Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today 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% 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), being held September 22 - 25, 2013 in Orlando, Fla. 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.
“a major scientific breakthrough that happens once every decade or so”
"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% in treated subjects, results which are in line with our non-human primate experience. We look forward to continued advancement of our ALN-TTRsc program, 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 U.K. 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% 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 commercialize 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 commercialize the ALN-TTR program in North and South America, Europe, and rest of the world.
Study reveals how DNA folding drives gene activity bursts