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

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

The findings support the claim that gene therapy may be a more permanent treatment for hemophilia B patients.¹ The study was: published in New England Journal of Medicine.

Fidanacogene elaparvovec is a promising gene therapy for hemophilia B patients | image credit: Tatyana Makarova – 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 placed a significant burden on families due to the need for regular injections, but still did not completely eliminate symptoms. Newer treatments, including small interfering RNA agents such as fitusiran, may represent an advance in preventing symptoms, Cuker and colleagues said, “but they still require regular administration.” Therefore, they said, there remains a significant unmet need for a more permanent solution to the disease.

One promising option is gene therapy.

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

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

“The transgene exploits 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 treatment is to return factor IX activity to the level considered in the range from mild hemophilia to normal levels, thus reducing bleeding events.

Previous research suggests the treatment is effective. A stage 1/2a to work The study, published in 2021 and involving long-term follow-up for up to 5 years, found that patients maintained improvements in factor IX levels, resulting in annual bleeding rates ranging from 0-0.9 throughout the study.² Remarkably, no patient restarted prophylactic factor IX therapy, and 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 these findings. Phase 3, open-label equivalence study uses the same dosage as before; 5×1011 vector genome copies per kilogram of body weight; This is one of the lowest doses of vector reported for a gene therapy to date, Cuker and colleagues noted.

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

Results showed that the annual bleeding rate decreased from 4.42 (95% CI, 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after treatment. It showed that he had fallen.

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

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

“More than half of the participants in this study were treated with glucocorticoids due to increased aminotransferase levels, which are assumed to predominantly indicate cellular immune responses (although one participant initiated glucocorticoid therapy in response to a decrease in factor IX levels before aminotransferase levels increased),” Cuker and his colleagues wrote. They said guidelines for when to initiate glucocorticoids vary, but in this trial they used a “relatively cautious approach and a low threshold for glucocorticoid initiation.”

Six patients resumed factor IX prophylaxis, but all reported initial response to fidanacogen elaparvovec. All of these were treated with glucocorticoids, but the majority of patients treated with glucocorticoids (79%) did not continue prophylaxis. More studies are needed to better understand why these patients should continue prophylaxis, the authors said.

But overall, the researchers said their data showed that fidanacogene elaparvovec had a “favorable benefit-risk profile” even at a low dose.

References:

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