Alnylam Accelerates Development of ALN-GO1, a Subcutaneously Administered Investigational RNAi Therapeutic for the Treatment of Primary Hyperoxaluria Type 1 (PH1)

Alnylam Pharmaceuticals, Inc.

, a leading RNAi therapeutics company, announced today that it has selected a Development Candidate (DC) for ALN-GO1, an investigational RNAi therapeutic targeting the enzyme glycolate oxidase (GO), also referred to as hydroxyacid oxidase 1 (HAO1), for the treatment of primary hyperoxaluria type 1 (PH1). PH1 is an ultra-rare orphan disease caused by mutations in a liver gene that results in excessive oxalate production and pathogenic accumulation of calcium oxalate kidney stones which can lead to irreparable kidney damage and, in approximately 80% of patients, end stage renal disease by age 30. There are no approved pharmaceutical therapies. New pre-clinical data with the ALN-GO1 DC were presented at the 48th European Society of Paediatric Nephrology (ESPN) Annual meeting – held September 3 – 5, 2015, in Brussels – showing up to 99% silencing of the HAO1 mRNA and up to 98% mean reduction of urinary oxalate in animal models of PH1. Based on these data and the significant unmet need in PH1, the company is accelerating its development timelines for ALN-GO1 and now plans to file a CTA in late 2015 and to initiate a Phase 1 study in early 2016. The ALN-GO1 DC employs Alnylam's proprietary enhanced stabilization chemistry (ESC)-GalNAc-siRNA conjugate platform, a clinically validated approach for RNAi therapeutics that enables subcutaneous dose administration with potent and highly durable effects and a wide therapeutic index. Alnylam will discuss its ALN-GO1 program at today's RNAi Roundtable webinar series at 9:00 a.m. ET. "We believe that ALN-GO1 represents a truly innovative approach for the treatment of PH1, an ultra-rare orphan disease with enormous unmet need where there are no approved pharmaceutical options. In our pre-clinical studies, we've demonstrated robust pharmacologic effects including an up to 99% silencing of the HAO1 mRNA in non-human primates and an up to 98% mean reduction of urinary oxalate in models of PH1. We've selected our ALN-GO1 Development Candidate, an ESC-GalNAc-siRNA conjugate that enables subcutaneous dosing with potent and highly durable target gene silencing effects with a wide therapeutic index," said Rachel Meyers, Ph.D., Senior Vice President of Research at Alnylam. "From our ongoing human experience with ESC-GalNAc conjugates, we believe that ALN-GO1 has the potential to achieve a once monthly, and possibly once quarterly, subcutaneous dose regimen with a favorable tolerability profile. Based on the significant unmet need in PH1 and what we believe to be the promise of our approach, we are accelerating our development plans for ALN-GO1, and now expect to file a CTA in late 2015 and initiate a Phase 1 study in early 2016." "PH1 is an ultra-rare orphan disease affecting approximately six to seven people per million globally. This devastating disease, which is often diagnosed in early childhood, is caused by failure to break down oxalate in the liver, leading to excessive oxalate overproduction which damages organs and leads to kidney failure either in infancy or, in the majority of patients, by their mid-twenties. PH1 represents an area of significant unmet medical need as there are no approved therapeutics available. Once renal function is compromised, progressive systemic oxalate production can lead to severe illness and death, leaving combined liver-kidney transplant as the only treatment option," said Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatric Nephrologist and Clinical Lead, Birmingham Children's Hospital NHS Trust. "The potential advancement of an investigational medicine like ALN-GO1 into clinical trials would represent a major advance for people living with PH1 and their families. As a treating physician, I am encouraged by the potential of a non-surgical therapy that could alter the course of this devastating disease." New preclinical study results for ALN-GO1 were presented at the ESPN meeting showing potent, dose-dependent, and durable silencing of the HAO1 mRNA in mice, rats, and non-human primates (NHP). In wild-type animals, HAO1 silencing resulted in dose-dependent increases in serum glycolate. In mouse and rat models of PH1, ALN-GO1 administration resulted in profound lowering of urinary oxalate, with an essentially one-to-one correlation between oxalate lowering and mRNA silencing. Administration of ALN-GO1 resulted in a mean reduction in urinary oxalate of up to 98% in a rat PH1 model with weekly subcutaneous doses. In an ongoing NHP study, ALN-GO1 demonstrated an up to 99% silencing of HAO1 mRNA and showed corresponding increases in serum glycolate levels of up to 4 fold. In NHP, a single subcutaneous dose of ALN-GO1 showed durable efficacy supporting the potential for a once monthly, and possibly a once quarterly, low volume subcutaneous dose profile in human studies. PH1 is an autosomal recessive disorder of glyoxylate metabolism, where hepatic detoxification of glyoxylate is impaired due to mutation of the AGXT gene – which encodes the liver peroxisomal alanine-glyoxylate aminotransferase (AGT) enzyme – resulting in excessive oxalate production. Excess oxalate in PH1 patients is unable to be fully excreted by the kidneys leading to the formation of recurrent kidney stones and the deposition of calcium oxalate crystals in the kidneys and urinary tract. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium deposition in the kidneys, and renal obstruction by calcium stones. Compromised kidney function exacerbates the disease as oxalate is released into systemic circulation potentially resulting in subsequent accumulation and crystallization in bones, eyes, skin, heart, and central nervous system, leading to severe illness and death. About 50% of patients will have kidney failure by age 15, and about 80% will have end stage renal disease by age 30. Current treatment options are very limited and although combined organ transplantation of liver and kidneys has been successful, it is a risky procedure and limited due to organ availability. The enzyme GO works upstream of AGT to oxidize glycolate to glyoxylate. Human genetics show that a loss of function mutation in the production of GO results in a 20-fold increase in the amount of glycolate in urine, with normal oxalate levels and normal kidney function. Co-inheritance of GO deficiency in mice with the AGXT mutation that causes PH1 completely prevents disease. These human and mouse genetic data strongly suggest that knockdown of GO through silencing of the HAO1 mRNA may starve the disrupted pathway of glyoxylate and safely reduce the oxalate burden in patients with PH1. ALN-GO1 RNAi Roundtable Webinar Information Alnylam will be reviewing these new pre-clinical data and discussing both PH1 and the future development of ALN-GO1 in an RNAi Roundtable webinar today, Tuesday, September 8, 2015 at 9:00 a.m. ET. Speakers include: David Erbe, Ph.D., Director, Research, Alnylam Moderator: Barry Greene, President and Chief Operating Officer, Alnylam Guest Speaker: Sally-Anne Hulton, M.D., FRCPCH, MRCP, FCP, MBBCh, Consultant Paediatric Nephrologist and Clinical Lead, Birmingham Children's Hospital NHS Trust Guest Speaker: Kim Hollander, Executive Director, Oxalosis & Hyperoxaluria Foundation To register for the webinar, please visit the Capella section of the Alnylam website. A replay of the webinar and downloadable PDF of the presentation will be available on Capella shortly after the Roundtable. Genzyme Alliance 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-GO1, 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.