Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial

Abstract

This multinational, randomized, single-blind trial investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in 74 previously treated patients with hemophilia B (FIX activity ≤2 IU/dL). Patients received prophylaxis for 52 weeks, randomized to either 10 IU/kg or 40 IU/kg once weekly or to on-demand treatment of 28 weeks. No patients developed inhibitors, and no safety concerns were identified. Three hundred forty-five bleeding episodes were treated, with an estimated success rate of 92.2%. The median annualized bleeding rates (ABRs) were 1.04 in the 40 IU/kg prophylaxis group, 2.93 in the 10 IU/kg prophylaxis group, and 15.58 in the on-demand treatment group. In the 40 IU/kg group, 10 (66.7%) of 15 patients experienced no bleeding episodes into target joints compared with 1 (7.7%) of 13 patients in the 10 IU/kg group. Health-related quality of life (HR-QoL) assessed with the EuroQoL-5 Dimensions visual analog scale score improved from a median of 75 to 90 in the 40 IU/kg prophylaxis group. Nonacog beta pegol was well tolerated and efficacious for the treatment of bleeding episodes and was associated with low ABRs in patients receiving prophylaxis. Once-weekly prophylaxis with 40 IU/kg resolved target joint bleeds in 66.7% of the affected patients and improved HR-QoL. This trial was registered at www.clinicaltrials.gov as #NCT01333111.

Figure 1

Patient enrolment and outcomes. A total of 86 patients were screened, of whom 12 were screening failures, leaving 74 patients who were exposed to nonacog beta pegol. At the screening visit, the patient and the investigator decided together whether the patient should be allocated to prophylaxis (59 patients) or on-demand treatment (15 patients). Patients allocated to prophylaxis were randomly assigned to once-weekly dosing of either 10 or 40 IU/kg. A total of 7 patients were withdrawn during the trial, distributed evenly between the treatment groups. None of the withdrawals were a result of adverse events. Screening failures and withdrawals together constituted 19 (22%) of the 86 screened patients. A total of 17 patients participated in a pharmacokinetic session at trial initiation, and all but 1 had a second pharmacokinetic session after 12 to 44 weeks of prophylaxis, leaving 16 patients (7 in the 10 IU/kg group and 9 in the 40 IU/kg group) with complete pharmacokinetic assessments.

Figure 2

Mean predose FIX activity during trial. The graph shows the mean (± standard error of the mean) FIX activity in predose samples for the 10 IU/kg and 40 IU/kg prophylaxis groups. A 1-stage clotting assay was used to determine the FIX activity (IU/dL) in predose blood samples collected at clinical visits during the trial. Analysis was performed at a central laboratory, using a product-specific reference standard for calculation of the FIX activity.