Alnylam Begins Subcutaneous ATTR Trial

Alnylam Pharmaceuticals has begun a pilot Phase II study of ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting the transthyretin (TTR) gene in development for the treatment of TTR-mediated amyloidosis (ATTR). The trial, which is now open for enrollment, is aimed at evaluating the tolerability and preliminary clinical activity of ALN-TTRsc in TTR cardiac amyloidosis patients with familial amyloidotic cardiomyopathy (FAC) — which is caused by autosomal dominant mutations in the TTR gene — or senile systemic amyloidosis (SSA) — which is caused by idiopathic accumulation of wild-type TTR in the heart. The company expects to present data from the Phase II trial in late 2014, and assuming positive results, begin a Phase III trial in TTR cardiac amyloidosis patients by the end of 2014.

A Phase I study of ALN-TTRsc demonstrated robust knockdown of as much as 94% of serum TTR. ATTR is caused by mutations in the TTR gene which cause abnormal TTR amyloid protein deposits to accumulate in various tissues including peripheral nerves and heart, resulting in neuropathy and/or cardiomyopathy.

ALN-TTRsc is an investigational drug being developed for the treatment of TTR cardiac amyloidosis, including both FAC and SSA, and is a subcutaneously administered RNAi therapeutic that comprises a TTR-specific 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 advance in clinical development.

The Phase II trial is an open-label, multi-dose study of ALN-TTRsc, designed to enroll approximately 15 TTR cardiac amyloidosis patients with FAC or SSA. The primary objective of the study is to evaluate the general tolerability of ALN-TTRsc. Patients will receive five daily doses followed by five weekly doses of 5 mg/kg, with follow-up through Day 90; in the Phase I ALN-TTRsc study, this dose resulted in TTR knockdown of as much as 93% and a mean nadir knockdown of approximately 88%, and was found to be generally safe and well tolerated. Secondary objectives include assessment of clinical activity as measured by knockdown of serum TTR levels and additional tests, such as cardiac imaging, circulating cardiac biomarkers, six-minute walk test, New York Heart Association classification, and measures of heart failure symptoms and quality of life. Patients completing the Phase II trial will be eligible to participate in an open-label extension (OLE) study for further assessment of general tolerability and clinical activity with long-term dosing; the ALN-TTRsc Phase II OLE study is expected to be initiated in mid-2014.