Margaret V. Ragni, MD, MPH
Dr. Ragni has participated in six trials of Fc fusion factor VIII and factor IX proteins, will be participating in a trial of a pegylated factor VIII protein, and has served on the Biogen Idec Advisory Board. Dr. Ragni also receives research funding from Baxter Bioscience, Baxter Healthcare, Bayer, Biogen Idec, CSL Behring, and past funding from Novo Nordisk.
Study Titles: Multiple studies of long-acting recombinant replacement factors for treatment of hemophilia A and B
Clinicaltrials.gov Identifiers: NCT01395810, NCT01386528, NCT01440946, NCT01458106, NCT01480180, NCT0148911, NCT01493778, NCT01496274, NCT01580293, NCT01662531, NCT01731600, NCT01736475, and NCT01467427
Coordinators: Baxter, Bayer, Biogen Idec, CSL Behring, and Novo Nordisk
Participating Centers: 12 to 93 sites in North America, South America, Europe, Asia, Africa, and Australia
Accrual Goal: 12 to 172 patients
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Study Design: The table lists 13 currently enrolling trials of long-acting recombinant factor VIII (rF.VIII) or rF.IX for treatment of patients with hemophilia A or hemophilia B, respectively. These are multinational phase II/III or III trials designed to test whether long-acting factors are safe and effective in the treatment of hemophilia. The trials test the agents in the setting of active bleeding and for prophylaxis (for use in preventing spontaneous bleeding or in preventing excess bleeding in patients undergoing surgical procedures). In some studies, pharmacokinetics are assessed. Eligibility criteria are males with previous factor exposure with severe hemophilia A or B, defined as a plasma F.VIII or F.IX concentration of < 0.01 U/ml in some studies or up to < 0.02 U/ml in other studies. The products include rF.VIII or rF.IX that are pegylated, glycopegylated, fused with albumin, or fused with the Fc fragment of IgG. Phase I studies of the products listed in the table (left) have to date demonstrated safety, prolonged half-life, and delayed clearance as compared with standard rF.VIII and rF.IX. The dosing regimens, modeled from pharmacokinetic data, vary from approximately twice weekly for the long-lasting rF.VIII products to approximately once weekly for the long-lasting rF.IX products. The primary endpoint for the non-surgical prophylactic studies is incidence of anti-VIII antibody or anti-IX antibody formation, and secondary endpoints include hemostasis for bleeding episodes and annualized bleed rates. For the surgical studies, the primary endpoint is hemostasis.
Rationale: It is well established that prophylaxis prevents spontaneous bleeding in individuals with severe hemophilia. Using current available replacement therapy to maintain the goal for effective prophylaxis (>1% plasma factor levels), rF.VIII is dosed approximately three times weekly and rF.IX is dosed approximately twice weekly. Although prophylaxis clearly reduces the incidence of major morbidity and disability, patient compliance is poor due to venous access problems frequently encountered in children and to inconvenience in the case of adults (Walsh CE et al. Haemophilia. 2009;15:1014-1021). The availability of replacement factors with a longer half-life than that of currently available products might reduce the frequency of infusion such that ports may no longer be required in young children, and a reduction in dosing frequency may encourage participation by those who have been reluctant previously to attempt prophylaxis. The more favorable pharmacokinetics of the longer-acting replacement factors may further reduce the morbidity that is a consequence of recurrent hemarthroses and thereby improve the quality of life of patients with hemophilia. A long-range goal is to tailor therapy based on individual pharmacokinetic modeling.
Comment: Although the development of longer-acting replacement therapy has generated a great deal of excitement in the field, the cost:benefit ratio is a concern as the pricing of the new agents is unknown. To add perspective to this issue, the current cost of replacement therapy for an adult with hemophilia A ranges from $149,000 to $360,000 annually. Thus, depending on pricing, the availability of the longer-acting recombinant proteins could conceivably lower the cost of replacement therapy because less frequent dosing would be required. Economic constraints, however, limit treatment options for patients with hemophilia in much of the world as approximately 75 percent of replacement therapy is used by 15 percent of the total affected population (Skinner M. Haemophilia. 2012;18(Suppl 5):3-5). Without a major reduction in cost, this skewing of use of replacement therapy is likely to persist despite the advent of the longer-acting recombinant proteins. Although much work is left to be done in the field, patients with hemophilia A and hemophilia B and their treating physicians have reasons for optimism given the development of long-acting replacement proteins and the recent progress in gene therapy for hemophilia B. A trove of information should accrue from the broad range of studies being conducted on the long-acting replacement factors, and the effort and resources invested in the organization and implementation of these multinational clinical trials merits recognition.
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