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

• Published in: Nature medicine Vol. 21; no. 5; pp. 492 - 497
• Main Authors: Sehgal, Alfica, Barros, Scott, Ivanciu, Lacramioara, Cooley, Brian, Qin, June, Racie, Tim, Hettinger, Julia, Carioto, Mary, Jiang, Yongfeng, Brodsky, Josh, Prabhala, Harsha, Zhang, Xuemei, Attarwala, Husain, Hutabarat, Renta, Foster, Don, Milstein, Stuart, Charisse, Klaus, Kuchimanchi, Satya, Maier, Martin A, Nechev, Lubo, Kandasamy, Pachamuthu, Kel'in, Alexander V, Nair, Jayaprakash K, Rajeev, Kallanthottathil G, Manoharan, Muthiah, Meyers, Rachel, Sorensen, Benny, Simon, Amy R, Dargaud, Yesim, Negrier, Claude, Camire, Rodney M, Akinc, Akin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2015; Nature Publishing Group
• Subjects: 13; 13/89; 631/154/436/2388; 631/61/391/3932; Animals; Antithrombins; Antithrombins - chemistry; Biomedicine; Blood Coagulation - drug effects; Cancer Research; Care and treatment; Coagulation; Dosage and administration; Dose-Response Relationship, Drug; Drug targeting; Factor IX - chemistry; Factor VIII - chemistry; Female; Genetic aspects; Health aspects; Hemophilia; Hemophilia A - drug therapy; Hemophilia A - genetics; Hemostasis; Hemostasis - drug effects; Homozygote; Humans; Infectious Diseases; letter; Male; Metabolic Diseases; Methods; Mice; Molecular Medicine; Mutation; Neurosciences; RNA; RNA Interference
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.3847

An siRNA targeting antithrombin promotes hemostasis in mouse and nonhuman primate models of hemophilia and could represent a new therapeutic option for this disease. 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 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 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.