In trial, giroctocogene fitelparvovec safely prevents hemophilia A bleeds
Full trial data show benefits of Pfizer gene therapy over nearly 3 years
Nearly two-thirds of hemophilia A patients given a single infusion of the investigational gene therapy giroctocogene fitelparvovec were free of bleeding episodes a median of almost three years after being treated, according to full data from the Phase 3 AFFINE clinical trial.
These new data add to top-line findings from earlier this year, which showed that bleed rates among participants in the Phase 3 study (NCT04370054) were significantly lower after the gene therapy when compared with the period before the trial’s start, when patients were using standard-of-care preventive treatments, or prophylaxis. Those earlier findings showed the study had met its main goal, according to giroctocogene fitelparvovec developer Pfizer.
Now, Andrew Leavitt, MD, lead investigator of AFFINE and a professor at the University of California San Francisco, said these long-term results show the possible benefits of the gene therapy for hemophilia A patients undergoing time-consuming routine prophylaxis.
“A one-time treatment with giroctocogene fitelparvovec significantly reduced bleeding events for both total and treated bleeds, demonstrating the potential to lessen disease and treatment burden for appropriate patients living with hemophilia A,” Leavitt said in an emailed statement to Hemophilia News Today.
The full trial findings were discussed in a presentation by Leavitt, titled “Efficacy and Safety of Giroctocogene Fitelparvovec in Adults With Moderately Severe to Severe Hemophilia A: Primary Analysis Results from the Phase 3 AFFINE Gene Therapy Trial.” The presentation was given at the Annual Meeting and Exposition of the American Society of Hematology (ASH), held Dec. 7-10 in San Diego and virtually.
Giroctocogene fitelparvovec tested in AFFINE Phase 3 trial
In hemophilia A, mutations in the F8 gene lead to a lack of functional factor VIII (FVIII), an important blood clotting protein. This leaves patients susceptible to prolonged or spontaneous bleeding episodes, and their long-term effects.
Standard-of-care prophylaxis involves lifelong factor replacement therapy, in which a version of the missing protein is provided to patients via regular into-the-vein, or intravenous, infusions.
“People with hemophilia A often manage their condition with frequent [intravenous] infusions or injections to prevent repeated joint bleeds that can lead to significant joint damage that negatively impacts day-to-day activities and long-term joint health,” Leavitt said.
Giroctocogene fitelparvovec is a gene therapy designed to deliver a shorter but functional version of the F8 gene to the body’s cells. This is expected to enable cells to continuously produce their own FVIII, thereby offering long-term bleed prevention with a single infusion. The therapy is packaged into a viral carrier that helps deliver it to liver cells, where FVIII is produced.
AFFINE enrolled 75 men with moderately severe or severe hemophilia A, who had FVIII activity levels of no more than 1% of normal. All tested negative for antibodies against the gene therapy’s viral carrier and had no history of inhibitors, or neutralizing antibodies against FVIII that can make replacement therapies less effective.
Prior to the study, participants had completed at least six months of treatment in a lead-in Phase 3 clinical trial (NCT03587116), during which they received standard-of-care prophylaxis.
Upon entering AFFINE, all stopped using prophylaxis and were given a single infusion of giroctocogene fitelparvovec. They’re being monitored for up to five years initially, and then for as long as 15 years in a longer-term follow-up study.
No bleeds seen for nearly 3 years for 64% of patients given gene therapy
The trial’s main goal was to evaluate patients’ annualized bleed rate, or ABR — the number of bleeds per year — after receiving the gene therapy. This was assessed starting three months after the infusion and up to at least 15 months, or slightly longer than one year.
As previously reported, among the 50 men who comprised the study’s main efficacy population, the mean total ABR was significantly lower after gene therapy relative to the lead-in period — 1.24 vs. 4.73 — meeting the trial’s main goal. Moreover, the mean ABR for bleeds that required treatment dropped significantly, from 4.08 pre-infusion to 0.07, after the gene therapy.
As part of the new presentation, Pfizer also shared data from a sensitivity analysis from which a single patient with inconsistent bleed reporting was removed. The data still showed a significant reduction in mean total ABR with giroctocogene fitelparvovec compared with routine prophylaxis (0.26 vs. 4.65).
The company also reported that 64% of participants experienced no bleeding events over a median follow-up of 33.6 months, or nearly three years, after receiving the gene therapy, and 88% had no treated bleeds during that time.
”Giroctocogene fitelparvovec [treatment] … resulted in superior bleed protection vs. routine FVIII prophylaxis and significant reductions in bleeding.
The annualized infusion rate of FVIII replacement products also dropped significantly after gene therapy, from a mean of 124.39 pre-treatment to 0.21 post-treatment. A single patient returned to FVIII prophylaxis approximately 16 months after receiving the gene therapy.
Most participants (84%) achieved FVIII activity levels greater than 5% of normal by 15 months post-infusion. Mean FVIII activity levels reached more than 50% of normal by about a year after the gene therapy and remained relatively stable thereafter.
The treatment was generally well tolerated. About three-quarters of participants experienced infusion-related reactions and two-thirds saw temporary elevations in liver enzymes, but these were usually mild and manageable.
About half of the participants experienced temporary FVIII elevations greater than 150% in the first months after treatment. While this can raise the risk of blood clots, no such events were reported except in one person who had a history of blood clots, the data showed.
Overall, “giroctocogene fitelparvovec … resulted in superior bleed protection vs. routine FVIII prophylaxis and significant reductions in bleeding,” the researchers concluded in the presentation’s abstract.
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