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. ATTR represents a major unmet medical need with significant morbidity and mortality; Familial Amyloidotic Polyneuropathy (FAP) affects approximately 10,000 people worldwide and FAC affects at least 40,000 people worldwide. Senile systemic amyloidosis (SSA) is a non-hereditary form of TTR cardiac amyloidosis caused by idiopathic deposition of wild-type TTR; its prevalence is generally unknown, but is associated with advanced age. 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. Alnylam is also developing patisiran (ALN-TTR02), an intravenously administered RNAi therapeutic targeting TTR for the treatment of ATTR patients with FAP.
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 5 daily doses followed by 5 weekly doses of 5 mg/kg, with follow-up through Day 90; in the Phase I ALN-TTRsc study, this dose resulted in an up to 93% TTR knockdown 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 (including echocardiography and cardiac MRI), circulating cardiac biomarkers (NT-proBNP and troponins T and I), 6-minute walk test, New York Heart Association (NYHA) classification, and measures of heart failure symptoms and quality of life (Kansas City Cardiomyopathy Questionnaire and EQ-5D QOL). 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.