Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, has reported positive top-line results from its ongoing phase I trial of ALN-TTRsc, a subcutaneously administered RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The company is reporting that ALN-TTRsc achieved robust and statistically significant (p<0.01) knockdown of serum TTR protein levels of greater than 80 per cent in healthy volunteer subjects, in line with results for ALN-TTRsc previously reported in non-human primates.

In addition, to date ALN-TTRsc was found to be generally safe and well tolerated. Dose escalation in this trial continues and results will be presented at the Annual Scientific Meeting of the Heart Failure Society of America (HFSA), which will be held on September 22 to 25, 2013 in Orlando, Florida. These human study results are the first to be reported for Alnylam’s proprietary GalNAc-siRNA conjugate delivery platform, enabling subcutaneous dosing of RNAi therapeutics with a wide therapeutic index.

“These clinical results with ALN-TTRsc establish human translation for RNAi therapeutics that utilize our GalNAc-siRNA conjugate delivery platform. This platform enables subcutaneous dose administration with a wide therapeutic index and has now become our primary approach for development of RNAi therapeutics. As a result, we believe these data are very meaningful not only for the continued advancement of ALN-TTRsc, but also for the continued execution on our entire ‘Alnylam 5x15’ product strategy,” said John Maraganore, Ph.D., chief executive officer of Alnylam. “Specifically, we are very excited to report top-line results from the study showing statistically significant knockdown of serum TTR to levels greater than 80 per cent in treated subjects, results which are in line with our non-human primate experience. We look forward to continued advancement of our ALN-TTRsc programme, including presentation of data from the phase I trial at the HFSA meeting in September, start of a phase II study in familial amyloidotic cardiomyopathy patients by the end of this year, and – assuming positive results – start of a pivotal phase III trial for ALN-TTRsc in 2014.”

ATTR is caused by mutations in the TTR gene which cause abnormal amyloid protein deposits to accumulate in various tissues including peripheral nerves and heart, resulting in neuropathy and/or cardiomyopathy. ATTR represents a major unmet medical need with significant morbidity and mortality; familial amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC) affects at least 40,000 people worldwide. ALN-TTRsc, which is being developed for the treatment of FAC, is a subcutaneously administered RNAi therapeutic that comprises an siRNA conjugated to a GalNAc ligand that enables receptor-mediated delivery to the liver. ALN-TTRsc is the first GalNAc-siRNA – and the first subcutaneously delivered – systemic RNAi therapeutic to enter clinical development stages. Alnylam is also developing ALN-TTR02, an intravenously administered RNAi therapeutic targeting TTR for the treatment of FAP patients with ATTR.

The ongoing phase I trial of ALN-TTRsc is being conducted in the UK as a randomized, double-blind, placebo-controlled, single- and multi-dose, dose-escalation study, enrolling up to 40 healthy volunteer subjects. Subjects received single or multiple ascending subcutaneous doses of ALN-TTRsc ranging from 1.25 to 10 mg/kg. The primary objective of the study is to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc. Secondary objectives include assessment of clinical activity of the drug as measured by serum TTR levels. Upon completion of the phase I trial, the company plans to start a phase II clinical study of ALN-TTRsc in FAC patients in late 2013 and, assuming positive results, expects to start a pivotal phase III trial for ALN-TTRsc in FAC patients in 2014.

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 administration resulted in an approximately 80 per cent reduction of TTR at doses as low as 2.5 mg/kg. In single- 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; these results demonstrate an approximately 100-fold therapeutic index for GalNAc-siRNA conjugates.

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialise RNAi therapeutics, including ALN-TTR02 and ALN-TTRsc, for the treatment of ATTR in Japan and the broader Asian-Pacific region. Alnylam plans to develop and commercialise the ALN-TTR programme in North and South America, Europe, and rest of the world.

TTR-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and fatal disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein. Mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.

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. Research findings demonstrate potent and durable target gene silencing, as well as a wide therapeutic index, with subcutaneously administered GalNAc-siRNAs from multiple “Alnylam 5x15” programmes.