Fidanacogene Elaparvovec Shows Strong Results in Open-Label Phase 3 Study

A new report says the gene therapy fidanacogene elaparvovec (Beqvez) appears to outperform prophylaxis factor IX concentrate in terms of both bleeding reduction and factor IX stability in patients with hemophilia B.

The findings support the case that gene therapy may represent a more durable mode of therapy for people with hemophilia B.¹ The study was published in the New England Journal of Medicine.

Fidanacogene elaparvovec is a promising gene therapy for patients with hemophilia B | image credit: Татьяна Макарова - stock.adobe.com

The current standard of care for hemophilia B is regular intravenous administration of plasma-derived or recombinant factor IX products. However, corresponding author Adam Cuker, MD, MS, of the University of Pennsylvania, and colleagues, said the treatment protocol results in a substantial burden on families due to the regular need for injections, and yet it still does not fully eliminate symptoms. Newer therapies, including small interfering RNA agents like fitusiran, may represent an advancement in symptoms prevention, Cuker and colleagues said, “but they still require regular administration.” Thus, there remains a significant unmet need for a more durable solution to the disease, they said.

One promising option is gene therapy.

“Gene therapy could enable patients to live without the need for ongoing treatments and the burden of ongoing disease management,” they explained.

The FDA has approved the gene therapy FIX-R338L (FIX-Padua) for the treatment of hemophilia B. The therapy has also been approved in Europe. Fidanacogene elaparvovec is an adeno-associated virus vector designed to deliver transgene production of FIX-R338L.

“The transgene leverages the hepatic-control region of the gene encoding apolipoprotein E (APOE), a liver-specific human α1-antitrypsin promoter, and a codon-optimized FIX-R388L minigene,” Cuker and colleagues explained.

The goal of the therapy is to restore factor IX activity to what would be considered in the range from mild hemophilia to normal levels, thereby reducing bleeding episodes.

Previous research suggests the therapy is effective. A phase 1/2a study published in 2021 that included long-term follow-up of up to 5 years, found that patients sustained improvement in factor IX levels, resulting in annualized bleeding rates ranging from 0-0.9 over the course of the study.² Notably, none of the patients resumed prophylactic factor IX therapy, and the 4 patients who underwent 6 surgical procedures during the follow-up period were able to do so without bleeding complications.

The new study builds on those findings. The phase 3, open-label non-inferiority study uses the same dosage as the earlier, 5x1011 vector genome copies per kilogram of body weight, which Cuker and colleagues noted is one of the lowest vector doses reported for a gene therapy to date.

The new study involved 45 patients who received the therapy, 44 of whom completed at least 15 months of follow-up. All of the patients were men between the ages of 18 and 65 years who had hemophilia with factor IX levels of 2% or less.

The results showed the annualized rate of bleeding decreased from 4.42 (95% CI, 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after therapy.

“At 15 months, the mean factor IX activity was 26.9% (median, 22.9%; range, 1.9 to 119.0) by one-stage SynthASil assay,” the authors noted.

They added that 28 participants (62%) received glucocorticoids.

“More than half the participants in this study were treated with glucocorticoids, predominantly for increased aminotransferase levels that were presumed to indicate cellular immune responses (although one participant started glucocorticoid therapy in response to a decrease in factor IX levels before the aminotransferase levels increased),” Cuker and colleagues wrote. They said guidance about when to initiate glucocordicoids varies, but they said for this trial they used a “relatively cautious approach and a low threshold for glucocorticoid initiation.”

Six patients resumed factor IX prophylaxis, though all reported an initial response to fidanacogene elaparvovec. All of those were treated with glucocorticoids, though most patients treated with glucocorticoids (79%) did not resume prophylaxis. The authors said more work is needed to better understand why those patients needed to resume prophylaxis.

Overall, though, the investigators said their data show fidanacogene elaparvovec had a “favorable benefit-risk profile,” even at a low dose.

References:

1. Cuker A, Kavakli K, Frenzel L, et al. Gene therapy with fidanacogene elaparvovec in adults with hemophilia B. N Engl J Med. 2024;391(12):1108-1118. doi:10.1056/NEJMoa2302982
2. Samelson-Jones BJ, Sullivan SK, Rasko JEJ, et al. Follow-up of more than 5 years in a cohort of patients with hemophilia B treated with fidanacogene elaparvovec adeno-associated virus gene therapy. Blood. 2021;138 (Supplement 1):3975. doi:10.1182/blood-2021-150541