Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study

Abstract

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.

Graphical abstract

Figure 1.

PROPEL study design. Design of this phase 3, prospective, randomized, open-label, multicenter clinical study (#NCT02585960); initiated November 2015, completed August 2018. *In the Nijmegen modification of the Bethesda assay. †Randomization occurred after the PK assessment and was stratified according to patients’ prestudy treatment regimen and ABR (prophylaxis with ABR <5 vs prophylaxis with ABR ≥5 vs on-demand) independent of their individual characteristics (ie, PK profile, activity level, or bleeding activity). ‡Prophylactic dose and dosing frequency with rurioctocog alfa pegol were based on the patient’s individual PK assessment and could be adjusted to maintain the target FVIII trough level on the basis of FVIII assessments at each study visit during the first 6-month study period.

Figure 2.

Patient disposition. A total of 135 patients enrolled in the study: 120 patients received the initial PK dose of rurioctocog alfa pegol and 115 patients received at least 1 prophylactic dose of rurioctocog alfa pegol. *Patients either completed a previous rurioctocog alfa pegol study (#NCT01599819, #NCT01736475, #NCT02210091, #NCT02615691, #NCT01913405, or #NCT01945593) or were naive to rurioctocog alfa pegol. †One patient in the screen failure category erroneously received the PK infusion and, although not included in the flowchart, is included in the safety analysis and PK analysis sets.