Individualized Prophylaxis with Achieving Higher Minimum Levels as a Possible Path to Optimal Treatment of Hemophilia A
Prophylactic administration of factor VIII (FVIII) concentrate is the standard of care for individuals with severe hemophilia A. Traditionally, the goal of prophylaxis has been to maintain minimum FVIII levels > 1%. However, it has been shown that this goal may not protect many hemophiliacs from bleeding episodes. So how does prophylaxis that maintains higher FVIII levels stand? These insights were brought by the PROPEL study, whose results were recently published in Blood magazine.
PROPEL Study
A randomized multicenter phase III study investigated the efficacy and safety of two prophylaxis regimens using Adynovi (pegylated FVIII belonging to the so-called extended half-life products). Study participants were men with severe hemophilia A aged 12–65 years, whose average annual bleeding rate was ≥ 2 under previous prophylactic treatment.
The primary goal of the study was the proportion of patients without any bleeding episodes during the 6th–12th month of the study. Secondary goals included the proportion of patients without spontaneous bleeding episodes and spontaneous joint bleeding, overall annual bleeding rate (ABR), and other parameters.
Randomization and Analysis
The study involved 115 men who were randomized into a group with a target minimal (trough) level of 1–3% (n = 57) or 8–12% (n = 58). For efficacy analysis, results were evaluated in the group of patients who received at least one dose of the drug (FAS – full analysis set) and also in the group treated entirely in accordance with the study protocol (PPS – per protocol set). In PPS, higher efficacy of the drug is usually shown since no significant deviation occurred during treatment, but the real clinical efficacy of the drug is better reflected by the broader study population allowing for deficiencies or artificial supplementation of missing data (FAS).
Results
In the group with a lower target minimum level, no bleeding episode occurred in 42% of patients in the 6th–12th month of the study, while at a higher minimum level it was 62% (in the FAS population). This difference was numerically, but not statistically significant (p = 0.055). A statistically significant difference was only observed in the PPS population: 40% compared to 67% of patients were completely without any bleeding episodes (p = 0.015).
Among the secondary goals of the study, a significant difference in the proportion of patients without spontaneous joint bleeding was already shown in the FAS population. The lower minimum level could prevent spontaneous joint bleeding in 65% of patients, while the higher level in 85% (p = 0.026). In the PPS population, statistically significant differences were observed in the proportion of patients without spontaneous bleeding (60 vs. 81%; p = 0.038) and without spontaneous joint bleeding (65 vs. 91%; p = 0.008).
The target FVIII level was well achievable and well sustained with the established dosing. The number of prophylactic infusions per week averaged 2.3 in the 1–3% target level group (range 1.5–3.5) compared to 3.6 in the 8–12% group (range 1.6–6.8). Adherence to the individualized prophylaxis plan reached 86% for individuals with a lower target level and 93% in the group with the higher goal.
No deaths, serious thrombotic events, or treatment discontinuations related to adverse events occurred in the study. A transient low titer inhibitor was observed in 1 patient in the higher target level group, otherwise, the incidence of adverse events did not differ significantly.
Achieving Target Levels is Feasible
Many patients with hemophilia achieved the planned target level when administering Adynovi within the recommended weekly dose (40–50 IU/kg 2× per week). Weekly factor consumption varied, and overlapping dosing schedules between both arms were observed, indicating a large variability in FVIII half-life among individual patients. This supports the importance of individualized prophylaxis based on individual pharmacokinetics and efficacy. The dosing interval to achieve a target minimum level of 8–12% mainly included every-other-day administration or extended dosing intervals.
Conclusion
There is no universal prophylactic FVIII administration scheme for all patients, and individualized prophylaxis brings great benefits to many patients. Targeting higher minimum levels can reduce the risk of bleeding. It is especially suitable for individuals who bleed under the already set standard prophylactic regimen or for those with a severe form of hemophilia who want to live an active life. At the same time, it was shown that targeting higher minimum levels in prophylaxis does not change the safety of treatment.
(eza)
Source:
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 2021; 137 (13): 1818–1827, doi: 10.1182/blood.2020005673.
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