Absence of Inhibitor Development in the Routine Clinical Use of Alphanate^® in Patients with Severe Hemophilia A: Results From a Long-Term Post-Marketing Surveillance Study.

Studies assessing the safety, tolerability and efficacy of a licensed drug are of utmost value for caregivers, patients and authorities to overcome the shortcomings of pre-licensing trials and to obtain information on the behavior of a drug in routine clinical conditions. Moreover, there is a paucity of data addressing the clinical outcome of treatment strategies in patients with severe hemophilia A, an especially vulnerable subset that presents the highest prevalence of antibody inhibitors. Late onset inhibitors may arise in patients who have accumulated hundreds of exposure days or after an intensive treatment episode.

To assess the immunogenicity and overall safety associated with long-term use of Alphanate^®, a highly purified plasma-derived factor VIII concentrate containing high-molecular weight multimers of von Willebrand Factor, a prospective, non-randomized, multicenter, post-authorization surveillance study was initiated in 2002 with the intention of involving at least 50 evaluable patients. Only previously treated patients (PTPs) diagnosed with severe hemophilia A (<1% FVIII:C) between 6 and 65 years of age who have been previously treated with plasma-derived Factor VIII products other than Alphanate^® are eligible to be enrolled. The primary endpoint of the study was the incidence of Factor VIII inhibitors and secondary endpoints were aimed to evaluate product tolerability and hemostatic efficacy. Treatment with Alphanate^® was given as needed for routine prophylaxis, bleeding episodes or hemorrhage and prior to physiotherapy or surgical procedures.

As of December of 2008, the investigation had recruited 31 patients of which 29 (94%) had received at least one infusion of Alphanate^® and 21 (68%) had completed the planned 24-30 month observational period with a minimum of 50 exposure days. The mean dose infused was 33.6 IU/kg (range: 18.3-73.1 IU/kg) and volume per patient per infusion was 1774 IU (range 395-3329 IU). Of the 29 subjects that had received approximately a total of 6.9 million units of Alphanate^® through 4704 infusions, none had developed inhibitors (0%) and none had seroconverted for hepatitis A, B, C or HIV-1/2. Overall, 12 (42.6%) subjects experienced a total of 50 commonly reported adverse events (AEs), 3 classified as serious, none of which were considered related to the study drug and none occurred during drug infusion. Furthermore, no patients had withdrawn from the study because of AEs and there were no reports of thromboembolic or other thrombotic events.

The results included herein confirm the excellent immunogenicity and overall safety profile of Alphanate^® in the treatment of PTPs with severe hemophilia A.

Páez:Instituto Grifols S.A.: Employment. Pinciaro:Grifols Biologicals Inc.: Employment. Woodward:Instituto Grifols S.A.: Employment.