Alnylam Presents Key Pre-Clinical Proof-of-Concept Data for ALN-AS1, an RNAi Therapeutic Targeting Aminolevulinate Synthase-1 (ALAS-1) for the Treatment of Porphyria

May 17, 2013 – Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has presented key pre-clinical proof-of-concept data from its RNAi therapeutic program targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria including acute intermittent porphyria (AIP). The new research findings were presented at the International Congress of Porphyrins and Porphyrias being held May 16 – 18, 2013 in Lucerne, Switzerland. Specifically, Alnylam scientists and collaborators at the Icahn School of Medicine at Mount Sinai in New York City presented data from pre-clinical models of the human disease showing that RNAi therapeutics targeting ALAS-1 can completely block the abnormal production of toxic intermediates of the heme biosynthesis pathway that cause the symptoms and disease pathology of AIP. Alnylam’s AIP drug candidate, ALN-AS1, is part of the company’s “Alnylam 5×15” 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.

“Our pre-clinical data clearly show that RNAi therapeutics targeting ALAS-1 can achieve potent, rapid, and durable suppression of the toxic heme biosynthesis intermediates that cause the symptoms and disease pathology of AIP. As such, these findings provide key, pre-clinical, proof-of-concept data for our ALN-AS1 program, which we believe could become a transformative therapy for patients with AIP, an ultra-rare genetic disease with enormous unmet medical need,” said Jared Gollob, M.D., Vice President, Clinical Research at Alnylam. “We are now extending these pre-clinical results to a GalNAc-siRNA conjugate development candidate that enables subcutaneous dose administration, and our current data with prototype molecules provide clear validation of this strategy. With our ongoing efforts, we expect to finalize selection of a GalNAc-siRNA development candidate for our ALN-AS1 program in late 2013, leading to an investigational new drug filing for this program in 2014.”

“AIP is an ultra-rare genetic disorder caused by an inherited deficiency in porphobilinogen deaminase that can result in accumulation of toxic intermediates in the heme biosynthesis pathway. Patients with AIP present with acute and/or recurrent attacks including severe, life-threatening abdominal pain, peripheral and autonomic neuropathy, and neuropsychiatric manifestations,” said Robert J. Desnick, M.D., Ph.D., Dean for Genetics and Genomic Medicine and Professor and Chair Emeritus of theDepartment of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City. “There is clear need for new therapies to treat acute attacks and prevent recurrent attacks, and we are very encouraged by the potential of an RNAi approach for the treatment of this debilitating, life-threatening disease.”

“Our pre-clinical work with Alnylam has shown that RNAi-mediated silencing of ALAS-1 results in essentially complete abrogation of the toxic heme biosynthesis intermediates that cause the symptoms and disease pathophysiology of AIP. In preliminary studies, we have also shown that RNAi-mediated silencing of ALAS-1 is more effective than heme administration in the treatment of an acute attack,” saidMakiko Yasuda, M.D., Ph.D., Assistant Professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City. “RNAi has the potential to serve as a novel treatment for AIP, and we look forward to continuing our close collaborative efforts with Alnylam on the advancement of this program to the clinic.”

There are approximately 5,000 patients in the U.S. and Europe that suffer acute porphyria attacks annually, and approximately 500 patients are afflicted with recurrent debilitating attacks. Treatment options for AIP patients suffering from an acute 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 knockdown ALAS-1, an enzyme upstream of porphobilinogen deaminase (PBGD), in hepatocytes. 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 these patients. A subcutaneously administered RNAi therapeutic targeting ALAS-1 could be used as a prophylactic approach to prevent attacks and as a therapy for acute attacks.

The new research results support the advancement of RNAi therapeutics as a promising strategy for the prevention and/or treatment of acute attacks in patients with AIP. In the new studies, Alnylam scientists and collaborators at Icahn School of Medicine at Mount Sinai presented findings from a mouse model of AIP. Prophylactic administration of an ALAS-1 specific siRNA completely protected the mice from phenobarbital-induced up-regulation of hepatic ALAS-1 mRNA and the resulting accumulation of the neurotoxic ALA and PBG heme biosynthesis precursors. This protective effect was dose responsive and durable, with a single dose administration resulting in a protective effect that lasted for at least two weeks. Further, in a treatment model, a single dose of ALAS-1 siRNA rapidly reduced the high levels of plasma ALA and PBG that were elevated during a phenobarbital-induced acute attack. Further, preliminary comparative studies show that ALAS-1 siRNA administration was more effective than heme administration in the treatment of an acute attack. Finally, the company presented results from its ongoing GalNAc-siRNA conjugate efforts enabling subcutaneous dose administration. In particular, a prototype GalNAc-siRNA targeting ALAS-1 was shown to be effective in blocking ALA and PBG production in both prophylactic and treatment models of AIP. The company is on track to designate a GalNAc-siRNA development candidate, ALN-AS1, in late 2013 resulting in an investigational new drug (IND) filing in 2014.

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