Date: 2014-12-01
Type of information: Publication of results in a medical journal
phase:
Announcement: publication of results in the Journal of the American Chemical Society
Company: Alnylam Pharmaceuticals (USA - MA)
Product: GalNAc-conjugated siRNA
Action
mechanism: GalNAc-siRNA conjugates are a clinically validated, proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNA therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor (ASGPR). This targeted delivery platform enables specific, potent and durable knockdown of hepatocyte-expressed disease genes with subcutaneous dosing and a wide therapeutic index. Alnylam has obtained broad intellectual property protection for its GalNAc-conjugate delivery platform for RNA therapeutics. Amongst other issued and granted patents, the Manoharan et al. patent (US 8,828,956) includes claims directed to compositions including those comprising a modified RNA agent linked to a biantennary or triantennary ligand. Specifically, the patent includes claims that broadly cover single-stranded or double-stranded chemically modified RNA therapeutics conjugated with an N-acetylgalactosamine (GalNAc) ligand, independent of length, sequence, or disease target.
Disease:
Therapeutic area:
Country:
Trial details:
Latest
news: * On December 1, 2014, Alnylam Pharmaceuticals, a leading RNAi therapeutics company, announced the publication of a peer-reviewed article in the Journal of the American Chemical Society describing the discovery of GalNAc-conjugated siRNA as a novel strategy for delivery of RNAi therapeutics. The paper, titled \"Multivalent N-Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing,\" (Nair et al., J. Am. Chem. Soc., doi:10.1021/ja505986a) documents the pioneering discovery of GalNAc-siRNA conjugates as a novel delivery approach for potent and durable knockdown of hepatocyte-expressed disease targets in vivo. Alnylam\'s GalNAc-siRNA conjugate platform is a clinically validated delivery technology that is being employed in essentially all of Alnylam\'s RNAi therapeutic pipeline programs. Recently, the company presented positive initial Phase 2 data with revusiran (ALN-TTRsc), a GalNAc-conjugated RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR cardiac amyloidosis; revusiran is a first generation GalNAc-conjugate that utilizes Standard Template Chemistry (STC). In the Phase 2 multi-dose study, revusiran demonstrated clinical activity with an up to 98.2% knockdown of serum TTR - the disease-causing protein - and was found to be generally well tolerated in patients with TTR cardiac amyloidosis and advanced disease burden. The Phase 2 results support advancement of revusiran in a Phase 3 randomized, double-blind, placebo-controlled study in TTR cardiac amyloidosis, and the company expects to start the study before year\'s end.
Earlier this year, Alnylam reported positive top-line clinical results with ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders; ALN-AT3 employs a second generation GalNAc-conjugate chemistry termed \"Enhanced Stabilization Chemistry,\" or \"ESC.\" In the first part of a Phase 1 clinical study, where ALN-AT3 was administered at low doses to healthy human volunteers, a single 0.03 mg/kg subcutaneous dose resulted in an up to 32% knockdown of serum AT and increases in thrombin generation. These clinical results suggest that ESC-GalNAc conjugates have a greater than 50-fold enhanced potency in humans as compared with STC-GalNAc conjugates due to enhanced stability in humans. Alnylam expects to present initial data from the ALN-AT3 Phase 1 study, including results in human volunteers and the first, lowest dose cohort of hemophilia subjects, at the American Society of Hematology meeting being held from December 6 - 9, 2014.
In addition, Alnylam has presented extensive non-human primate data with other ESC-GalNAc-siRNA conjugates, including ALN-PCSsc - an investigational RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia - and ALN-CC5 - an investigational RNAi therapeutic targeting complement C5 for the treatment of complement-mediated diseases. Recently, the company has filed and received approval for a Clinical Trial Application (CTA) to initiate a Phase 1 study of ALN-PCSsc in normal human volunteers with elevated LDL-C; the company expects to start the Phase 1 study by the end of 2014 and plans to report initial clinical data in mid-2015. In the case of ALN-CC5, Alnylam remains on track to file a CTA by the end of 2014, and expects to report initial clinical data in mid-2015.
In addition to data on siRNA conjugates, additional proof-of-concept for GalNAc-conjugates as a potent delivery platform for RNA therapeutics was recently reported by Regulus Therapeutics with positive interim clinical data with RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122 for the treatment of hepatitis C virus (HCV) infection. As reported by Regulus, interim results from an ongoing clinical study demonstrated that treatment with a single subcutaneous dose of 2 mg/kg of RG-101 as monotherapy resulted in significant and sustained reductions in HCV RNA, as well as a mean viral load reduction of 4.1 log10 at day 29; RG-101 was reported to be well tolerated in the study. Regulus has a license to Alnylam\'s GalNAc-conjugate technology in the field of microRNA therapeutics through the companies\' 2007 license agreement. Further, Isis Pharmaceuticals has reported successful adoption of GalNAc-conjugated antisense oligonucleotides (ASOs) in pre-clinical studies. Isis has obtained a license to Alnylam\'s GalNAc-conjugate technology in the field of single-stranded oligonucleotide therapeutics, including ASOs, through the companies\' 2004 license agreement.
