Fidanacogene Elaparvovec Gene Therapy Demonstrates Long-Term Safety and Efficacy in Hemophilia B Over 6 Years: Study

In the follow-up study, participants who received a one-time intravenous infusion of fidanacogene elaparvovec at a dose of 5×10¹¹ vector genomes (vg) per kilogram — one of the lowest AAV doses tested in gene therapy — continued to maintain meaningful levels of factor IX activity for up to six years.

The findings were published online in the New England Journal of Medicine on April 16, 2025.

Hemophilia B, a rare genetic disorder caused by factor IX deficiency, typically requires lifelong infusions of clotting factor to prevent bleeding. Gene therapy offers a potential long-term solution, enabling the body to produce factor IX internally. In early trials, Fidanacogene elaparvovec, an AAV-based vector carrying a high-activity factor IX variant (FIX-Padua), showed promising sustained expression. However, the long-term safety and efficacy of this treatment remained uncertain.

To address this gap, John E.J. Rasko, University of Sydney, Central Clinical School, Faculty of Medicine and Health, Sydney, and colleagues aimed to evaluate the durability of clinical benefit and the safety profile of fidanacogene elaparvovec over an extended follow-up period of 3 to 6 years.

For this purpose, the researchers initially conducted a 12-month study in which 15 participants with severe or moderately severe hemophilia B (defined by factor IX coagulant activity ≤2% of normal) received a single infusion of fidanacogene elaparvovec at a dose of 5×10¹¹ vector genomes per kilogram of body weight. Following this, participants were eligible to enroll in a 5-year follow-up study to assess long-term outcomes. Safety end points included monitoring adverse events and laboratory parameters, while efficacy was evaluated through the annualized bleeding rate and sustained factor IX activity levels.

The following were the key findings:

• Fourteen participants consented to long-term follow-up and completed at least 3 years (median follow-up: 5.5 years; range: 3 to 6 years), with 8 participants still ongoing at data cutoff.
• No treatment-related adverse events were reported after the first year.
• Nine serious adverse events occurred in 4 participants, none of which were thrombotic or related to the treatment.
• No participants developed factor IX inhibitors during the follow-up period.
• Mean factor IX activity remained within the mild hemophilia range throughout follow-up.
• The mean annualized bleeding rate was less than 1, with 10 participants experiencing no treated bleeding episodes.
• Surveillance liver ultrasounds from year 1 onward showed no evidence of malignancy.
• Steatosis was observed in 4 participants with weight gain and elevated aminotransferase levels (maximum ALT: 77 U/L).
• One participant with a history of hepatitis C, hepatitis B, HIV infection, and high BMI showed progression of advanced liver fibrosis.
• Thirteen surgical procedures were performed in 8 participants; exogenous factor IX was used in 10 procedures without any unexpected bleeding complications.

"Fidanacogene elaparvovec demonstrated sustained efficacy and a favorable safety profile over 3 to 6 years, with only mild or no adverse effects observed at a low AAV dose of 5×10¹¹ vg/kg—among the lowest tested for any indication," the authors concluded.

Reference:

Rasko JEJ, Samelson-Jones BJ, George LA, Giermasz A, Ducore JM, Teitel JM, McGuinn CE, High KA, de Jong YP, Chhabra A, O'Brien A, Smith LM, Winburn I, Rupon J. Fidanacogene Elaparvovec for Hemophilia B - A Multiyear Follow-up Study. N Engl J Med. 2025 Apr 17;392(15):1508-1517. doi: 10.1056/NEJMoa2307159. PMID: 40239068.