Quantitative pharmacokinetic model to characterize and extrapolate long-term FVIII activity levels in patients with severe hemophilia A treated with valoctocogene roxaparvovec

Background

Valoctocogene roxaparvovec delivers a B-domain deleted factor VIII (FVIII) coding sequence with an adeno-associated virus vector to reduce bleeding and FVIII concentrate use in people with severe hemophilia A. The aim is to characterize the long-term trajectory of transgene-derived FVIII activity using a linear mixed effects (LME) model to estimate mean and median FVIII activity levels 5 years post-infusion.

Methods

In GENEr8-1, an open-label, single-arm, multicenter phase 3 trial, 134 participants with severe hemophilia A received a single 6x1013 vg/kg dose of valoctocogene roxaparvovec. FVIII activity was assessed using the chromogenic substrate assay and one-stage assay.ⁱ Ln-transformed FVIII activity values from week 76 to 104 were fit to the LME model with random effects for participants on slope and intercept using a restricted maximum likelihood method with the lmer package in the R software. The precision of parameter estimates and model diagnostics were evaluated to confirm goodness-of-fit. The model and extrapolation approach was further qualified by comparing to observed FVIII activity at week 156.

Results

A previously published quantitative pharmacokinetic (PK) modelⁱⁱ was updated to extrapolate FVIII activity levels to 5 years post-infusion. The final LME model dataset included 928 observations from 120 participants. The long-term trajectory of FVIII activity was consistent with first-order elimination kinetics starting at week 76. Model parameter estimates were consistent with the previously published model as shown in Table 1; diagnostic plots showed no major deficiencies. FVIII activity was extrapolated to 5 years post-gene transfer (Table 2). Mean and median FVIII activity extrapolations at week 156 were consistent with observed values, confirming adequacy of the model.

Conclusion

Pharmacokinetic modeling indicates valoctocogene roxaparvovec-derived FVIII activity levels will remain in the mild hemophilia range for ≥5 years post-gene transfer for the majority of patients treated.

Offenlegung Interessenkonflikt:

Marco Stadler is an employee of BioMarin Pharmaceutical.

References

i Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med 2022;386:1013-25.

ii Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. N Engl J Med. 2023;388(8):694-705. doi:10.1056/NEJMoa2211075