Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase I clinical trial with ALN-TTRsc, an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR). ALN-TTRsc is a subcutaneously administered RNAi therapeutic that comprises an siRNA conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand. GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. ALN-TTRsc is the first GalNAc-siRNA to enter clinical development stages. Following approval of the CTA, Alnylam expects to initiate a Phase I study with ALN-TTRsc early in 2013 with data expected to be reported in mid-2013.
“RNAi therapeutics hold great promise for the treatment of ATTR due to their ability of achieving rapid, potent, and durable knockdown of TTR, the disease-causing protein. At Alnylam, we are committed to advancing an industry leading effort for patients with ATTR. Accordingly we are advancing both ALN-TTR02, an intravenously administered RNAi therapeutic currently in a Phase II clinical trial in patients, and now ALN-TTRsc, a subcutaneously administered RNAi therapeutic,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “This CTA filing for ALN-TTRsc marks our first for an RNAi therapeutic that utilizes our proprietary GalNAc conjugate delivery platform enabling subcutaneous dose administration. Our pre-clinical studies with ALN-TTRsc have confirmed the ability of achieving over 80% TTR knockdown at single digit mg/kg doses with a very wide therapeutic index. We very much look forward to the continued advancement of ALN-TTRsc, including the start of this Phase I clinical trial in healthy volunteers early in the year with data expected mid-year.”
ATTR is an autosomal dominant inherited disease caused by mutations in the TTR gene, which is expressed predominantly in the liver and results in the accumulation of pathogenic deposits of mutant and wild-type TTR protein in multiple extra-hepatic tissues, including the peripheral nervous system, gastrointestinal tract, and heart. Pre-clinical studies have shown that subcutaneous administration of ALN-TTRsc resulted in potent and sustained suppression of TTR. In non-human primates, ALN-TTRsc was administered in a loading dose regimen of once a day for five days, followed by a maintenance dose regimen of once a week for four weeks resulting in an approximately 80% reduction of TTR at doses as low as 2.5 mg/kg. TTR knockdown was achieved rapidly, with nadir TTR levels observed at about day 14. Suppression of TTR of approximately 80% was sustained with the weekly maintenance dose, and recovery to baseline levels was observed at day 40 after the last dose. At an ED 80 dose of 2.5 mg/kg and based on solubility of the GalNAc-siRNA, subcutaneous administration of ALN-TTRsc is expected to be achieved in human studies at a dose volume of approximately 1 mL. In single dose and multi-dose pre-clinical safety studies in rodents and non-human primates, ALN-TTRsc was found to be generally safe and well tolerated. Specifically, at doses as high as 300 mg/kg in non-human primates, ALN-TTRsc was well tolerated with no clinical signs, no adverse laboratory or histopathologic findings, no elevations in cytokines or complement, and no significant injection site reactions.
“ATTR presents a tremendous unmet medical need and is an example of a disease caused by overproduction of a mutant protein. RNAi therapeutics represent a novel and compelling approach for the treatment of ATTR, as they have been shown to achieve robust knockdown of serum levels of both wild-type and mutant TTR,” said Philip Hawkins, FMedSci., Professor of Medicine, University College London Medical School. “I am encouraged by the clinical data to date with ALN-TTR02 and the pre-clinical data shown with ALN-TTRsc. As such, I look forward to the clinical translation of this new RNAi therapeutic, as it represents a promising potential treatment option for patients suffering from this disease.”