An investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B

Abstract

Fitusiran is an RNA interference therapeutic that targets antithrombin (AT) in the liver and interferes with AT translation by binding and degrading messenger RNA-AT, thereby silencing AT gene expression and preventing AT synthesis. In both preclinical and clinical studies, AT knockdown results in dose-dependent AT lowering when fitusiran is given weekly or monthly subcutaneously. In clinical trials, fitusiran dose escalation has resulted in improved thrombin generation and clinical hemostasis as measured by reduction in annualized bleed rate. Unlike currently licensed drugs, this improvement was not only in patients with hemophilia A but in also those with hemophilia B, with or without inhibitors. In dental and surgical procedures, fitusiran also provided perioperative hemostasis in association with AT lowering. Fitusiran is well tolerated, with minor local injection site reactions, but in one subject with severe hemophilia A, the concomitant use of daily high-dose factor VIII, inconsistent with trial guidance to avoid high, repeat doses of clotting factor, was associated with fatal thrombosis, suggesting the need for caution when using hemostatic agents in conjunction with fitusiran. Preclinical in vitro and in silico studies indicate improvement in thrombin generation in rare bleeding disorder plasmas, including in plasmas from patients with severe factors V, VII, and X deficiency, suggesting potential therapeutic benefit.

Keywords:

• congenital bleeding disorder
• clotting factor
• fitusiran
• mRNA
• novel bypass

Acknowledgments

This study was supported by NHLBI 1-T32 110849-01-A1; HRSA Federal Hemophilia Treatment Centers, Grant H30MC24050-04-00; and PA-DOH State Support of Hemophilia Center of Western PA, SAP #41000058531. MVR received research funding from Alnylam, Bayer, Biomarin, Bioverativ, Novo Nordisk, Sangamo, Shire, and Spark and has served on Advisory Boards for Alnylam, Bayer, Biomarin, Bioverativ, and Spark. The first preliminary results on fitusiran were presented online as a PowerPoint at http://www.alnylam.com/wpcontent/uploads/2017/07/ISTH-2017_Pasi_Fitusiran-OLE_CAPELLA-Deck_vFINAL_2017.07.10-1.pdf & http://www.alnylam.com/web/assets/ASH-2016_Fitusiran_ NONINHIBITORS_04Dec2016_CAPELLA2.pdf.

Author contributions

Both authors contributed to conception and design, drafting and revising the manuscript, and both authors are accountable for all aspects of the work.

Disclosure

Both authors report no conflicts of interest in this work.