New Trial Data Call into Question Long-Term Efficacy of BioMarin’s Hemophilia A Gene Therapy

BioMarin HQ/ Courtesy of BioMarin

BioMarin HQ/courtesy of BioMarin

Updated trial data show patients treated with BioMarin Pharmaceutical's severe hemophilia A gene therapy expressed substantially lower factor VIII levels after five years compared with one year, calling into question the drug’s long-term benefits.

Patients with hemophilia A lack sufficient quantities of functioning factor VIII, a clotting protein, and thus have a higher risk of painful and life-threatening bleeds compared with the general population. A fractional improvement is all that’s needed to help reduce symptoms and improve quality of life, but current evidence is uncertain how large a fraction of factor VIII is needed to do so.

New data from BioMarin’s open-label, Phase I/II study, announced during a session at the International Society on Thrombosis and Haemostasis (ISTH) 2021 Virtual Congress, show the first seven patients dosed with valoctocogene roxaparvovec (valrox) had a median of 8.2% the amount of factor VIII levels that would be found in a healthy individual. In contrast, the level of factor VIII was 60.3% after a one-year follow-up.

Valrox is administered as a single infusion. Current standard of care, however, involves infusion of factor VIII two to three times per week. But factor VIII infusion doesn’t prevent all bleeding events, creating an unmet treatment need in severe hemophilia A.

Patients in the Phase I/II study were mostly free of symptoms despite consistent reductions in protein levels over time. Valrox reduced the annualized bleeding rate in six patients by 95%. At 5 years, six out of the seven patients in the study had no bleeding events.

In a statement, Professor Michael Laffan, a lead investigator for the Phase I/II study who serves as the Faculty of Medicine in the Department of Immunology and Inflammation at Imperial College London, was generally optimistic about the study findings: “The consistent and impressive bleed control in the majority of the study participants out to five years in this study, which is the longest duration of clinical experience for any gene therapy in hemophilia A, which increases our understanding of the interplay between Factor VIII expression, ABR, and Factor VIII infusion rate as it relates to hemostatic efficacy.”

Durability of the treatment, as with most other gene therapies, is a concern as patients receiving this type of treatment can receive a dose only once. But whether valrox can be a one-time cure remains to be seen, warranting further long-term trial data.

Last year, the FDA made the surprising move of rejecting BioMarin’s approval application for valrox, citing the need for additional durability data before allowing the company to market the therapy. The agency asked the company to complete its Phase III study and submit two-year follow-up efficacy and safety data. The last patient is expected to complete the two-year follow-up study in November of this year.

BioMarin resubmitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for valrox last month. Earlier this month, the EMA validated the company’s resubmission of the MAA. That submission included efficacy and safety data for 134 participants in the Phase III GENEr8-1 trial who had been followed for one year or longer after treatment. Patients in the trial were also followed for up to four and three years in two different dose cohorts in the Phase I/II dose escalation study.


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