The Immunogenicity, Safety and Efficacy of N8-GP in Previously Untreated Patients (PUPs) with Severe Hemophilia A: pathfinder6 End-of-Trial Results

Background/Aims:

N8-GP (turoctocog alfa pegol) is a recombinant, glycoPEGylated, extended half-life factor VIII (FVIII) replacement product approved for the prevention and treatment of bleeding episodes in patients with hemophilia A. Clinical studies have shown good efficacy and safety in pediatric, adolescent and adult previously treated patients. Previously untreated patients (PUPs) with severe hemophilia A are at the highest risk of developing inhibitory antibodies against FVIII. Here, we present the end-of-trial results of pathfinder6, a clinical trial evaluating the immunogenicity, safety and efficacy of N8-GP in PUPs with severe hemophilia A.

Methods and materials:

Pathfinder6 (NCT02137850) was an open-label, multinational, single-arm, phase 3 trial investigating N8-GP treatment in PUPs with severe hemophilia A (FVIII activity <1%), enrolling male children, <6 years old, with no previous exposure to FVIII concentrates (5 previous exposure days; EDs to blood components was acceptable) and no FVIII inhibitors. The primary endpoint was the FVIII inhibitor incidence (two consecutive tests ≥0.6 Bethesda units (BU); high-titer was >5 BU). All patients with ≥10 EDs or if they reported an inhibitor within 10 EDs were included in the inhibitor incidence analysis. Patients <24 months old had the option of pre-prophylaxis (low dose or >1 week between doses of N8-GP) or prophylaxis. Patients ≥24 months old or after ≥20 EDs to N8-GP were treated with prophylaxis.

Results:

Overall, 81 patients received at least 1 dose of N8-GP and were included the end-of-trial analysis, with 49 patients completing the trial. The mean treatment period was 2.8 (2.2) years (standard deviation; SD) with a maximum treatment duration of 7.4 years. Of the 70 patients eligible for inhibitor analysis, 21 developed inhibitors (11 high-titer), resulting in an incidence rate of 30.0% (15.7% high-titer). All episodes of inhibitor development occurred within the first 20 EDs to N8-GP (Figure). Eight patients received immune tolerance induction therapy: 4 patients experienced success, 2 patients withdrew and 2 had ongoing therapy at the trial's end.

Sixty-nine patients received N8-GP prophylaxis for a mean (SD) of 2.9 (2.1) years. The annualized bleeding rate was 1.35 (0.6; 3.5) (median, interquartile range). In total, 13% of patients did not bleed while on prophylaxis, a proportion that increased with each year on regimen. On prophylaxis, 80.7% of bleeding episodes were traumatic and 97.4% of bleeding episodes were of mild or moderate severity (Table). The hemostatic success rate for bleeding episodes while patients were on prophylaxis was 91.9%. Adverse events (AEs) and serious AEs occurred at the rates of 3.4 and 0.4 events per patient year, respectively.

As previously reported, temporarily decreased incremental recovery (IR) associated with anti-PEG IgG antibodies was observed in 17 non-inhibitor patients within the first 5 EDs of exposure. IR returned to the expected range in all patients who continued N8-GP dosing. AEs in patients with temporarily decreased IR were generally mild and consistent with those experienced by the overall population and no events of hypersensitivity related to N8-GP occurred. No other safety signals or unexpected AEs occurred.

Conclusions:

Overall, in pathfinder6, PUPs were treated with N8-GP for up to 7.4 years. The rates of inhibitor (30.0%) and high-titer inhibitor (15.7%) development were within the expected ranges. During prophylaxis PUPs had a median ABR of 1.35, the proportion of patients with no bleeding episodes increased with each consecutive year of treatment, and 91.9% of bleeding episodes were treated successfully, indicating the PUPs can be successfully treated with N8-GP.

Kenet:Shire: Research Funding; Alnylam: Research Funding; BPL: Consultancy, Research Funding; ASC Therapeutics: Consultancy; Novo Nordisk: Consultancy, Honoraria; UniQure, SPark, Sobi, CSL: Honoraria; Sanofi-Genzyme: Consultancy, Honoraria; BioMarin Pharmaceutical Inc.: Consultancy, Honoraria; Opko Biologics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Roche: Consultancy, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Chuansumrit:Novo Nordisk: Consultancy, Honoraria; Grifols: Honoraria; Roche: Honoraria; Takeda: Honoraria. Matsushita:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Japan Blood Products: Honoraria; CSL Behring: Honoraria; Bayer Yakuhin: Honoraria, Membership on an entity's Board of Directors or advisory committees; KM biologics Co.: Honoraria; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Fujimoto: Honoraria; Sysmex Corp.: Honoraria. Young:Hema Biologics: Consultancy, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Biomarin: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy; Pfizer: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Spark: Consultancy, Research Funding, Speakers Bureau; Grifols: Research Funding; CSL Behring: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria; LFB: Consultancy; Viatris: Patents & Royalties. Yadav:Novo Nordisk: Current Employment. Zak:Novo Nordisk: Current Employment. Male:Bayer, Baxalta/Shire/Takeda, Biotest, CSL Behring, Novo Nordisk, SOBI: Consultancy, Research Funding; Bayer, Biotest, CSL Behring, Grifols, Novo Nordisk, Roche, Takeda: Consultancy, Honoraria.