The Phase 1 trial will be conducted in normal healthy volunteers. Initiation of this trial is based on encouraging pre-clinical results, including data presented last year at the Oligonucleotide Therapeutics Society (OTS) meeting held October 11 – 14, 2015. The Company has guided that it expects to report initial clinical data from this study in late 2016, and if positive, plans to initiate a Phase 3 study in 2017.
"We believe ALN-TTRsc02 has the potential to become a best-in-class, once-quarterly, subcutaneous treatment regimen for the treatment of ATTR amyloidosis," said Eric Green, Vice President, General Manager, TTR Program.
"With just four doses anticipated per year, ALN-TTRsc02 could offer patients with ATTR amyloidosis an important new therapeutic option to manage their disease. In parallel, we continue to make great progress with patisiran and revusiran, with data from both programs expected to be presented at the International Symposium on Amyloidosis meeting next month."
The Phase 1 trial of ALN-TTRsc02 is a randomized, placebo-controlled, single ascending-dose study designed to enroll up to a total of 100 normal healthy volunteers (NHVs).
The primary objective of the study is to evaluate safety and tolerability of a single subcutaneous dose of ALN-TTRsc02. Secondary objectives include evaluation of pharmacokinetics and clinical activity for ALN-TTRsc02, as measured by knockdown of serum TTR levels in NHVs, and identification of the appropriate dose and regimen for a pivotal study.
ALN-TTRsc02 utilizes the company’s Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate delivery platform, which enables high potency and durability with a very wide therapeutic index.
Clinical results from other RNAi therapeutic programs in Alnylam’s pipeline that utilize ESC-GalNAc technology have demonstrated robust target gene knockdown and durability supportive of the potential for a quarterly and, possibly, bi-annual dosing regimen.
ALN-TTRsc02 Pre-clinical Data
In pre-clinical studies, including those in non-human primates (NHPs), ALN-TTRsc02 achieved potent and highly durable knockdown of serum TTR of up to 99% with multi-month durability achieved after just a single dose at 1 mg/kg, supportive of a potentially once quarterly dose regimen.
In 13-week toxicology studies, ALN-TTRsc02, when given monthly for four doses, was generally well-tolerated with no significant adverse events at doses as high as 120 mg/kg in rats or 300 mg/kg in NHPs. There were no effects on platelet counts observed in either study.
About ATTR Amyloidosis
Transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis) is a progressively debilitating and often fatal disease caused by deposition of TTR in peripheral tissues. TTR protein is produced primarily in the liver and is normally a carrier of vitamin A. In hereditary ATTR amyloidosis (hATTR), mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.
hATTR represents a major unmet medical need with significant morbidity and mortality; hATTR with polyneuropathy (hATTR-PN) – also known as familial amyloidotic polyneuropathy (FAP) – affects approximately 10,000 people worldwide and hATTR with cardiomyopathy (hATTR-CM) – also known as familial amyloidotic cardiomyopathy (FAC) – is estimated to affect at least 40,000 people worldwide.
hATTR-PN patients have a life expectancy of 5 to 15 years from symptom onset, and the only approved treatment options for early stage disease are liver transplantation and tafamidis (approved in Europe, certain countries in Latin America and Japan, where it is approved for all stages of disease). hATTR-CM is fatal within 2.5 to 5 years of diagnosis and treatment is currently limited to supportive care.
Wild-type amyloidosis (wtATTR) – also called 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. There is a significant need for novel therapeutics to treat patients with ATTR amyloidosis.
Sanofi Genzyme Alliance
In January 2014, Alnylam and Sanofi Genzyme, the specialty care global business unit of Sanofi, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Sanofi Genzyme obtained the right to access certain programs in Alnylam’s current and future Genetic Medicines pipeline in the rest of the world (ROW) through the end of 2019, together with certain broader co-development/co-commercialization rights and/or global rights for certain programs.
In the case of patisiran, Alnylam will advance the product in North America and Western Europe, while Sanofi Genzyme will advance the product in the ROW. In the case of revusiran, Alnylam and Sanofi Genzyme will co-develop/co-commercialize the product in North America and Western Europe, while Sanofi Genzyme will advance the product in the ROW. In the case of ALN-TTRsc02, Sanofi Genzyme will have the right to opt into the program with co-development/co-commercialization rights.