Haemophilia B gene therapy benefit sustained through 5 years

The final 5-year data from the phase III HOPE-B study demonstrated consistently low annualized bleeding rates and durable endogenous factor IX expression in haemophilia B patients, with no late hepatotoxicity or treatment-related oncogenicity observed.

In the full analysis population, the adjusted annualized bleeding rate for all bleeding events decreased from 4.16 during the lead-in period where patients were on standard-of-care factor IX prophylaxis to 1.52 during months 7 through 60 after gene therapy, representing a reduction of 63 percent (95 percent confidence interval [CI], 24–82), reported lead study author Dr Steve Pipe from the University of Michigan in Ann Arbor, Michigan, US. [N Engl J Med 2025;doi:10.1056/NEJMoa2514332]

The decrease in bleeding rate held true across spontaneous (from 1.52 to 0.53, for a 65-percent reduction), joint (from 2.34 to 0.35, for an 85-percent reduction), and traumatic (from 2.01 to 0.43, for a 78-percent reduction) bleeding events.

Pipe emphasized that at years 4 and 5, the annualized bleeding rate approached zero for all bleeds (0.4), spontaneous bleeding (0.8–0.9), joint bleeding (0.9–0.16), and traumatic bleeding (0.17–0.28).

Stable factor IX activity

Endogenous factor IX activity remained stable over 5 years, with a mean of 39 IU/dL at month 6 and 36.1 IU/dL at year 5.

According to Pipe, factor IX activity at year 5 was at therapeutic levels for most patients, with 31 percent being in the no haemophilia range (40 to <100 IU/dL), 48 percent in the solidly mild range (12 to <40 IU/dL), and 9 percent were in the low-mild range (5 to <12 IU/dL). “These individuals, as expected, had a high rate of freedom from factor IX prophylaxis post-gene therapy.”

At year 5, 94 percent of patients remained free from factor IX prophylaxis, 4 percent remained on prophylaxis (nonresponders), and 2 percent resumed prophylaxis.

Mean exogenous factor IX consumption decreased by 96 percent, from 257,339 IU/year during the lead-in period to 10,924 IU/year during months 7 through 60 after gene therapy (mean difference, −246,415 IU/year, 95 percent CI, −287,975 to −204,856). These data included patients who continued on factor IX prophylaxis for lack of gene therapy efficacy or resumed prophylaxis, as Pipe pointed out.

Favourable safety profile

As for safety, “etranacogene dezaparvovec has continued to show a favourable safety profile over 5 years,” he said.

A total of 100 treatment-related adverse events (AEs) were documented over the 5-year follow-up, and 91 of them occurred within the first 6 months after the infusion. The reason these treatment-related AEs were clustered in the first 6 months was because most of them were related to either infusion reactions or alanine transaminase (ALT) increases, according to Pipe.

The nine patients with increased ALT in the first 6 months were treated successfully with corticosteroids for a mean of 81.4 days. One patient with early ALT elevation experienced a loss of factor IX activity around 24 months in the absence of transaminitis and subsequently resumed factor IX prophylaxis.

Even in patients who had the early ALT elevation, annualized bleeding rates were substantially reduced, Pipe said. “So, even though they significantly ended up in the lower bounds of the overall factor IX expression, this actually didn’t have a clinical impact on them as they still maintained good bleed control.”

Treatment goals met

Etranacogene dezaparvovec is an AAV5-mediated, liver-directed gene therapy and is the first and only approved gene therapy for treating adults with moderately severe or severe haemophilia B with or without AAV5 neutralizing antibodies, Pipe said. The approval was based on the initial results of HOPE-B showing the superiority of etranacogene dezaparvovec to standard prophylaxis, with a 64-percent bleed reduction over months 7–18 vs the lead-in period and a favourable safety profile. [N Engl J Med 2023;388:706-718]

The 5-year data from HOPE-B demonstrate that “etranacogene dezaparvovec meets the goals for treatment of haemophilia B,” including bleed reduction, stable factor IX activity levels for years after one-time infusion, elimination of continuous factor IX prophylaxis, and long-term safety, he concluded.

HOPE-B was an open-label, single-dose, single-arm trial conducted in 54 adult male patients (mean age 41.5 years, 38.9 percent had detectable AAV5 neutralizing antibodies at baseline) with severe or moderately severe haemophilia B (factor IX activity ≤2 IU/dL). Exclusion criteria included factor IX inhibitors, active hepatitis B/C infection, uncontrolled HIV infection, and evidence of advanced liver fibrosis. Patients with pre-existing AAV5 neutralizing antibodies were allowed.

The patients received a single infusion of etranacogene dezaparvovec at 2x10¹³ gc/kg after a ≥6-month lead-in period. A total of 50 patients completed the 5-year follow up. They were rolled over into the IX-TEND 3003 study and will be monitored for up to 15 years, Pipe said.