Alnylam Pharmaceuticals Inc., a leading RNAi therapeutics company, announced that it has initiated dosing in its phase I clinical trial with ALN-PCS, an RNAi therapeutic targeting proprotein convertase subtilisin/kexin type 9, or PCSK9, for the treatment of severe hypercholesterolemia. The study is aimed at evaluating the safety and tolerability of ALN-PCS in subjects with elevated low-density lipoprotein cholesterol (LDLc, or "bad" cholesterol). In addition, the study will evaluate clinical activity of ALN-PCS based on measurements of plasma PCSK9 protein and serum LDLc levels. Alnylam expects to present data from this study at year's end.

“We believe ALN-PCS has the potential to make a significant impact in the treatment of severe hypercholesterolemia, as this RNAi therapeutic targets both intracellular and extracellular PCSK9, a target validated by human genetics that is known to play a central role in LDLc metabolism. The primary objective of this phase I study is to demonstrate safety and tolerability of ALN-PCS in subjects with elevated baseline LDLc. In addition, we also believe we have an opportunity to assess preliminary human proof of concept based on blood measurements of PCSK9 protein and LDLc levels,” said Akshay Vaishnaw, PhD, MD, senior vice president, chief medical officer of Alnylam. “The start of this trial also marks an important milestone in our Alnylam 5x15 product efforts, as it is the first program using our second generation lipid nano-particle technology to enter clinical testing, where we aim to have important safety, tolerability, and clinical activity data by this year's end.”

ALN-PCS is a systemically delivered RNAi therapeutic targeting PCSK9, a disease gene validated by human genetics that is involved in the metabolism of LDLc. By targeting the PCSK9 mRNA, ALN-PCS depletes both intracellular and extracellular PCSK9 protein, thereby phenocopying the human genetics observed in loss of function PCSK9 mutations (N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum. Genet. (2006) 79: 514-523). An RNAi therapeutic targeting PCSK9 has the potential to lower tissue and circulating plasma PCSK9 protein levels resulting in higher LDL receptor levels in the liver, and subsequently lower LDLc levels, without any change in high-density lipoprotein (HDL, or "good" cholesterol) levels. Lower LDLc is associated with a decreased risk of cardiovascular disease, including myocardial infarction. Pre-clinical data from the ALN-PCS program have shown specific silencing of PCSK9 mRNA in the liver and reduced plasma PCSK9 protein levels of up to 90%, with an ED50 (the dose that provides a 50% silencing effect) estimated at approximately 0.06 mg/kg for both mRNA and protein reduction. These studies have also demonstrated a greater than 50% reduction in levels of LDLc, which is rapid and durable, lasting for weeks after a single dose.

“Cardiovascular disease is the leading cause of mortality worldwide, with elevated LDLc remaining the major risk factor. It is clear that new therapeutic options are needed for patients who cannot achieve target LDL levels with current drugs. As a key regulator of LDL receptor levels, PCSK9 is arguably one of the most important targets for development of molecular medicines for hypercholesterolemia,” said Jay Horton, MD, Professor of Internal Medicine - Digestive and Liver Diseases, University of Texas Southwestern Medical Centre. “An RNAi therapeutic targeting this genetically validated gene has the potential to rapidly and durably lower LDL cholesterol - while preserving HDL cholesterol - and may also function synergistically with statins.”

The phase I trial of ALN-PCS is being conducted in the UK as a randomized, single-blind, placebo-controlled, single-ascending dose study, enrolling approximately 32 healthy volunteer subjects with elevated baseline LDLc (>116mg/dL). The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-PCS, with patients being enrolled into five sequential cohorts of increasing doses ranging from 0.015 to 0.25 mg/kg. Secondary objectives include characterization of plasma and urine pharmacokinetics of ALN-PCS, and assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein and LDLc levels measured from serial blood samples prior to and following dosing. ALN-PCS is an RNAi therapeutic that utilizes proprietary Alnylam second-generation lipid nanoparticle (LNP) technology, specifically the MC3 lipid.

“ALN-PCS is Alnylam's fourth RNAi therapeutic to enter clinical development, highlighting our continued commitment and focus on advancement of breakthrough medicines to patients. This milestone also exemplifies our ongoing transition from 'platform company' to 'product company',” said John Maraganore, PhD, chief executive officer of Alnylam. “We look forward to results from this new phase I study at year's end as it defines an important data point for broader execution on our 'Alnylam 5x15' product strategy, including our programmes in transthyretin-mediated amyloidosis, refractory anaemia, and haemophilia.”

Severe hypercholesterolemia affects more than 500,000 people worldwide and is characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the U.S. Most forms of hypercholesterolemia can be treated through dietary restrictions and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving low-density lipoprotein cholesterol (LDLc, or "bad" cholesterol) goals by statin therapy including genetic familial hypercholesterolemia patients, acute coronary syndrome patients, high risk cardiovascular patients, and other patient populations that are statin intolerant or statin resistant. As a result, there is a significant need for novel therapeutics to treat patients with severe hypercholesterolemia whose disease is inadequately managed by existing therapies.

The "Alnylam 5x15" strategy, launched in January 2011, 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. This strategy leverages Alnylam's clinical progress on siRNA delivery, including definitive human proof-of-concept data for systemic delivery. By the end of 2015, the company expects to have five such RNAi therapeutic programmes in advanced clinical development. These include ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anaemia, ALN-APC for the treatment of haemophilia, and one additional program from the company's ongoing discovery efforts that will be designated and advanced into development later in 2011. Alnylam intends to commercialize the products arising under the "Alnylam 5x15" strategy itself in the United States and potentially certain other countries; the company will seek development and commercial partners in other global territories.

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.