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An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia.

Abstract
Hemophilia A and B are inherited bleeding disorders characterized by deficiencies in procoagulant factor VIII (FVIII) or factor IX (FIX), respectively. There remains a substantial unmet medical need in hemophilia, especially in patients with inhibitory antibodies against replacement factor therapy, for novel and improved therapeutic agents that can be used prophylactically to provide effective hemostasis. Guided by reports suggesting that co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, we developed an RNA interference (RNAi) therapeutic (ALN-AT3) targeting antithrombin (AT) as a means to promote hemostasis in hemophilia. When administered subcutaneously, ALN-AT3 showed potent, dose-dependent, and durable reduction of AT levels in wild-type mice, mice with hemophilia A, and nonhuman primates (NHPs). In NHPs, a 50% reduction in AT levels was achieved with weekly dosing at approximately 0.125 mg/kg, and a near-complete reduction in AT levels was achieved with weekly dosing at 1.5 mg/kg. Treatment with ALN-AT3 promoted hemostasis in mouse models of hemophilia and led to improved thrombin generation in an NHP model of hemophilia A with anti-factor VIII inhibitors. This investigational compound is currently in phase 1 clinical testing in subjects with hemophilia A or B.
AuthorsAlfica Sehgal, Scott Barros, Lacramioara Ivanciu, Brian Cooley, June Qin, Tim Racie, Julia Hettinger, Mary Carioto, Yongfeng Jiang, Josh Brodsky, Harsha Prabhala, Xuemei Zhang, Husain Attarwala, Renta Hutabarat, Don Foster, Stuart Milstein, Klaus Charisse, Satya Kuchimanchi, Martin A Maier, Lubo Nechev, Pachamuthu Kandasamy, Alexander V Kel'in, Jayaprakash K Nair, Kallanthottathil G Rajeev, Muthiah Manoharan, Rachel Meyers, Benny Sorensen, Amy R Simon, Yesim Dargaud, Claude Negrier, Rodney M Camire, Akin Akinc
JournalNature medicine (Nat Med) Vol. 21 Issue 5 Pg. 492-7 (May 2015) ISSN: 1546-170X [Electronic] United States
PMID25849132 (Publication Type: Journal Article)
Chemical References
  • Antithrombins
  • Factor VIII
  • Factor IX
Topics
  • Animals
  • Antithrombins (chemistry)
  • Blood Coagulation (drug effects)
  • Dose-Response Relationship, Drug
  • Factor IX (chemistry)
  • Factor VIII (chemistry)
  • Female
  • Hemophilia A (drug therapy, genetics)
  • Hemostasis (drug effects)
  • Homozygote
  • Humans
  • Male
  • Mice
  • Mutation
  • RNA Interference

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