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.