Alnylam advances Development Candidate for ALN-AS1 for treatment of hepatic porphyrias

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it is advancing its Development Candidate for ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP). The new pre-clinical research findings, presented at the 9th Annual Meeting of the Oligonucleotide Therapeutics Society being held October 6 - 8, 2013 in Naples, Italy, show that subcutaneous administration of a GalNAc-siRNA targeting ALAS-1 leads to rapid, dose-dependent, and long-lasting knockdown of ALAS-1 mRNA and complete inhibition of the toxic intermediates that mediate the symptoms and pathology of AIP. Based on these findings, including results in non-human primate studies, the company has selected its ALN-AS1 Development Candidate and expects to file an Investigational New Drug (IND) application for this RNAi therapeutic in 2014. ALN-AS1 is part of the company's "Alnylam 5x15" product development and commercialization strategy, in which the company aims to advance five genetic disease target programs into clinical development, including programs in late stages, by the end of 2015. In addition, the company presented new pre-clinical data with its proprietary, clinically validated GalNAc-siRNA conjugate delivery platform for subcutaneous delivery of RNAi therapeutics with a wide therapeutic index.

"We are very pleased to advance ALN-AS1 as a new Development Candidate in our 'Alnylam 5x15' pipeline, with the goal of filing an IND in 2014. Our new pre-clinical data show that subcutaneous administration of ALN-AS1 results in complete suppression of the toxic heme biosynthesis intermediates that cause the symptoms and pathology of AIP," said Rachel Meyers, Ph.D., Vice President of Research and RNAi Lead Development at Alnylam. "ALN-AS1 now becomes our third RNAi therapeutic utilizing our GalNAc-siRNA conjugate delivery platform to enter development stages, extending our progress with ALN-TTRsc for the treatment of transthyretin-mediated amyloidosis, where we intend to soon initiate a Phase II trial, and ALN-AT3 for the treatment of hemophilia, where we plan on filing our IND by the end of this year. With the recent clinical validation of our GalNAc-siRNA conjugate delivery platform, we have increased confidence that ALN-AS1 could become a transformative therapy for patients with AIP, an ultra-rare genetic disease with enormous unmet medical need. We very much look forward to filing our IND for this program in 2014."

Hepatic porphyrias, including AIP, are ultra-rare orphan diseases caused by loss-of-function mutations in enzymes involved in heme biosynthesis, leading to accumulation of toxic heme intermediate precursors. In the case of AIP, there are approximately 5,000 patients in the U.S. and Europe that suffer acute, life-threatening porphyria attacks every year; there are approximately 500 patients afflicted with recurrent debilitating attacks, often occurring once per month. Treatment options for AIP patients suffering from an attack are limited, and include the use of heme preparations that show limited efficacy and are associated with a number of complications. Currently, there are no drugs available to prevent attacks from occurring. Alnylam's approach is to knock down ALAS-1, an enzyme upstream of porphobilinogen deaminase (PBGD), the defective gene in AIP. RNAi-mediated silencing of hepatocyte ALAS-1 could reduce the abnormal production of the toxic heme intermediates, specifically aminolevulinic acid (ALA) and porphobilinogen (PBG), which mediate the symptoms and disease pathology in AIP patients. Alnylam believes that a subcutaneously administered RNAi therapeutic targeting ALAS-1 has the potential to be used as a prophylactic approach to prevent attacks and also as a therapy for acute attacks.

The new research results presented at OTS support the selection of the ALN-AS1 Development Candidate for further advancement toward clinical trials. Specifically, multi-dose administration of a GalNAc-siRNA targeting ALAS-1 led to rapid, dose-dependent, and long-lasting knockdown of the ALAS-1 mRNA in non-human primates, with an ED50 of approximately 1.25 mg/kg. Further, in a rat model of AIP, ALN-AS1 administration at doses as low as 2.5 mg/kg resulted in a complete blunting of phenobarbital-induced over-production of PBG and ALA, the toxic heme intermediates in AIP. The company now plans to initiate IND-enabling studies with the goal of filing an IND in 2014.

In addition, Alnylam scientists presented new pre-clinical data on the pharmacokinetic and pharmacodynamic properties of GalNAc-siRNA conjugates. Results showed that target gene silencing is achieved at very low levels of liver tissue exposure. Specifically, the tissue drug level associated with 50% target gene silencing (EC50) was determined to be 0.1 micrograms of GalNAc-siRNA per gram of liver tissue. This tissue level is about 1000-fold lower than other oligonucleotide platforms, where the EC50 for liver target gene knockdown is reported to be about 100 micrograms per gram of tissue (Yu et al., Biochem Pharmacol 2009;77:910-919). In additional studies, the levels of GalNAc-siRNA loaded into the RNA-Induced Silencing Complex (RISC) were quantified and determined to be 0.001 microgram per gram of liver tissue, which corresponds to about 500 to 1000 siRNA molecules per cell for RNAi-mediated target gene knockdown. The ability of GalNAc-siRNA to achieve target gene knockdown at low tissue exposure underscores the potential for a wide therapeutic index for these RNAi therapeutics.

"This year's OTS meeting highlights continued progress for oligonucleotide therapeutics, and Alnylam is pleased to be a part of this overall endeavor. We are particularly excited to present our advances with RNAi therapeutics that employ our GalNAc-siRNA conjugate delivery platform for hepatocyte target gene silencing. Indeed, we believe our recent clinical data serve to validate this approach and also confirm a remarkable one-to-one correlation of target knockdown in non-human primate studies as compared with human trials," said Muthiah (Mano) Manoharan, Ph.D., Senior Vice President of Drug Discovery at Alnylam. "New results presented at OTS highlight the applicability of GalNAc-siRNA conjugates across a broad range of hepatocyte-expressed target genes. Moreover, we have demonstrated that target gene knockdown with GalNAc-siRNA is achieved at tissue drug levels of approximately 0.1 micrograms/gram, representing an approximately 1000-fold improvement in potency as compared with other oligonucleotide therapeutic platforms. We believe that these findings of target gene knockdown at very low tissue exposure could significantly improve the therapeutic index for RNA therapeutics, and underscore our belief that GalNAc-siRNA conjugates represent a best-in-class strategy for systemic RNA therapeutics for liver-expressed disease genes."


Alnylam Pharmaceuticals, Inc.


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