Bleeds Plummet After Experimental Gene Therapy

SAN DIEGO — Promising early results from an ongoing randomized, open-label, single-arm, Phase 3 study could pave the way for a Pfizer product to become the second US Food and Drug Administration (FDA)-approved gene therapy for hemophilia A.

In an efficacy population of 50 patients with hemophilia A, the AFFINE trial found that their mean annualized bleeding rate (ABR) fell from 4.73 pre-infusion with giroctocogene fitelparvovec to 1.24 post-infusion (week 12 to 15 or more months, −3.49, −6.06 to −0.91; P = .004), researchers reported earlier this month at American Society of Hematology (ASH) 2024 Annual Meeting. Sixty-four percent had no bleeding events over a median follow-up of 33.6 months (14.5-44.4).

The ABR for treated bleeds fell from 4.08 to 0.07 (−4.01, −5.57 to −2.45; P 

“The primary endpoint for this trial was a reduction in total bleeds in patients, and that was achieved,” said Hematologist and first author Andrew D. Leavitt, MD, of the University of California at San Francisco,in an interview. “More impressive was the reduction in treated bleeds, a kind of a surrogate marker for bleeds of clinical significance to the individual. And as one would expect or hope to see in a gene therapy trial, there was a significant and marked reduction in the use of factor.”

Moving forward, he said, the message to clinicians is that “there’s every reason to believe that they will have yet another option for their patients.”

Gene Therapy on the Rise in Hemophilia 

Gene therapy has arisen as an approved therapy for hemophilia over just the last few years. Two gene therapies for hemophilia B have been approved by the FDA since 2022, and one was approved for hemophilia A, the more common type, in 2023.

As Leavitt noted, one-time treatment with gene therapy offers an alternative to treatment with blood factor, long the mainstay of hemophilia therapy.

“One of the real pluses of gene therapy is the potential to remove the burden of hemophilia, which is large and, I suspect, underappreciated even by providers,” he said. “You have to sit down with your patients and really get a real good sense of just how difficult it is for them to manage with many products on the market over the last few decades.”

Why is there a need for multiple gene therapy products? “A patient may have neutralizing antibodies against the proteins on the surface of gene therapy product A that prevents its use, but not on gene therapy B, which allows use of product B,” Leavitt said. “We need a few flavors so that we can offer gene therapy to the maximum number of interested patients.”

High Efficacy and an ‘Acceptable’ Safety Profile

For the study, researchers dosed 75 patients (mean age, 32.3 [19-59]; 100% men, 74.7% White and 18.7% Asian,) with hemophilia A with giroctocogene fitelparvovec, a hepatocyte-directed recombinant adeno-associated virus serotype 6 vector encoding a B-domain–deleted variant of human factor VIII. The efficacy population is 50 patients with at least 6 months of follow-up in the lead-in study.

The annualized infusion rate of exogenous FVIII was 124.39 mean annualized infusion rate prior to the treatment infusion vs 0.21 post-infusion, week 12 through at least 15 months (−124.18, −139.47 to −108.89; P 

Leavitt said the results are similar to other gene therapies for hemophilia in that “it is difficult to predict how high your factor level will become. There’s a broad range of outcomes for individuals, and the duration of expression remains an unknown.”

The study authors described the treatment as “generally well tolerated” with “an acceptable and manageable safety profile.”

Of the 75 subjects, 98.7% had adverse effects (AEs, 740 events) and 90.7% had treatment-related AEs. Common treatment-related AEs included hepatotoxicity (62.7%) and infusion-related reactions (73.3%). No subjects discontinued therapy due to AEs.

Nearly two thirds — 62.7% — of subjects used corticosteroids for a mean 114.6 days (11-296).

Study Findings ‘Look Really Good’

In an interview, Guy Young, MD, director of the Hemostasis and Thrombosis Program at Children’s Hospital Los Angeles and professor of Pediatrics, Keck School of Medicine of University of Southern California, Los Angeles, said that “generally speaking, the new data looks really good.” Young, who didn’t take part in the study, noted that factor levels following treatment were high, and one subject actually had a thrombotic event and needed to be treated with an anticoagulant.

The high factor levels could actually be a sign of lasting benefit vs valoctocogene roxaparvovec (Roctavian), the sole FDA-approved gene therapy for hemophilia A, which is linked to significant drops in factor level after 6 months, he said. “Wouldn’t it be better to start really high?”

Gene therapy for hemophilia is highly expensive, although proponents noted that insurers may save money over the long run if patients don’t require prophylactic treatment or therapy for bleeds.

A Pfizer spokesman declined to comment on the new therapy’s potential cost. In regard to when the therapy may receive FDA approval, he said “Pfizer is discussing this data with regulatory authorities.”

Pfizer funded this study. Leavitt disclosed ties with HEMA, Merck, Catalyst, Genentech, Pfizer, BioMarin, and Sangamo. Other study authors reported relationships with Pfizer. Young disclosed ties with Pfizer and BioMarin.