Gene Therapy for Severe Hemophilia A, BMN 270, Showing Early Promise in Clinical Trial

BioMarin Pharmaceuticals presented positive interim data from an open-label Phase 1/2 clinical trial of BMN 270, an investigational gene therapy for severe hemophilia A. The promising results, presented at the XXXII International Congress of the World Federation of Hemophilia (WFH), showed that patients had improved and sustained clotting function.

BMN 270 is designed to alter the genetic defect that causes hemophilia A — a missing or defective clotting factor VIII — by adding a corrected copy of the defective gene using an AAV-factor VIII vector. The investigational gene therapy, in mouse models of hemophilia A, was found to restore factor VIII plasma concentrations to levels projected to be adequate for normal clotting in humans.

The current Phase 1/2 clinical trial (NCT02576795) is assessing the efficacy and safety of escalating doses of BMN 270 in up to 12 patients with severe disease, as defined by the WFH as less than 1% of blood clotting factor. Its primary endpoints include the assessment of safety of a single intravenous infusion of BMN 270, and the change from baseline of factor VIII expression level at 16 weeks following infusion. The kinetics, duration, and magnitude of AAV-mediated factor VIII activity in patients will be established and correlated to an appropriate BMN 270 dose. Patients will be monitored for safety and treatment durability five years.

Data presented at the congress were taken from nine patients treated with a single dose of BMN 270. Seven received the highest dose of 6 x 10¹³ vg/kg.

At the July 6 cut-off date, data covered post-treatment follow-up ranging from 12 to 28 weeks.  Among the highest-dose patients at last evaluation,  six of seven patients had levels of Factor VIII over 50%, and the levels of seventh person was over 10%.

Additionally, four patients followed for the longest time had a mean level of Factor VIII of 146% at week 20, and two patients had factor VIII levels over 200% but no unanticipated clinical events or needed medical intervention. For the seven highest-dose patients, the median annualized rate of bleeding assessed from day of gene transfer to data cut-off period fell from 20 to 5.

There were no sustained elevated rises in liver toxicity (measured by ALT and other markers), as well as no serious adverse events observed.

ALT rises were not related with decreases in the levels of Factor VIII.  A steroid regimen given to patients on the highest dose was well-tolerated, and the patients are gradually decreasing their use. Two of the seven have been off steroid use for up to 2.5 weeks with no adverse effects on ALT levels or Factor VIII expression.

“These data provide strong proof of concept evidence that restoration of clotting function may be achieved by gene therapy,” John Pasi, PhD, a professor of Haemostasis and Thrombosis at Barts and the London School of Medicine and Dentistry, and the trial’s primary investigator, said in a press release.  “For the first time, patients have reason to hope to avoid bleeding and the opportunity to live a normal life.”

“We look forward to collaborating with experts and health authorities to design the next phase of investigation,” said Hank Fuchs, MD, chief medical officer at BioMarin. “Beginning in mid-2017, a Phase 2b study will seek to evaluate the optimal dose of BMN 270 using Factor VIII expression as the primary endpoint with material from the to-be-commercialized manufacturing process. If successful, this study could support an accelerated approval given the severe unmet need, the substantial effect and tolerability of the treatment.”

BMN 270 has received orphan drug designation from the European Commission and U.S. Food and Drug Administration (FDA).  Phase 3 study design and high volume manufacturing plans are underway.

Hemophilia A, the most common type of hemophilia, typically affects males, with an incidence estimated at 1 in 4,000-5,000 male births. People with severe disease often bleed spontaneously in their joints or muscles.