Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A published

Gene therapy with valoctocogene roxaparvovec reduced annualized rates of bleeding events and led to discontinuation of prophylactic factor VIII among patients with hemophilia A, according to results of a prospective study with multiyear follow-up published in The New England Journal of Medicine.

“The treatment burden is very significant for men with severe hemophilia A. Having to give prophylactic IV injections of factor VIII every other day to ensure that they do not bleed is a huge task,” K. John Pasi, MD, co-chair of the UK Thromboprophylaxis Forum and professor of hemostasis and thrombosis at Barts and the London School of Medicine and Dentistry, told Healio. “A treatment that is given once, provides levels of factor VIII that mean prophylaxis no longer will be needed, and that can reduce bleed rates massively and will last for years will be total game changer for many patients.”

Pasi and colleagues reported 2-year and 3-year efficacy and safety data following a single infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ, BioMarin) among 15 men with severe hemophilia A treated in a phase 1/phase 2 dose-escalation study initiated in June 2015.

“We know from an initial study and data we presented at meetings that quality-of-life scores for patients have risen dramatically after gene therapy across all domains,” Pasi told Healio. “Our initial gene therapy study publications from 2017 gave huge hope in the field that gene therapy was a real possibility and not some pipe dream for hemophilia. This latest study confirms both safety and the long-term beneficial impact of the treatment.”

Dosing of valoctocogene roxaparvovec included one patient assigned to 6 × 10¹² vector genomes (vg)/kg, one patient assigned 2 × 10¹³ vg/kg, seven patients assigned 6 × 10¹³ vg/kg and six patients assigned 4×10¹³ vg/kg. All participants were hospitalized and observed for 24 hours after infusion.

Results showed that, 2 years after infusion, all six patients who received 4 x 10¹³ vg/kg had median factor VIII expression of 13 IU/dL and a zero median annualized rate of bleeding events. Median use of factor VIII declined from 155.5 infusions to 0.5 infusions annually.

Bleeding in target joints, defined as three or more bleeding events within 6 months, resolved in five of six patients.

Factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events, which in turn led to episomal DNA stabilization for persistent expression.

Transgene-derived human factor VIII protein activity appeared similar to native human factor VIII in hemostatic ability. Researchers observed no inhibitor development, thromboses, deaths or persistent changes in liver function tests.

Three years after infusion, two patients — including the one who received 6 x 10¹² vg/kg and the one who received 2 x 10¹³ vg/kg — had factor VIII expression of less than 1 IU/dL. The seven patients who received 6 x 10¹³ vg/kg had a median factor VIII expression of 20 IU/dL, with a zero annualized rate of bleeding events and resolution of bleeding in all target joints.

Median use of exogeneous factor VIII declined from 138.5 infusions to zero infusions per year.

The study’s small sample size served as its primary limitation.

“Hemophilia as a therapy area is hugely exciting at the moment, with a range of new treatments such as bispecific antibodies, anti-TFPI [tissue factor pathway inhibitor], RNA interference, new-generation, super extended half-life factor products and, of course, gene therapy,” Pasi said. “I don’t doubt that together, these options will fairly radically change our perception of standard treatments as we learn more about them in a real-world setting and get to use them in the clinic.”