Phase I First-in-Humans Trial of ALN-TTRsc, a Novel RNA Interference Therapeutic for the Treatment of Familial Amyloidotic Cardiomyopathy (FAC)

Transthyretin (TTR) cardiac amyloidosis is caused by the deposition of liver-derived mutant and/or wild-type TTR in the myocardium, leading to heart failure and death. The hereditary form, known as familial amyloidotic cardiomyopathy (FAC), is most frequently associated with the Val122Ile mutation in older African-American and Afro-Caribbean males and is estimated to affect at least 40,000 people worldwide. Treatment options are limited, and include medical management of heart failure symptoms, as well as heart transplantation in a small number of patients young enough to undergo this procedure. ALN-TTRsc, which is being developed to treat FAC, is a subcutaneously administered RNA interference (RNAi) therapeutic. It is comprised of a small interfering RNA (siRNA) targeting both mutant and wild-type TTR mRNA conjugated to a N-acetylgalactosamine (GalNAc) ligand that enables receptor-mediated delivery to the liver via the asialoglycoprotein receptor expressed on hepatocytes. In non-human primates, repeat-dose subcutaneous administration of ALN-TTRsc resulted in potent and sustained suppression of serum TTR protein, with approximately 80% reduction observed at doses as low as 2.5 mg/kg. In single- and multi-dose pre-clinical safety studies, ALN-TTRsc was found to be generally safe and well tolerated at doses as high as 300 mg/kg in non-human primates. In March 2013, a Phase I, randomized, double-blind, placebo-controlled, single and multi-dose, dose escalation study was initiated in normal healthy volunteers with an anticipated enrollment of up to 40 subjects to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered ALN-TTRsc before proceeding to further development in FAC. In the multi-dose phase, subjects receive 5 daily doses as induction followed by 5 additional weekly maintenance doses. The pharmacodynamic effect of ALN-TTRsc is followed through serial measurements of serum TTR. In this presentation, we will provide an update on the results of this ongoing first-in-humans trial.