title: 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.
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Alfica
authors: A
authors: Sehgal
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Scott
authors: S
authors: Barros
authors: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Lacramioara
authors: L
authors: Ivanciu
authors: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, North Carolina, USA. .
authors: Brian
authors: B
authors: Cooley
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: June
authors: J
authors: Qin
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Tim
authors: T
authors: Racie
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Julia
authors: J
authors: Hettinger
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Mary
authors: M
authors: Carioto
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Yongfeng
authors: Y
authors: Jiang
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Josh
authors: J
authors: Brodsky
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Harsha
authors: H
authors: Prabhala
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Xuemei
authors: X
authors: Zhang
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Husain
authors: H
authors: Attarwala
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Renta
authors: R
authors: Hutabarat
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Don
authors: D
authors: Foster
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Stuart
authors: S
authors: Milstein
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Klaus
authors: K
authors: Charisse
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Satya
authors: S
authors: Kuchimanchi
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Martin A
authors: MA
authors: Maier
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Lubo
authors: L
authors: Nechev
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Pachamuthu
authors: P
authors: Kandasamy
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Alexander V
authors: AV
authors: Kel'in
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Jayaprakash K
authors: JK
authors: Nair
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Kallanthottathil G
authors: KG
authors: Rajeev
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Muthiah
authors: M
authors: Manoharan
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Rachel
authors: R
authors: Meyers
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Benny
authors: B
authors: Sorensen
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Amy R
authors: AR
authors: Simon
authors: Unité d'Hémostase Clinique, Hôpital Edouard Herriot, Université Lyon 1, Lyon, France.
authors: Yesim
authors: Y
authors: Dargaud
authors: Unité d'Hémostase Clinique, Hôpital Edouard Herriot, Université Lyon 1, Lyon, France.
authors: Claude
authors: C
authors: Negrier
authors: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Rodney M
authors: RM
authors: Camire
authors: Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors: Akin
authors: A
authors: Akinc
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000737:chemistry*; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005164:Factor IX / Q000737:chemistry*; D005169:Factor VIII / Q000737:chemistry*; D005260:Female; D006467:Hemophilia A / Q000188:drug therapy* / Q000235:genetics; D006487:Hemostasis / Q000187:drug effects; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D034622:RNA Interference
chemical_list: D000991:Antithrombins; D005169:Factor VIII; D005164:Factor IX