Alnylam Files Clinical Trial Application to Initiate a Phase 1 Study for ALN-AS1, a Subcutaneously Administered, Investigational RNAi Therapeutic Targeting Aminolevulinic Acid Synthase-1 (ALAS-1) for the Treatment of Hepatic Porphyrias

Alnylam Pharmaceuticals, Inc.

, a leading RNAi therapeutics company, announced today that it has filed a Clinical Trial Application (CTA) with the Swedish Medical Products Agency (MPA) to initiate a Phase 1 clinical trial with ALN-AS1, a subcutaneously administered investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS-1) for the treatment of hepatic porphyrias, including acute intermittent porphyria (AIP). Per the filed CTA, the Phase 1 trial of ALN-AS1 will be performed first in AIP patients who are asymptomatic “high excreters” (ASHE) – patients with a mutation in the porphobilinogen deaminase (PBGD) gene and elevated urinary aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, but no recent symptoms of a porphyria attack – and then in AIP patients who experience recurrent porphyria attacks. Following approval of the CTA, the company expects to initiate the Phase 1 study in mid-2015, with initial data expected to be reported in early 2016. ALN-AS1 now becomes the company's fifth clinical stage program in its Genetic Medicine Strategic Therapeutic Area (STAr) and the sixth clinical pipeline program overall. “We are very pleased to advance ALN-AS1, a key program in our Genetic Medicine STAr, to the clinical stage with this CTA filing. Our 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, the most common hepatic porphyria. Accordingly, we believe ALN-AS1 could become a transformative therapy for patients with hepatic porphyrias, a group of ultra-rare monogenic diseases with enormous unmet medical need,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “ALN-AS1 now becomes our fifth RNAi therapeutic that utilizes our proprietary, clinically validated GalNAc conjugate delivery platform to enter a clinical development stage, and the fourth that utilizes our optimized Enhanced Stabilization Chemistry GalNAc technology. We very much look forward to the continued advancement of ALN-AS1, including the start of our Phase 1 trial in mid-2015, with data expected in early 2016.” “Patients with AIP present with acute, and at times recurrent attacks that are characterized by severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, and in very severe cases paralysis and respiratory failure. Recurrent attack patients can spend a significant number of days in the hospital every month and many have a very poor quality of life,” said Robert J. Desnick, M.D., Ph.D., Dean for Genetic and Genomic Medicine and Professor and Chair Emeritus of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City. “Our lab's pre-clinical studies with ALN-AS1 support the potential for an RNAi therapeutic as a new investigational medicine for patients with hepatic porphyrias, and I am pleased with Alnylam's efforts and commitment to advance this program to the clinic. Based on its mechanism of action and pharmacological properties, I believe that ALN-AS1 could represent an attractive therapeutic strategy and potential new treatment option for patients with hepatic porphyrias.” ALN-AS1 is a subcutaneously administered, investigational RNAi therapeutic that utilizes Alnylam's proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate delivery platform. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index. In pre-clinical studies, 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 ALA and PBG, the toxic heme intermediates in AIP. As per the filed CTA, the Phase 1 trial of ALN-AS1 will be conducted in three parts. Parts A and B will be randomized (3:1, drug:placebo), single-blind, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 40 ASHE patients. The primary objective of these first two parts of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AS1. Secondary objectives include evaluation of clinical activity for ALN-AS1 as measured by reduction in plasma and urine levels of ALA and PBG. Part C will be an open-label, multi-dose study in up to eight AIP patients who experience recurrent porphyria attacks, and will assess safety, tolerability, PK/PD, and clinical activity of multiple doses of ALN-AS1. In addition, this part of the study will include an exploratory evaluation of the effects of ALN-AS1 on the number and severity of attacks, hematin and pain medication use, and number and duration of hospitalizations.