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


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 hemophilia1,2,3,4,5,6,7,8,9, 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.

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Figure 1: Therapeutic approach.
Figure 2: ALN-AT3 pharmacokinetics and pharmacodynamics in mice.
Figure 3: ALN-AT3 pharmacology in mice.
Figure 4: ALN-AT3 pharmacology in NHPs.

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We thank B. Bettencourt for assistance with statistical analysis.

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Authors and Affiliations



A.S. directed the pharmacology studies in rodents and NHPs, led research collaborations, and contributed to manuscript preparation. S.B., J.H., M.C. and Y.J. planned and conducted the toxicology studies. J.Q., T.R., J.B., H.P. conducted the rodent pharmacology studies and generation measurements. L.I. and R.M.C. planned and conducted the microvessel laser injury model studies. B.C. planned and conducted the saphenous vein bleed model studies. X.Z., H.A. and R.H. planned and conducted the pharmacokinetics studies. D.F., S.M., K.C., S.K., M.A.M., L.N., P.K., A.V.K., J.K.N., K.G.R. and M.M. contributed to the design, synthesis, screening and scale-up of ALN-AT3. R.M., B.S., A.R.S., Y.D. and C.N. provided program guidance and medical expertise in the area of hemophilia. A.A. directed the program and wrote the manuscript.

Corresponding author

Correspondence to Akin Akinc.

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Competing interests

A.S., S.B., J.Q., T.R., J.H., M.C., Y.J., J.B., H.P., X.Z., H.A., R.H., D.F., S.M., K.C., S.K., M.A.M., L.N., B.S., A.R.S., and A.A. are all employees of Alnylam Pharmaceuticals. L.I., B.C., Y.D., and R.M.C. received research funding from Alnylam Pharmaceuticals. C.N. received research funding and a consultancy from Alnylam Pharmaceuticals.

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Sehgal, A., Barros, S., Ivanciu, L. et al. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med 21, 492–497 (2015).

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