Once-monthly subcutaneous fitusiran treatment led to dose-dependent lowering of antithrombin levels among patients with hemophilia A or B without inhibitors and increased thrombin production, according to the results of a small phase I dose-escalation study.

Compared with baseline, levels of antithrombin dropped by 70%-89%, K. John Pasi, MB, ChB, PhD, of the Royal London Haemophilia Centre and the London School of Medicine and Dentistry and his associates reported at the International Society on Thrombosis and Haemostasis congress and simultaneously in the New England Journal of Medicine. There were no thromboembolic events during the study, and the most common adverse events were mild injection-site reactions, they added.

Patients with hemophilia typically need frequent infusions of clotting factors, creating an urgent need for new therapies. Fitusiran is an investigational RNA interference (RNAi) therapy that targets antithrombin. This multicenter, open-label, phase I study included four healthy volunteers and 25 patients with moderate or severe hemophilia A or B without inhibitors. The healthy participants received a single subcutaneous injection of fitusiran (0.03 mg/kg) or placebo. The hemophilia patients received three injections of fitusiran either once weekly (0.015, 0.045, or 0.075 mg/kg) or once monthly (0.225, 0.45, 0.9, or 1.8 mg/kg, or a fixed dose of 80 mg (N Engl J Med. 2017 July 10. doi: 10.1056/NEJMoa1616569).

The single fitusiran dose and the weekly treatment regimens both produced consistent, sustained drops in plasma antithrombin levels, which supported a longer interval between doses, the researchers said. A monthly dose of 0.225 mg/kg cut antithrombin levels by about 70%, compared with baseline (standard deviation, ±9%), while a monthly dose of 1.8 mg/kg produced about an 89% (standard deviation, ±1%) drop in antithrombin levels. The fixed 80-mg dose consistently lowered antithrombin levels by about 87%, compared with baseline. The decreases in antithrombin varied little during the weeks between doses and were associated with increased thrombin generation, regardless of whether patients had hemophilia A or B, Dr. Pasi and his associates said.

One patient stopped treatment because of severe chest pain, but the investigators ruled out thrombosis as a cause. Fitusiran targets the liver, and 36% of patients developed transient increases in liver aminotransferase levels, they noted. Most of these patients had a history of hepatitis C virus infection. An extension study (NCT02554773) is ongoing to assess longer-term safety and efficacy findings. The investigators also are studying fitusiran in patients with inhibitory alloantibodies.

Alnylam Pharmaceuticals provided funding. Dr. Pasi disclosed research funding, advisory board fees, and travel grants from Alnylam and Genzyme. Four coinvestigators also disclosed receiving support from Alnylam during the conduct of the study.


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