Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, is providing an update on its RNAi pipeline, platform, and technology at its R&D Day being held in New York today. Alnylam scientists and management will be joined by two guest speakers: Professor Allan Glanville, Director of Thoracic Medicine and Medical Director Lung Transplantation, St. Vincent’s Hospital, Sydney, will discuss respiratory syncytial virus (RSV) infection in the lung transplant patient population; and Professor Philip N. Hawkins, National Amyloidosis Centre, Division of Medicine, and University College London Medical School, Royal Free Hospital, will discuss transthyretin (TTR)-mediated amyloidosis (ATTR). Alnylam is developing RNAi therapeutics for the treatment of both RSV infection and ATTR, amongst other pipeline programs.
“We are pleased to share the exciting progress we’ve made in harnessing RNAi to develop novel medicines,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “In addition to advancing our pipeline of RNAi therapeutics, we continue to make important progress with our platform and technology. In particular, we are making major strides in our delivery research efforts and are now on a trajectory to achieve single microgram/kilogram gene silencing potency. Also, while our focus remains on therapeutic applications of RNAi, technology advances in other areas of drug discovery, such as biologics manufacturing, exemplify the broad transformative potential of RNAi.”
Alnylam is developing ALN-TTR, a systemically delivered RNAi therapeutic targeting the TTR gene for the treatment of ATTR, including familial amyloidotic cardiomyopathy (FAC) and familial amyloidotic polyneuropathy (FAP). ATTR is caused by mutations in the TTR gene, which is expressed in the liver, that result in the accumulation of toxic deposits of the mutant TTR protein in several tissues, including nerves, heart, and the gastrointestinal tract. There are more than 100 mutations that have been identified in the TTR gene; ALN-TTR targets a region of the gene common to wild-type and all known mutant forms of TTR, and therefore, has potential as a therapeutic for all patients with FAC and FAP.
New pre-clinical data demonstrate that ALN-TTR administration is associated with markedly reduced pathogenic deposition of mutant TTR in tissues. The new studies were performed in a transgenic mouse model where the human V30M mutated TTR is over-expressed, and were conducted by Alnylam scientists in collaboration with Dr. Maria Saraiva at the Institute for Molecular and Cell Biology in Portugal. Results showed that administration of ALN-TTR, as compared with control siRNA treatment, led to a marked and nearly complete reduction of mutant TTR protein accumulation by over 95% in peripheral tissues affected by disease. Specifically, ALN-TTR was found to block mutant TTR deposition in sciatic nerve, sensory ganglion, intestine, esophagus, and stomach - tissues that are associated with the sensory and autonomic neuropathy and the severe gastrointestinal dysfunction observed in patients with ATTR. The therapeutic efficacy for ALN-TTR was measured approximately one month after dosing.
Alnylam expects to file regulatory applications for ALN-TTR by the end of 2009 with a goal of initiating a Phase I clinical trial in early 2010. ALN-TTR is being advanced using stable nucleic acid-lipid particles (SNALP) delivery technology in collaboration with Tekmira Pharmaceuticals Corporation.
“Alnylam is advancing an important innovation in medicine to patients in need of new therapies. The progress we are making is reflected across our pipeline efforts, including our recent decision to advance ALN-RSV01 in a Phase IIb trial of adult lung transplant patients infected with RSV,” said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President, Clinical Research at Alnylam. “In addition, new data from our TTR program provide a clear validation of our RNAi therapeutics strategy in ATTR, where we block the production of TTR protein and its pathogenic deposition in tissues, thereby creating the potential to attenuate the cause of this devastating genetic disease. We certainly look forward to advancing this important program to patients.”
Alnylam also presented new data from its delivery research efforts showing the discovery of novel lipid materials that can be incorporated into lipid nanoparticles (LNPs) to achieve markedly improved in vivo potency for gene silencing with systemically delivered RNAi therapeutic. The improved potency of LNPs provides the opportunity to widen therapeutic index, decrease cost of goods, and broaden the number of tissues and cell types available for systemic RNAi. Alnylam showed new data on three distinct LNPs that derive from novel lipids discovered as part of the company’s collaborations with Tekmira, AlCana Technologies, Inc., University of British Columbia, and Massachusetts Institute of Technology (MIT). In rodent and non-human primate studies, all three novel LNPs demonstrated marked improvements in in vivo potency as compared with current generation LNPs. Specifically, in non-human primate studies, novel LNPs containing an siRNA targeting TTR demonstrated ED50 values (the dose of drug required to achieve a 50% silencing effect in vivo) of less than 30 micrograms/kilogram.