Alnylam Begins Phase 1 Clincial Trial For ALN-AS!

Alnylam Pharmaceuticals, Inc.

, a leading RNAi therapeutics company, announced today that it has initiated a Phase 1 clinical trial with ALN-AS1, a subcutaneously administered investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias, including acute intermittent porphyria (AIP). The Phase 1 trial of ALN-AS1 will be conducted initially in AIP patients who are asymptomatic "high excreters" (ASHE). These ASHE subjects have a defined mutation in the porphobilinogen deaminase (PBGD) gene and elevated urinary levels of aminolevulinic acid (ALA) and porphobilinogen (PBG), but do not have a current history of porphyria attacks or disease activity. Subsequently, the trial is designed to enroll AIP patients who experience recurrent porphyria attacks. The company expects to present initial clinical data from this trial in early 2016. "We believe ALN-AS1 has the potential to be a transformative therapy for patients with acute hepatic porphyrias, a group of ultra-rare monogenic diseases with enormous unmet medical need, and we're excited to now advance this innovative investigational medicine to the clinic. Our Phase 1 study aims to obtain data on safety and tolerability in addition to potential clinical activity in ASHE subjects and AIP patients with recurrent attacks," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "We're encouraged by the potential for ALN-AS1 to make a difference in the lives of people afflicted with acute hepatic porphyrias. In pre-clinical studies performed in rodent models of AIP, we have shown that subcutaneous administration of ALN-AS1 results in complete suppression of the toxic heme biosynthesis intermediates that cause disease symptoms and pathology. We very much look forward to the advancement of ALN-AS1 in the clinic and expect to share initial data from the Phase 1 trial in early 2016." "Patients with AIP often present with acute, and at times recurrent attacks that are characterized by severe abdominal pain, neuropathy, neuropsychiatric manifestations, and, in very severe cases, paralysis and respiratory failure. Novel therapies are needed for porphyria patients who suffer from recurrent attacks. These patients can spend a significant number of days in the hospital every month and have a very poor quality of life," said Eliane Sardh, M.D., Ph.D., Senior Physician at the Porphyria Centre Sweden and the Centre for Inherited Metabolic Diseases and Department of Endocrinology, Metabolism and Diabetes at Karolinska University Hospital in Stockholm, Sweden. "I am encouraged with the pre-clinical data to date with ALN-AS1, which I believe support the potential for an RNAi therapeutic as a novel therapeutic option for patients with AIP and other acute hepatic porphyrias." ALN-AS1 is a subcutaneously administered, investigational RNAi therapeutic that employs Alnylam's ESC-GalNAc delivery technology. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutic 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 ALN-AS1 led to rapid, dose-dependent, and long-lasting knockdown of the ALAS1 mRNA in the liver of 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 production of ALA and PBG, the toxic heme intermediates in AIP. Pre-clinical studies with RNAi therapeutics targeting ALAS1 have been published by Alnylam and collaborators previously (Yasuda et al., Proc Natl Acad Sci USA 2014;111(21):7777-7782). 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 subjects. The primary objective of Part A and Part B 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 urinary 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 and other disease symptoms, use of hematin and pain medications, number and duration of hospitalizations, and quality of life. "Patients afflicted with acute hepatic porphyrias, such as AIP, can suffer from severe and recurrent attacks that are potentially life-threatening and that can result in a markedly decreased ability to lead a normal functioning life. Current treatment options are limited, especially for patients with recurrent attacks that often require monthly hospitalizations for administration of hematin and pain management," said Desiree Lyon, Co-Founder and Executive Director of the American Porphyria Foundation. "Today is an important step forward for our patient community, as ALN-AS1, a promising investigational medicine for the treatment of acute hepatic porphyrias, has entered clinical testing. I am so pleased with Alnylam's commitment to make a difference in the lives of our patients." In addition to the Phase 1 trial, Alnylam and clinicians from the American Porphyria Consortium and The European Porphyria Network are currently enrolling patients in the EXPLORE trial, a prospective observational study of patients with acute hepatic porphyrias – including AIP, variegate porphyria, and hereditary coproporphyria – suffering from recurrent attacks. With this study, Alnylam and clinical investigators aim to learn more about the clinical course, management, and disease burden of patients with acute hepatic porphyrias that suffer from recurrent attacks. In January 2014, Alnylam and Genzyme, a Sanofi company, 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 Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline, including ALN-AS1, in the rest of the world. In certain defined instances, Genzyme has co-development/co-commercialization and/or global product rights. Genzyme's rights are structured as an opt-in that is triggered upon achievement of human proof-of-principle.