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
- 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 -
"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
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
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
In January 2014, Alnylam and Sanofi Genzyme, the specialty care global business unit of Sanofi, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Sanofi Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline, including ALN-AAT, in the rest of the world (ROW) through the end of 2019, together with certain broader co-development/co-commercialization rights and global product rights for certain products.
About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugates
GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in nearly all of Alnylam's pipeline programs, including programs in clinical development.
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.
Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines. Alnylam's pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs - including 4 in late stages of development - across its 3 STArs. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Ionis, Novartis, Roche, Takeda,
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, Alnylam's views with respect to the potential for RNAi investigational therapeutics, its expectations regarding the selection of a Development Candidate and filing of a Clinical Trial Application for ALN-AAT02, its expectations regarding its STAr pipeline growth strategy, and its plans regarding commercialization of RNAi therapeutics, constitute forward-looking statements for the purposes of the safe harbor provisions under
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