- An experimental gene therapy from BioMarin Pharmaceuticals Inc. dramatically reduced bleeding episodes in patients with hemophilia A, boosting levels of the blood clotting protein Factor VIII to near-normal or normal levels in 11 out of 13 patients after a one-time infusion of the drug.
- The updated study results, unveiled Saturday at the annual meeting of the American Society of Hematology, raise the possibility of controlling the genetic blood disorder over an extended period of time with a single treatment — rather than the current standard of multiple Factor VIII infusions per week.
- BioMarin plans to study its therapy, known as valoctocogene roxaparvovec, in two Phase 3 trials set to begin enrollment this month and early next year, respectively. Success in those trials could position BioMarin to disrupt the hemophilia field and challenge Swiss pharma Roche AG's newly OK'd drug Hemlibra.
Roche's Hemlibra (emicizumab), approved in the U.S. last month, is widely seen as a potentially disruptive treatment that could steal market share away from existing drugs made by Shire plc, BioVerartiv Inc. and Novo Nordisk A/S, largely due to its effectiveness as a longer-acting therapy.
BioMarin's progress with valoctocogene roxaparvovec, however, could in turn threaten Roche with the promise of a one-time, potentially curative treatment.
The biotech's gene therapy uses an adenovirus to deliver a functional copy of the gene that produces Factor VIII into the body. Most patients with hemophilia A are born with missing or defective Factor VIII, which renders them unable to produce blood clots and thus at risk of excessive and potentially life-threatening bleeding.
Other companies, such as Spark Therapeutics Inc., have advanced gene therapy candidates for hemophilia B, but hemophilia A is considered a more difficult disorder to treat with gene therapy.
"The clinical data to date for this investigational gene therapy exceeded our expectations, in terms of increasing Factor VIII levels and reducing the annualized bleed rate," said John Pasi, lead researcher on the study and professor of hemostasis and thrombosis at Barts and the London School of Medicine and Dentistry, in a statement.
"This clinical result has the potential to improve the lives of patients who now must infuse themselves with Factor VIII as often as every other day," he added.
BioMarin's results included data from patients treated with two different doses of valoctocogene roxaparvovec, and updated results provided by the company in July and October.
In three of the six patients who received a 4e13 vg/kg dose, Factor VIII activity increased to normal or near normal levels through 48 weeks of follow-up. Across all six, the median annualized bleed rates dropped to zero at four weeks post-infusion.
Seven patients were treated with a higher dose of 6e13 vg/kg and saw Factor VIII activity increase to well within the normal range — an effect sustained through a year and a half of follow-up. Median annualized bleed rates also fell to zero in this cohort.
All patients in both groups were able to discontinue prophylactic use of Factor VIII infusions after treatment. Previously, participants in the study had received up to 185 Factor VIII infusions per year to help prevent bleeding episodes — which still occurred despite the standard preventative treatment.
Importantly for a new technology like gene therapy, BioMarin's treatment was generally well tolerated. No immune responses to the viral vector used to deliver the corrected copy of the gene were detected and no patients developed inhibitors to treatment. Eleven patients experienced mild, but temporary, elevation in liver enzymes and two had serious adverse events that were successfully resolved.
H. Marijke van de Berg, a hematologist and director of the PedNet Haemophilia Research Foundation in the Netherlands, called gene therapy the "ultimate grail" for hemophilia A, but cautioned that BioMarin's exciting results still have limits.
"Because patients who have been recruited for the current trials had to be AAV-negative, without active hepatitis, and inhibitor-negative, most patients with hemophilia cannot yet benefit from gene therapy," van den Berg wrote in a editorial published Saturday in The New England Journal of Medicine.
Still, BioMarin's results Saturday suggest that goal could soon be in reach.