Alnylam Inc., a leading RNAi therapeutics company, has completed enrollment in its phase I trial with ALN-TTR02, an RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). Alnylam also announced that it has initiated a phase II trial with ALN-TTR02 aimed at evaluating clinical activity, safety, and tolerability of multiple once-monthly doses of ALN-TTR02 in ATTR patients.

Specifically, the study will evaluate the clinical activity of ALN-TTR02 based on measurement of serum levels of TTR, the disease-causing protein in patients with ATTR. ALN-TTR02 utilizes the company’s proprietary second-generation lipid nanoparticle (LNP) delivery technology using the “MC3” lipid. The company expects to present data from the Phase I trial early in the third quarter of 2012.

“We continue to focus on the clinical advancement of ALN-TTR02, the lead effort in our ‘Alnylam 5x15’ product strategy. With dosing completed in the phase I study, we are on track to report results early in the third quarter. Our phase II study is now underway, and will evaluate a once-monthly multi-dose regimen in ATTR patients,” said Akshay K Vaishnaw, MD, PhD, senior vice president and chief medical officer of Alnylam. “ALN-TTR02 utilizes our proprietary second-generation LNP delivery technology which has shown significant potency improvements in both pre-clinical and clinical studies, including recently reported results from our ALN-PCS hypercholesterolemia programme. We look forward to continuing to share clinical data from our ALN-TTR02 programme, and, assuming positive results in the current phase II study, we plan to advance to a pivotal trial in 2013.”

The phase II trial is an open-label, multi-centre, multi-dose, dose-escalation trial designed to enroll approximately 20 ATTR patients. Subjects will be enrolled into cohorts of increasing doses and will receive drug once every four weeks for two cycles. The primary objectives of the study are to evaluate the safety and tolerability of multiple doses of ALN-TTR02 and to measure clinical activity based on serial measurement of circulating serum TTR levels.

Transthyretin (TTR)-mediated amyloidosis (ATTR) is a hereditary, systemic disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier for thyroid hormones and retinol binding proteins. 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.

In its severest form, ATTR represents a major unmet medical need with significant morbidity and mortality as an orphan disease; FAP (familial amyloidotic polyneuropathy) affects approximately 10,000 people worldwide and FAC (familial amyloidotic cardiomyopathy) affects at least 40,000 people worldwide. ATTR patients with FAP have a mean life expectancy of five to 15 years from symptom onset and the only treatment options for early stage disease are liver transplantation and tafamidis; as a result there is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.

ALN-TTR02 is a systemically delivered RNAi therapeutic being developed for the treatment of ATTR, including FAP and FAC. ALN-TTR02 is formulated in a proprietary second-generation lipid nanoparticle technology, using the “MC3” lipid. Assuming positive results from the Phase II study, Alnylam expects to start a pivotal trial for ALN-TTR02 in 2013. Alnylam also plans to advance ALN-TTRsc, which utilizes a GalNAc-conjugate delivery approach and subcutaneous dose administration.

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNAs (siRNAs), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

The “Alnylam 5x15” strategy, launched in , establishes a path for development and commercialization of novel RNAi therapeutics to address genetically defined diseases with high unmet medical need. Products arising from this initiative share several key characteristics including: a genetically defined target and disease; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi delivery platform; the opportunity to monitor an early biomarker in phase I clinical trials for human proof of concept; and the existence of clinically relevant endpoints for the filing of a new drug application (NDA) with a focused patient database and possible accelerated paths for commercialization. By the end of 2015, the company expects to have five such RNAi therapeutic programs in clinical development, including programs in advanced stages, on its own or with a partner. The “Alnylam 5x15” programs include ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-APC for the treatment of haemophilia, ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-TMP for the treatment of haemoglobinopathies. Alnylam intends to focus on developing and commercializing certain programs from this product strategy itself in and potentially certain other countries; the company will seek development and commercial alliances for other core programs both in and in other global territories.