Alnylam Pharmaceuticals, Inc. a leading RNAi therapeutics company, presented new data at the 2010 International Chemical Congress of Pacific Basin Societies (Pacifichem), being held in Honolulu, Hawaii, December 15-20. New data show recent progress in the company's delivery efforts with siRNAs as well as results related to the translation of RNAi therapeutics in human clinical studies, specifically with the company's ALN-VSP liver cancer programme.

“As Alnylam advances its clinical programmes, we are also making notable progress in our delivery research efforts,” said Ken Koblan, PhD, chief scientific officer at Alnylam. “In particular, we reported new data today on systemic delivery of RNAi therapeutics using siRNA conjugates, our second most advanced delivery platform. Specifically, we have reached a major milestone in this effort with achievement of RNAi efficacy with subcutaneous dosing of novel siRNA conjugates at single digit milligram per kilogram doses. These new data open the door for broadened clinical opportunities for RNAi therapeutics with subcutaneous dose administration.”

“Alnylam is leading the translation of RNAi therapeutics in clinical development,” said Akshay Vaishnaw, MD, PhD, senior vice president, Clinical Research. “We currently have three programs in human clinical trials and expect two additional clinical programs in 2011. New data presented today document a clear correlation of the human pharmacokinetics of ALN-VSP with corresponding data from pre-clinical in vivo animal studies. We have thus demonstrated a predictable translation of our systemic delivery LNP platform in man, with relevance for additional Alnylam systemic delivery programs including our RNAi therapeutic programs targeting transthyretin and PCSK9.”

Alnylam has made significant advancements over the past year with systemic delivery of RNAi therapeutics. Previously, the company has reported on significant progress with its Lipid Nano-Particle (LNP) platform for systemic delivery to the liver and other cell types and tissues, including hepatic tumours, extra-hepatic tumours, immune cells, endothelial cells, and hepatic stellate cells.

Utilizing second-generation LNPs to deliver siRNAs, Alnylam has demonstrated an approximate 100-fold improvement in potency over first generation formulations, and has achieved an effective dose (ED50) at single digit microgram per kilogram dose levels (Akinc et al., Molecular Therapy, 18: 1357-1364, 2010; Love et al., Proc. Natl Acad. Sci. 107(5):1864-9, 2010; and Semple et al., Nature Biotechnology, 28: 172-178, 2010).

New data presented at the Pacifichem meeting related to progress made on the activity of novel GalNAc-conjugated siRNAs that result in improved in vivo gene silencing. Specifically, new research findings demonstrated improved potency and subcutaneous delivery for GalNac-conjugated siRNAs at low, clinically relevant doses.

In the case of a GalNAc-conjugated siRNA Targeting TransthyRetin (TTR), target gene silencing was achieved with an ED50 of approximately 5 mg/kg with a single subcutaneous injection. These results represent a greater than 25-fold improvement in target gene silencing with siRNA conjugates as compared with first-generation siRNA conjugates previously described (Soutschek et al., Nature 432, 173-178, 2004 and Wolfrum et al., Nature Biotechnology 25, 1149-1157, 2007).

Also presented at the Pacifichem meeting were new data from the company's ALN-VSP02 Phase I clinical study in patients with advanced malignancies with liver involvement. ALN-VSP02 is Alnylam's most advanced systemic RNAi program, and employs a first generation LNP developed by Tekmira Pharmaceuticals Corporation. ALN-VSP comprises two siRNAs designed to target two genes critical for the growth and survival of cancer cells: Vascular Endothelial Growth Factor (VEGF) and Kinesin Spindle Protein (KSP), also known as eglin 5 (Eg5).

Specifically, the company reported new human pharmacokinetic (PK) data that show a clear relationship of human and pre-clinical animal research findings. As previously reported, human PK parameters for ALN-VSP02 were found to be dose proportional with no evidence of cumulative effects upon patient re-dosing.

Based on new comparative analyses, human PK - blood drug levels over time - of ALN-VSP02 were found to correlate within a factor of only one- to two-fold with PK results from pre-clinical animal research studies. These new data thus demonstrate a predictable level of human exposure for RNAi therapeutics delivered using LNPs, providing broader validation of Alnylam's systemic delivery platform.

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 has the potential to treat disease and help patients in a fundamentally new way.

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world's top scientific journals including Nature, Nature Medicine, and Cell.