Alnylam initiates Phase II study with ALN-TTRsc for treatment of ATTR

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has initiated a pilot Phase II study with ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting the transthyretin (TTR) gene in development for the treatment of TTR-mediated amyloidosis (ATTR). The Phase II 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.

"Our recently presented Phase I study results of ALN-TTRsc demonstrated robust, up to 94% knockdown of serum TTR, which we believe provide an encouraging profile of clinical activity that warrants further advancement of this drug candidate for the treatment of TTR cardiac amyloidosis. We are pleased to announce that we have initiated our pilot Phase II trial with ALN-TTRsc, with the study now open for enrollment. Initiation of this Phase II trial highlights continued execution on our 'Alnylam 5x15' product development and commercialization strategy, which is focused on advancing RNAi therapeutics toward genetically defined targets for the treatment of diseases with high unmet medical need," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "This new study aims to evaluate the tolerability and preliminary clinical activity of ALN-TTRsc in patients with TTR cardiac amyloidosis. Since ALN-TTRsc achieves robust knockdown of serum TTR, the disease-causing protein in ATTR, we believe that this investigational agent has encouraging potential as a new therapeutic option for patients. Further, it is notable that ALN-TTRsc is the most advanced program in our pipeline that utilizes our GalNAc-conjugate approach for subcutaneous delivery of RNAi therapeutics, and the first to enter Phase II trials; as such, we are pleased with this important industry milestone with the continued development of RNAi therapeutics that utilize this delivery approach in clinical studies."

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.

Alnylam reported positive results from a Phase I trial with ALN-TTRsc in 28 healthy volunteers at the Heart Failure Society of America 17th Annual Scientific Meeting held in September 2013. The results of the clinical study showed that ALN-TTRsc administration led to robust, consistent, and statistically significant (p<0.01) knockdown of serum TTR of up to 94%. Knockdown of TTR was found to be rapid, dose-dependent, and durable. ALN-TTRsc was found to be generally safe and well tolerated in the study. Importantly, these human study results were 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.

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialize RNAi therapeutics, including patisiran 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.