Hemophilia A gene therapy superior to FVIII replacement in Phase 3 trial
Pfizer reports positive new top-line data on giroctocogene fitelparvovec
Note: This story was updated July 30, 2024, to clarify patients participating in AFFINE had moderately severe to severe disease, and that a secondary study goal involved the mean treated annualized bleeding rate.
Giroctocogene fitelparvovec, an investigational gene therapy for adults with hemophilia A, is generally well tolerated and superior to standard replacement therapy in reducing bleeds, according to new top-line results from a Phase 3 clinical trial.
The open-label trial, dubbed AFFINE (NCT04370054) and sponsored by Pfizer, has now treated 75 men with moderately severe to severe disease. It compared a patient’s annualized bleeding rate in the months before the study’s start — while on factor VIII (FVIII) prophylaxis, or preventive, replacement therapy — to that following at least 15 months after the one-time gene therapy infusion.
The early results show the gene therapy worked better than FVIII treatment to reduce bleeds, Pfizer announced in a company press release.
“I’m excited by the strength of these positive results from the AFFINE trial that … demonstrate the transformative potential of this gene therapy candidate to provide superior bleed protection compared with routine FVIII prophylaxis, while helping relieve the treatment burden for people living with hemophilia A,” said Andrew Leavitt, MD, AFFINE lead investigator at the Adult Hemophilia Treatment Center at the University of California, San Francisco.
According to Pfizer, further analyses of the full AFFINE dataset are continuing, with additional data to be presented at upcoming medical meetings.
Giroctocogene fitelparvovec designed as one-time treatment for patients
People with hemophilia A carry mutations in the F8 gene, which disrupts the production or function of FVIII, a blood clotting protein. Without sufficient FVIII, patients are unable to form blood clots and may experience prolonged bleeding episodes.
Standard treatment involves injecting lab-made FVIII into the vein, or intravenously (IV), either via routine prophylaxis to prevent or reduce bleed frequency, or on-demand to treat active bleeds.
“For people living with hemophilia A, the physical and emotional impact of needing to prevent and treat bleeding episodes through frequent IV infusions or injections cannot be underestimated,” Leavitt said.
Giroctocogene fitelparvovec, formerly called SB-525, provides patients a shorter but working version of the F8 gene. The gene therapy is delivered to liver cells, where FVIII is produced, by a modified, harmless adeno-associated virus. Following a one-time IV infusion, its goal is to increase FVIII levels in the bloodstream and prevent bleeds.
For people living with hemophilia A, the physical and emotional impact of needing to prevent and treat bleeding episodes through frequent IV infusions or injections cannot be underestimated.
The gene therapy is now undergoing testing in AFFINE and a Phase 1/2 clinical trial (NCT03061201) called Alta. Enrolling men with severe hemophilia A, the Alta trial showed that a single dose of giroctocogene fitelparvovec prevented bleeds and the need for prophylaxis for at least two years.
Pfizer then launched a lead-in Phase 3 clinical trial (NCT03587116) ahead of AFFINE to monitor the safety and efficacy of replacement therapy for at least 150 days, or about five months. Those who completed six months of routine prophylaxis therapy could then enter AFFINE, in which all participants received a single infusion of gene therapy.
Patient screening and dosing in AFFINE was voluntarily paused by Pfizer in 2021 after some participants showed FVIII levels higher than 150% of normal, potentially increasing the risk of blood clots. While no side effects were reported, the company amended the protocol to help manage these patients.
As a result, the U.S. Food and Drug Administration (FDA) placed a clinical hold on the trial, pausing recruitment and dosing. The FDA then lifted the clinical hold in 2022 and enrollment resumed with an updated protocol.
Hemophilia A gene therapy found to reduce bleed rate by 98% in trial
The primary outcome for AFFINE was to compare the annualized bleeding rate (ABR), or the number of bleeds per year, up to at least 15 months after gene therapy relative to the ABR observed during the lead-in study. Participants are followed for five years, and then up to 15 years as part of a longer-term follow-up study.
AFFINE achieved its primary objective by demonstrating that treatment with giroctocogene fitelparvovec significantly reduced the mean total ABR compared with the pre-infusion period (1.24 vs. 4.73).
In key secondary measures, most patients (84%) maintained FVIII activity greater than 5% at 15 months post-infusion, with the majority of participants showing FVIII activity at least as high as 15%. Moreover, the mean treated ABR dropped from 4.08 during the pre-infusion period to 0.07 post-infusion, a statistically significant 98.3% reduction, according to the company.
Among all dosed participants, one patient (1.3%) returned to FVIII prophylaxis after gene therapy infusion.
While treatment was generally well tolerated, about half of the participants experienced transient elevations in FVIII greater than 150%, with no effect on efficacy and safety results. Serious adverse events occurred in 15 patients (20%), including 13 events in 10 patients (13.3%) that were considered related to treatment. Gene therapy-related events were generally resolved through clinical management.
“We are very pleased with these positive results from the Phase 3 AFFINE study demonstrating the safety and efficacy of our one-time gene therapy candidate for people with hemophilia A,” said James Rusnak, MD, PhD, Pfizer’s senior vice president and chief development officer of internal medicine and infectious diseases, research and development.
“We look forward to advancing this latest innovation to help address the medical and treatment burden associated with frequent and time-consuming IV infusions or injections,” Rusnak added.
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