Phase III Results Announced for Clotting Factor Candidate in Hemophilia Patients
FDA submission expected in first half of 2013 (Oct. 31)
Results from the global phase III A-LONG trial have shown that a long-lasting recombinant factor VIII Fc fusion protein (rFVIIIFc, Biogen Idec) was effective in the control and prevention of bleeding, in routine prophylaxis, and in perioperative management in patients with hemophilia A. The recombinant fusion protein was generally well-tolerated. Additional analyses of the A-LONG study are ongoing.
The product’s manufacturer plans to submit a Biologics License Application (BLA) to the FDA in the first half of 2013.
A total of 165 male patients aged 12 years and older were enrolled in the study, which had three treatment arms: individualized prophylaxis (n = 118), weekly prophylaxis (n = 24), and episodic (on-demand) treatment (n = 23). In the individualized prophylaxis arm, the patients were treated with 25 to 65 IU/kg of rFVIIIFc every 3 to 5 days, which was individualized to maintain factor trough levels sufficient to prevent bleeding. In the weekly prophylaxis arm, the patients were treated with a weekly dose of 65 IU/kg. In the episodic treatment arm, the patients received rFVIIIFc as needed for bleeding. rFVIIIFc was also evaluated in the perioperative management of a subgroup of patients who required major surgical procedures. Most of the patients (93%) completed the study.
Recombinant FVIIIFc was generally well-tolerated. No inhibitors to rFVIIIFc were detected, and no cases of anaphylaxis were reported in any patients, all of whom switched from commercially available factor VIII products. The investigators determined that no serious adverse events were related to the study drug. The most common adverse events occurring outside of the perioperative management period were nasopharyngitis, arthralgia, headache, and upper respiratory tract infection.
The median annualized bleeding rates, including spontaneous and traumatic bleeds, were 1.6 in the individualized prophylaxis arm, 3.6 in the weekly prophylaxis arm, and 33.6 in the episodic-treatment arm. In the individualized prophylaxis arm, the median dosing interval was 3.5 days. During the last 3 months of the study, 30% of the patients in the individualized prophylaxis arm achieved a mean dosing interval of 5 days.
Bleeding control was assessed in all patients who experienced a bleeding episode during the study. Overall, 98% of bleeding episodes were controlled by one or two injections of rFVIIIFc.
In addition, rFVIIIFc was assessed in the perioperative management of nine patients undergoing nine major surgical procedures. The treating physicians rated the hemostatic efficacy of rFVIIIFc as good or excellent in all of these surgeries.
The A-LONG trial included a pharmacokinetic (PK) analysis of rFVIIIFc. In a protocol-defined subset of patients with extensive PK sampling, the approximate terminal half-life of rFVIIIFc was 19.0 hours, compared with 12.4 hours for Advate (antihemophilic factor [recombinant], plasma/albumin-free method; Baxter), which was consistent with the results of a phase I/IIa study of rFVIIIFc.
Hemophilia A is a rare, inherited disorder in which the ability of a person's blood to clot is impaired. Hemophilia A occurs in about one in 5,000 male births annually and is caused by having substantially reduced or no factor VIII protein, which is needed for normal blood clotting. People with hemophilia A therefore need injections of factor VIII to restore the coagulation process and to prevent frequent bleeds that could otherwise lead to pain, irreversible joint damage, and life-threatening hemorrhages.
The Medical and Scientific Advisory Council of the National Hemophilia Foundation recommends prophylaxis as the optimal therapy for patients with severe hemophilia A. Prophylaxis for hemophilia A usually requires injections three times per week or every other day to maintain a sufficient circulating level of clotting factor.
Source: Biogen Idec, October 31, 2012.