RNA Interference Therapy Fitusiran Improves Thrombin Generation in Patients With Hemophilia

The investigational RNA interference therapy fitusiran lowered levels of antithrombin in patients with hemophilia A or B with or without inhibitors, leading to improved thrombin generation, according to interim results from a phase II extension study presented at the 2017 Congress of the International Society on Thrombosis and Haemostasis.

The findings appeared to confirm results from a phase I, dose-escalation study of fitusiran in patients with hemophilia with or without inhibitors, noted the authors, led by K. John Pasi, MBChB, PhD, from Barts and the London School of Medicine and Dentistry in the United Kingdom.

In the phase I study, 30 patients with moderate or severe hemophilia A or B without inhibitors received three subcutaneous injections of fitusiran administered either once-weekly (at doses of 0.015, 0.045, or 0.075 mg/kg) or once-monthly (at doses of 0.225, 0.45, 0.9, or 1.8 mg/kg or a fixed dose of 80 mg), and 16 patients with inhibitors received three subcutaneous injections of fitusiran 50 or 80 mg once-monthly. Patients who received the once-monthly treatment experienced an average, dose-dependent maximum antithrombin reduction of 70 percent to 89 percent from baseline. Based on those results, the researchers selected once-monthly, fixed doses of fitusiran 50 and 80 mg for the phase II extension study.

The phase II study included 33 patients (age range = 19-61 years) – 14 patients with inhibitors (3 patients at the 50 mg dose and 11 at the 80 mg dose) and 19 without inhibitors (10 patients at the 50 mg dose and 9 at the 80 mg dose) – who were previously treated in the phase I study.

Patients were treated for a median of 11 months (range = 0-20 months). Five patients discontinued treatment: four because of withdrawal of consent and one because of asymptomatic aspartate and alanine aminotransferase (ALT) elevation in a patient with chronic hepatitis C infection.

During follow-up, 23 patients (70%) experienced an adverse event (AE). The majority of AEs were mild or moderate and unrelated to fitusiran; however, six patients reported serious AEs, two of which were deemed possibly related to fitusiran. The most common AEs included injection-site reactions (n=6; 18%), abdominal pain (n=3; 9%), diarrhea (n=3; 9%), and headache (n=3; 9%).

Eleven patients experienced ALT increases three times the upper limit of normal. Ten of those cases resolved during study follow-up, eight without dose interruptions. The authors also noted that all of those patients were hepatitis C virus–antibody positive.

No thromboembolic events occurred during the study, and there was “no clinical or laboratory evidence of pathologic clot formation,” the researchers reported. There were also no instances of drug-induced inhibitor formation.

At a median of 13 months (range = 2-19 months) after first fitusiran dose, patients at both dose levels experienced a nearly 80 percent reduction in antithrombin levels. Thrombin-generation levels appeared to return to the lower end of the normal range (FIGURES).

Patients experienced a total of 93 bleeding events (25 in 10 patients without inhibitors and 68 in 5 patients with inhibitors). Sixteen patients (48%) experienced no bleeding events during the study, for an overall median annualized bleeding rate of one (range = 0-3). The authors noted that all bleeding events were managed with replacement factor or bypassing agent.

A phase III trial evaluating fitusiran 80 mg once-monthly is under way.

The study is limited by its open-label, non-randomized design and small patient population.

The study was supported by Alnylam Pharmaceuticals, the manufacturer of fitusiran.

The authors report no conflicts.


Pasi KJ, Georgiev P, Mant T, et al. Fitusiran, an investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia: interim results from a phase 2 extension study in patients with hemophilia A or B with and without inhibitors. Abstract ASY 01.2. Presented at the International Society of Thrombosis and Haemostasis 2017 Congress, June 8-13, 2017; Berlin, Germany.

*Data transfer 15June2017
AT, antithrombin; SEM, standard error of the mean; HV, Healthy Volunteer
†Only patients with >56 days in OLE included in analysis; patients excluded from TG analysis if they administered factor or bypassing agent within 48 hours
‡Healthy volunteers with AT lowering <25% (Pasi KJ, et al. N Engl J Med. 2017; epub ahead of print.)