Targeting Higher Factor VIII Troughs Reduced Bleed Rates in Patients With Severe Hemophilia A

Targeting factor VIII (FVIII) trough levels of 1 to 3% and 8 to 12% with rurioctocog alfa pegol effectively reduced bleeding rates in patients with severe hemophilia A, but fewer bleeds occurred in the 8% to 12% group, according to research published in Blood. Rurioctocog alfa pegol consumption varied widely in each arm with overlapping ranges, emphasizing the need for personalized treatment, the authors noted.

“Higher FVIII trough levels will reduce bleeding, with individualization of dosing representing an important tool to reach this goal,” said Robert Klamroth, MD, of the Vivantes Friedrichshain Hospital in Berlin, Germany, when asked how these findings might impact clinical care.

The study included male patients with severe hemophilia A who ranged in age from 12 to 65 years (median = 29). All participants had an annualized bleeding rate (ABR) ≥2 and had received prior FVIII treatment. The authors also noted that, at baseline, a higher proportion of patients in the 8 to 12% arm had ≥4 joints with ≥4 spontaneous bleeds each, compared with the 1 to 3% arm.

Dr. Klamroth and colleagues compared the efficacy and safety of using patients’ pharmacokinetic profiles to guide dosing of rurioctocog alfa pegol prophylaxis to reach one of two target FVIII trough levels: lower levels of 1 to 3% (n=57) or elevated levels of 8 to 12% (n=58).

The dose and infusion frequency were both based on each patient’s pharmacokinetic profile, comprising:

  • incremental recovery
  • plasma half-life
  • acute body weight
  • target FVIII trough level

The primary endpoint of the analysis was the proportion of patients who had no bleeding events (including spontaneous and injury-related bleeds) during the second 6 months of treatment.

In the full analysis set (which included all randomized patients who received any prophylaxis), the estimated proportion of patients with zero total bleeds with targeted rurioctocog alfa pegol prophylaxis was 42% in the 1 to 3% arm and 62% in the 8 to 12% arm (p=0.055). Looking at specific types of bleeds, rates of no spontaneous bleeds were 60% versus 76% in the low trough arm (p=0.101), and rates of spontaneous joint bleeds were 65% versus 85%, respectively (p=0.026).

Prophylaxis with rurioctocog alfa pegol reduced total ABRs during the 12-month study period in both treatment arms, compared with participants’ historical ABRs in the year prior to enrollment. In the full analysis, ABRs in the 1 to 3% and 8 to 12% were as follows:

  • total ABR: 3.6 vs. 1.6
  • spontaneous ABR: 2.5 vs. 0.7
  • spontaneous joint ABR: 2.0 vs. 0.5
  • joint ABR: 2.6 vs. 1.1

In the 95 patients in the per-protocol analysis set, which excluded those who terminated treatment early, the proportions of patients with zero bleeds were 40% in the low trough arm and 67% in the elevated trough arm (p=0.015). In post-hoc analyses, the number of joints with ≥4 spontaneous bleeds from baseline in patients with at least 6 months of follow-up decreased in all but one patient in the 1 to 3% arm and one patient in the 8 to 12% arm.

“The paradigm before this study was to convert patients with severe hemophilia A to moderate hemophilia A with a FVIII trough level around 1%,” said Dr. Klamroth, “but in the higher dose arm, patients were converted to mild hemophilia A, an approach that’s possible with extended half-life FVIII products and pharmacokinetic-tailored individual dosing.”

In the full analysis set, patients in the 1 to 3% and 8 to 12% arms received a median of 2 and 3.4 infusions per week, respectively, at 30.3 and 38.4 IU/kg per infusion. Similar results were observed in the per-protocol analysis set. “Many [participants] met their target FVIII troughs using rurioctocog alfa pegol prophylaxis at rates within or below the recommended weekly dose (40-50 IU/kg, twice weekly),” the authors reported. “Weekly consumption was variable and overlapping ranges between treatment arms likely reflect the heterogeneity of patients’ FVIII terminal half-life,” they added, which supports the use of personalized treatment based on pharmacokinetic profiles and patterns of bleeding.

Seventy patients (60.9%) experienced an adverse event (AE), including 7 (6%) who experienced a serious AE. One event was characterized by low-titer inhibitors, but the event was transient and resolved before the study ended. No deaths, serious thrombotic events, or AE-related discontinuations were recorded. Together, the safety and efficacy findings support the hypothesis that an elevated FVIII trough can benefit patients with hemophilia A, without changing the safety profile of bleeding prophylaxis.

The study’s findings are limited by the inclusion of only adolescents and adults with histories of high ABRs (≥2) and only patients with hemophilia A who were receiving prophylaxis. According to Dr. Klamroth, these limitations may reduce the generalizability of the findings to patients with a history of lower ABRs.

Study authors report relationships with Baxalta, which sponsored this trial.

Reference

Klamroth R, Windyga J, Radulescu V, et al. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: Results from the phase 3 PROPEL study. Blood. 2020 November 4. [Epub ahead of print]