the other RNAi candidates in our pipeline to date. In this case, however, we observed a low incidence of asymptomatic, transiently elevated liver enzymes. We plan to advance a follow-on molecule in efforts to optimize the tolerability profile for this program, and we aim to file a CTA for ALN-AAT02 in 2017. We remain committed to developing RNAi therapeutics for alpha-1 liver disease, a rare genetic disease with significant unmet need where liver transplantation is the only treatment option beyond supportive care."

New clinical data were presented from the Phase 1/2 trial of ALN-AAT, in which the safety and efficacy of ALN-AAT were evaluated in normal healthy volunteers, and are as of a data transfer date of June 30, 2016. In this study, subjects in Part A (N=20) were enrolled into 5 ascending dose groups (N=4 per group, randomized 3:1 drug:placebo), and received a single subcutaneous dose of ALN-AAT at doses ranging from 0.1 mg/kg to 6 mg/kg. Subjects in Part B (N=6, randomized 4:2 drug:placebo) received 4 doses of ALN-AAT at 1 mg/kg administered every 28 days. ALN-AAT administration resulted in potent, dose-dependent and durable knockdown of serum AAT. A single 6 mg/kg dose of ALN-AAT attained an AAT knockdown of up to 88.9% with a mean maximal knockdown of 83.9 +/- 2.6%. The pharmacodynamic effects of ALN-AAT were highly durable, where a single dose at 6 mg/kg maintained mean AAT knockdown of 75.0 +/- 1.2% at approximately six months.

ALN-AAT was shown to be generally well tolerated in healthy adult volunteers. There were no drug-related serious adverse events (SAEs), discontinuations due to adverse events (AEs), or injection site reactions reported. Transient, asymptomatic, and dose-dependent increases in liver enzymes were observed in 3 out of 15 healthy volunteers exposed to single doses of ALN-AAT. Since the target patient population for ALN-AAT has established liver disease, Alnylam plans to advance a follow-on molecule targeting a different sequence for further development. Specifically, the Company is finalizing selection of a new Development Candidate -- ALN-AAT02 -- and plans to rapidly advance this compound towards the clinic, with a planned CTA filing in 2017.

In addition, several posters were presented by Alnylam researchers describing significant advances made in optimizing Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc platform, including improved potency, duration of activity, and tolerability, based on a greater mechanistic understanding of GalNAc conjugate features. Amongst other talks, a comprehensive review of non-clinical data from toxicology studies of multiple GalNAc conjugates was presented, highlighting a wide therapeutic index, with no evidence of thrombocytopenia or pro-inflammatory effects, across the platform. In contrast, thrombocytopenia, pro-inflammatory effects, and nephrotoxicity have been reported with phosphorothioate-containing antisense oligonucleotides (ASOs) (Frazier, Toxicol Pathol, 43:78-89(2015)). In an additional presentation, comparative studies of GalNAc conjugated siRNAs and ASOs revealed differences in efficacy and PK across the two RNA platforms. Finally, early research presented in a poster showed that recent advances in siRNA design from Alnylam's ESC-GalNAc platform could potentially be translated to robust RNAi-mediated silencing in muscle using cholesterol conjugates, demonstrating the future potential of the platform for extra-hepatic delivery.

To view the clinical and non-clinical data described in this press release, please visit www.alnylam.com/capella.

About Alpha-1 Antitrypsin (AAT), AAT Deficiency, and Alpha-1 Liver Disease

Alpha-1 antitrypsin deficiency is an autosomal disorder that results in disease of the lungs and liver. AAT is a liver-produced serine proteinase inhibitor with the primary function of protecting the lungs from neutrophil elastase and other irritants that cause inflammation. About 95% of people with alpha-1 antitrypsin deficiency are homozygous and carry two copies of the abnormal Z allele (PiZZ) which expresses the Z-AAT protein. In the liver, misfolding of the mutant Z-AAT protein hinders its normal release into the blood, thereby causing it to aggregate in hepatocytes, leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are estimated to be approximately 120,000 individuals with the PiZZ mutation in the U.S. and major European countries, and of these, about 10% have an associated liver pathology (alpha-1 liver disease) caused by the misfolded Z-AAT protein. The only treatment options presently available for alpha-1 liver disease patients are supportive care and, in the case of advanced cirrhosis, liver transplantation. RNAi-mediated inhibition of AAT in people with alpha-1 liver disease may represent a promising new way to treat this rare disease.
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