Targeting Antithrombin: The Key to Achieving Hemostatic Balance in Hemophilia Patients?

Targeting the endogenous anticoagulant antithrombin (AT) in patients with hemophilia restored hemostatic balance and prevented severe bleeding in people with severe forms of the disease, according to research exploring the investigational RNAi therapy fitusiran (formerly known as ALN-AT3).

The results of this study, which were presented at the ASH annual meeting by lead investigator K. John Pasi, of the Royal London Haemophilia Centre at Barts and the London School of Medicine and Dentistry in the United Kingdom, support the hypothesis that targeting AT improves thrombin generation and can potentially reset patients’ hemostatic balance –providing an alternative to factor concentrates.

“The opportunity to provide a once-monthly subcutaneous therapy that could effectively prevent bleeding in severe hemophilia would be quite transformational for patients who would otherwise have to receive factor concentrates infusions intravenously every other day,” Prof. Pasi told ASH Clinical News. “Put simply, this is a massively exciting prospect.”

Fitusiran blocks the gene mutation that produces AT. “This is a new technology harnessing RNA interference, a natural mechanism for controlling gene expression,” he explained.

In this multicenter, phase I study, Prof. Pasi and colleagues evaluated the safety and tolerability of fitusiran in healthy volunteers and patients with moderate to severe hemophilia. The study was designed in three parts:

  • Part A, in which four healthy volunteers were randomized to receive either 30 mcg/kg fitusiran or a placebo.
  • Part B, in which 12 patients with severe hemophilia were assigned to receive ascending doses of fitusiran (three weekly doses of 15 mcg/kg group [n=3], 45 mcg/kg group [n=6], or 75 mcg/kg [n=3]).
  • Part C, which aims to enroll several cohorts (n=3 per cohort) and will assess a monthly dosing schedule (three doses) of fitusiran in patients with severe hemophilia.

Enrollment has been completed in the first three cohorts, and enrollment of up to three additional cohorts is planned.

At the time of the data presentation, part A of the trial (the single ascending dose study in healthy volunteers), had been completed, while parts B and C are ongoing. Prof. Pasi presented results from the first 24 patients enrolled in the trial.

In part A, there were no serious adverse events (AEs) or injection-site reactions observed. Investigators found that the drug was well tolerated in all hemophilia patients, with no serious AEs in any cohorts reported.

Focusing on AT knockdown (the reduction of AT from baseline), patients treated with the highest dose of fitusiran (75 mcg/kg) experienced a mean AT knockdown of 79 percent (p<0.05). The nadir levels were achieved between days 28 and 42 of treatment.

The maximum level of plasma AT knockdown was 88 percent, the authors noted, resulting in thrombin generation increases. Prof. Pasi and researchers further explored the association between AT knockdown and thrombin generation in a post-hoc analysis and found that, among the nine patients with a greater than 75 percent AT knockdown, peak thrombin generation increased by 285 percent (p<0.001) – correlating with the peak thrombin generation observed in healthy volunteers (range = 64-210 nM).

A total of 43 bleeding events were reported in 24 patients, with mean and median estimated annualized bleeding rates (ABRs) of 34±10 and 13, respectively. In patients achieving the highest level of AT knockdown (>75%), however, mean and median ABRs were 6±3 and 0, respectively (p<0.05).

In an additional post-hoc analysis of data from three cohorts in part C of the study, monthly fitusiran dosing also appeared to reduce median estimated ABR during treatment “onset period” (the period from day 0-28 when initial AT reduction is ongoing) and an “observation period” (the period from day 29 to the last day available, to a maximum of day 112), dropping from 12.6 during the onset period to 4.3 in the observation period.

Importantly, Prof. Pasi and colleagues observed no clinical thromboembolic events or clinically significant increases in D-dimer levels.

“Emerging clinical data suggest that targeting AT could be a promising approach for restoring hemostatic balance in hemophilia,” the authors concluded. “The potential for low-volume subcutaneous administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make fitusiran a potentially encouraging investigational therapy.”


Pasi KJ, Georgiev P, Mant T, et al. A subcutaneously administered investigational RNAi therapeutic (ALN-AT3) targeting antithrombin for treatment of hemophilia: interim weekly and monthly dosing results in patients with hemophilia A or B. Abstract #551. Presented at the 2015 ASH Annual Meeting, December 7, 2015; Orlando, Florida.