Impact of maintaining higher FVIII trough levels with BAX 855: Rationale and design of the PROPEL study

H.-Y. Lee1, B. E. Abbuehl2, A. Hafeman3, W. Engl2, L. Patrone3, L. A. Valentino4, B. M. Ewenstein5 (1Zurich, Switzerland, 2Vienna, Austria, 3Westlake Village, CA, United States, 4Chicago, IL, United States, 5Cambridge, MA, United States)

Bleeding disorders, coagulation and fibrinolytic factors
Date: 17.02.2017,
Time: 17:15 - 18:15

Objective: Despite improvements in prophylaxis for hemophilia A, desired outcomes for patients have not yet been achieved. In the pivotal PROLONG‐ATE study with BAX 855 (ADYNOVATE) – a polyethylene glycol (PEG)ylated, full‐length, extended half-life (EHL) recombinant factor VIII (FVIII) built on ADVATE – 39.6% of patients achieved zero bleeding and 57.4% experienced zero hemarthroses on prophylaxis intended to maintain a >1% FVIII trough. However, preliminary data suggest that maintaining higher trough levels may further reduce hemarthroses, enable more patients to experience zero bleeding, preserve long‐term joint health, and improve quality of life (QoL).

Methods: In the Phase 3 BAX 855 Continuation Study, previously treated patients (PTPs) with severe hemophilia A (FVIII<1%) could remain on a fixed dose prophylaxis regimen, receiving 45 ±5 IU/kg (≥12y) or 50 ±10 IU/kg (<12y) twice weekly. Alternatively, patients could elect to receive prophylaxis based on individual PK (PKP), targeting FVIII trough levels >=3%.

Results: Patients on PKP (n=15) maintaining >=3% FVIII experienced an estimated mean (95% confidence interval [CI]) total annualized bleeding rate (ABR) of 1.56 (0.56, 4.38). In contrast, patients on twice weekly prophylaxis (n=120) in the pivotal study exhibited a mean (95%CI) estimated total ABR of 4.3 (3.4, 5.5). These preliminary data suggest that maintaining higher FVIII trough levels with FVIII replacement therapy may result in lower ABR. To investigate the efficacy of 2 FVIII trough levels (1‐3% and 8‐12%), a prospective randomized Phase 3 clinical study (PROPEL) has been initiated. PTPs aged 12‐65y with FVIII<1% and ABR >=2 are eligible. The dose is based on the patient’s PK with infusions twice weekly (1‐3%) or every other day (8‐12%). The primary objective is to compare the proportion of bleeding‐free patients during the second 6‐month study period. Key secondary objectives include ABR, consumption, safety & tolerability, and health‐related QoL. Correlation of thrombin generation assay with FVIII levels and ABR will also be explored.

Conclusion: The novel design of the PROPEL Study (NCT02585960) evaluates the effects of maintaining higher FVIII trough levels through PK-guided dosing with BAX 855, an EHL FVIII replacement therapy, with the goal of increasing FVIII coverage and bleed protection allowing more patients to be bleeding‐free through a personalized treatment approach.