First Report on the Safety and Efficacy of a Long-Acting Recombinant FVIII (turoctocog alfa pegol, N8-GP) during Major Surgery in Patients with Severe Hemophilia a

Introduction

N8-GP (turoctocog alfa pegol) is an extended half-life, recombinant factor VIII (FVIII) that has a site-specific glycoPEGylation in the truncated B-domain. Upon activation, the glycopegylated domain is cleaved from N8-GP yielding FVIIIa, which is identical to endogenous FVIIIa. Pathfinder^TM 2 and pathfinder™3 (www.ClinicalTrials.gov identifiers: NCT01480180 and NCT01489111, respectively) are ongoing international, open-label, non-randomized, phase 3 clinical trials of N8-GP in patients aged ≥12 years with severe hemophilia A and with a documented history of at least 150 exposure days to other FVIII products, in line with regulatory guidelines. All patients in the pivotal pathfinder^TM 2 trial are offered entry into pathfinder^TM 3 if major surgery is required, thus enabling patients to undergo surgery without having to switch to another FVIII product. After completion of pathfinder^TM 3, patients returned to the prophylactic or on-demand treatment arm in pathfinder^TM 2 as per their prior participation in the trial. We report a planned main phase interim analysis of the single-arm pathfinder^TM 3 trial evaluating the efficacy and safety of N8-GP during surgical procedures in patients with severe hemophilia A.

Methods

Patients recruited into the pathfinder^TM 3 trial were males aged ≥12 years (aged ≥18 years in France and the Netherlands) with severe hemophilia A (FVIII activity level <1 IU/dl). Eligible patients undergoing major surgery received N8-GP before, during, and after surgery. At screening (0-3 weeks prior to surgery), all eligible patients received a single dose of N8-GP 50 U/kg at the clinic to evaluate FVIII activity recovery and required dose level for surgery. On the day of surgery, all patients received a fixed pre-operative loading dose of N8-GP (50 U/kg), up to 2 hours prior to the start of surgery. During and after surgery, N8-GP dosing was at the investigators' discretion. The dose level of N8-GP during this trial was chosen so that FVIII activity levels recommended by World Federation of Hemophilia (WFH) guidelines were targeted; higher levels could be necessary depending on type of surgery and standard practice at the site. Postoperative assessments, including monitoring for FVIII activity, were conducted daily for Days 1-6, and once between Days 7-14. Efficacy of N8-GP during surgical procedures was assessed using a 4-point scale of "excellent, good, moderate, or poor". In addition, transfusion requirements, consumption and estimated blood loss were recorded as part of the efficacy assessment. Blood sampling for FVIII activity and laboratory safety parameters was done at all trial visits.

Results

The main phase interim analysis includes results from 16 patients (median age of 36.5 years; range: 15−66 years) who underwent 18 major surgical procedures (including synovectomy, joint replacement, ankle arthrodesis, and psoas pseudo tumor excision). All surgeries were effectively performed with N8-GP. Hemostasis was successful (i.e., rated as 'excellent' or 'good') on completion of surgery in 17 (94.4%) procedures, and no change of treatment regimen was needed in any patient. For one procedure (complicated total hip replacement) the hemostatic response was rated 'moderate' (5.6%) in a patient with multiple comorbidities and low platelet count at day of surgery. The postsurgical hemostatic effect success rate with N8-GP was 100%. N8-GP was well tolerated and no safety issues were identified during this trial; no FVIII inhibitors were detected, and no thromboembolic events occurred.

Conclusions

As the first report for a longer-acting glycoPEGylated FVIII product, the results from pathfinder™ 3 indicate that N8-GP is effective and well tolerated with a favorable safety profile for perioperative management of major surgical procedures in patients with severe hemophilia A.