Alnylam Pharmaceuticals, Inc.(Nasdaq: ALNY), a leading RNAi therapeutics company, is presenting new data today from its GalNAc-conjugate siRNA programs for the systemic delivery of RNAi therapeutics at the XX International Roundtable on Nucleosides, Nucleotides and Nucleic Acids being held August 5-9 in Montreal, Canada. GalNAc-conjugate siRNA are designed to achieve targeted delivery of RNAi therapeutics to hepatocyte cells of the liver through uptake by the asialoglycoprotein receptor. The research findings demonstrate potent and durable target gene silencing with subcutaneously administered GalNAc-conjugate siRNA from Alnylam’s ALN-TTRsc and ALN-AT3 pre-clinical programs. In addition, extensive safety evaluation studies demonstrate a wide therapeutic index for GalNAc-conjugate siRNA. ALN-TTRsc is an RNAi therapeutic targeting transthyretin (TTR) for the treatment of transthyretin-mediated amyloidosis (ATTR), and ALN-AT3 is an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia; both are key programs in the ‘Alnylam 5x15’ product development strategy.
“Our conjugate delivery platform is now ready for clinical translation, and enables subcutaneous dose administration of RNAi therapeutics with a very wide therapeutic index. We believe these advances clearly extend the potential of RNAi medicines, complementing the success we have already achieved in systemic delivery with lipid nanoparticles,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “We are very excited to now fully integrate this delivery approach in our ‘Alnylam 5x15’ efforts with ALN-TTRsc for the treatment of ATTR, ALN-AT3 for the treatment of hemophilia, and potentially future programs. We anticipate submitting investigational new drug applications for ALN-TTRsc by the end of 2012 and for ALN-AT3 in 2013.”
Data presented today showed potent, dose-dependent, and durable knockdown of serum TTR with Alnylam’s GalNAc-conjugate approach in its ALN-TTRsc pre-clinical program. Specifically, subcutaneous administration of ALN-TTRsc resulted in potent and sustained suppression of TTR, the disease-causing protein in ATTR. In non-human primates, ALN-TTRsc was administered in a loading regimen of once a day for five days, followed by a maintenance regimen of once a week for four weeks resulting in an approximately 80% reduction of TTR at doses as low as 2.5 mg/kg. TTR knockdown was achieved rapidly, with nadir TTR levels observed at about day 14. Suppression of TTR of approximately 80% was sustained with a weekly maintenance dose, and recovery to baseline levels was observed at day 40 after the last dose. At an ED 80 dose of 2.5 mg/kg and based on solubility of the GalNAc-siRNA, subcutaneous administration of ALN-TTRsc is expected to be achieved in human studies at a dose volume of approximately 1 mL. In single dose and multi-dose pre-clinical safety studies in rodents and non-human primates, ALN-TTRsc was found to be generally safe and well tolerated. Specifically, at doses as high as 300 mg/kg, ALN-TTRsc was well tolerated with no clinical signs, no adverse laboratory or histopathologic findings, no elevations in cytokines or complement, and no significant injection site reactions. Therefore, the “no adverse effect level,” or “NOAEL,” was determined to be greater than or equal to 300 mg/kg and the therapeutic index was determined to exceed 100-fold.
In addition, new data was presented from Alnylam’s ALN-AT3 program, which targets AT for the treatment of hemophilia. Results from a pre-clinical rodent study demonstrated that weekly subcutaneous administration of ALN-AT3 resulted in potent and durable AT suppression. Specifically, repeat dosing with ALN-AT3 showed an ED 50 for AT plasma protein knockdown of less than 0.75 mg/kg. Knockdown of AT was achieved rapidly, with nadir suppression observed at day 14. Weekly injections at doses as low as 0.75 mg/kg provided sustained AT knockdown of approximately 80%. In addition, subcutaneous administration of ALN-AT3 in non-human primates also resulted in potent, dose-dependent, and durable AT knockdown, with an ED 50 for AT knockdown of approximately 1 mg/kg after a single dose. Studies in non-human primates showed a very durable response, where a single subcutaneous dose of ALN-AT3 achieved nadir knockdown of AT plasma levels at about day 15, with effects lasting over 22 days. Alnylam believes these data will support a once-a-week or twice-a-month subcutaneous dosing paradigm for ALN-AT3, at doses less than 1 mg/kg and injection volumes of less than 1 mL. ALN-AT3 was found to be generally safe and well tolerated in these pre-clinical studies.About RNA Interference (RNAi) 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.