Patients with severe hemophilia A who receive pharmacokinetic (PK)-guided prophylaxis with the extended half-life recombinant factor VIII (rFVIII) rurioctocog alfa pegol (TAK-660) may benefit from elevated FVIII troughs without a change in adverse events, according to the results of the prospective phase 3 PROPEL study, presented at the Thrombosis & Hemostasis Summit of North America (THSNA) 2020 Virtual Conference.
“Tailoring prophylactic rFVIII dose and/or administration frequency to individual pharmacokinetic profiles has been postulated to achieve lower annualized bleeding rates,” wrote the authors.
The phase 3 PROPEL study (ClinicalTrials.gov Identifier: NCT02585960) was a randomized, multicenter study conducted in 19 countries that investigated the efficacy and safety of PK-guided TAK-660 prophylaxis targeting standard or elevated FVIII trough levels in patients with severe hemophilia A.
Eligible patients were aged 12 to 65 years with baseline FVIII less than 1%, annualized bleeding rate (ABR) of 2 or more, and previous plasma-derived/rFVIII treatment. All patients underwent a PK assessment then were randomized to 12 months PK-guided prophylaxis targeting reference (REF) FVIII troughs of 1% to 3% or elevated (ELE) troughs of 8% to 12%. The primary outcome was the percent of patients with a total ABR equal to 0 during the second 6 months of the study. Secondary outcomes were total ABR, spontaneous and joint ABR (AJBR), TAK-660 consumption, and safety.
In total, 115 patients (predominantly White and Asian) were randomly assigned to receive 1 or more prophylactic dose (REF, 57 patients; ELE, 58 patients). The efficacy analysis was conducted on both the full analysis set (randomized, ≥1 prophylactic dose) and the per-protocol analysis set (second 6 months prophylaxis completed and no significant protocol deviations; REF, 52 patients; ELE, 43 patients). The median age among both sets was 29 years (range, 12 to 61 years).
For the primary endpoint, the percent of patients with a total ABR of 0 was 42% in the REF arm and 62% in the ELE arm (P =.0545) in the full analysis set, and 40% in the REF arm and 67% in the ELE arm in the per-protocol analysis set (P =.0154).
Improvements were also documented for the proportions of patients with no spontaneous bleeds and no spontaneous joint bleeds in both the full analysis set (REF vs ELE, 60% vs 76%; P =.101 and 65% vs 85%; P =.026, respectively) and the per-protocol analysis set (REF vs ELE, 60% vs 81%; P =.038 and 65% vs 91%; P =.008, respectively).
According to the investigators, target FVIII troughs were reliably achieved and maintained. At the end of the study, the median FVIII trough level was 2.6 IU/dL (IQR, 1.8-3.1 IU/dL) for the REF arm and 11.3 IU/dL (IQR, 8.8-13.6 IU/dL) for the ELE arm. Every-other-day dosing was used by 19.3% and 60.3% of patients in the REF and ELE arms, respectively; whereas, daily dosing was used by 0% and 12.1% of patients in the REF and ELE arms, respectively
“Patients with favorable PK profiles may achieve [8% to] 12% FVIII troughs with a twice-weekly or more extended regimen,” wrote the authors.
The safety profile of TAK-660 was reportedly consistent with its profile in previous clinical studies and was similar between the 2 study arms. Overall, adverse events (AEs) occurred in 70 patients (61%), and serious AEs occurred in 7 patients (6%). In the ELE arm, 1 patient had a serious AE considered related to treatment (transient low-titer anti-FVIII inhibitor of 0.6 BU at week 8; no anti-FVIII binding antibodies).
“Results from PROPEL provide proof of concept that PK-guided rurioctocog alfa pegol prophylaxis targeting [8% to] 12% FVIII troughs can improve bleed outcomes without an impact on safety, and emphasize that personalized treatment for hemophilia A should be considered,” concluded the authors.
Disclosures: The study was sponsored by Baxalta (now part of Shire), a Takeda company. Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Radulescu VC, Klamroth R, Windyga J, et al. Efficacy and safety results from a phase 3, randomized, multicenter study of rurioctocog alfa pegol pharmacokinetic-guided prophylaxis targeting two factor VIII trough levels in patients with severe hemophilia A (PROPEL study): a consideration for persona. Abstract presented at: THSNA 2020 Thrombosis & Hemostasis Summit of North America; October 27-30, 2020. Abstract 15.