Largest Hemophilia B Gene Therapy Study to Date Hits Early Benefit, Safety Marks


The historic phase 3 HOPE-B trial shows all but 1 treated patient discontinued prophylaxis after a single dose of etranacogene deaparvovec.

Steven W. Pipe, MD

Steven W. Pipe, MD (UMich)

The first reported phase 3 trial data for hemophilia B treated with a gene therapy show investigational agent etranacogene dezaparvovec resulted in severely ill patients being able to discontinue prophylaxis without bleeding events at 26 weeks.

The Health Outcomes with Pauda Gene; Evaluation in Hemophilia B (HOPE-B) study—the largest hemophilia B gene therapy trial to date—was presented during the late-breaking abstract presentation of the American Society of Hematology (ASH) 2020 Annual Meeting this week.

Reported by the team of international investigators and led by Steven W. Pipe, MD, of the University of Michigan, the findings establish etranacogene dezaparvovec’s benefit and safety in treating severe to moderately severe hemophilia B.

The Gene Therapy

Etranacogene dezaparvovec is an investigational gene therapy that is comprised of adeno-associated virus serotype 5 (AAV5) vector containing codon-optimized Padua variant human factor IX (FIX) gene with a liver-specific promoter.

The single-dose, hemophilia B-investigated agent previously provided mean FIX activity of 41% sustained at 1 year post-dose among 3 treated patients in a phase 2b study.

The Trial

Though gene therapy trials generally exclude patients with pre-existing neutralizing antibodies (Nabs) to the capsid serotype, Pipe and colleagues noted early clinical trials suggested generally prevalent titers of anti-AAV5 Nabs may not limit the transduction success associated with etranacogene dezaparvovec.

As such, the phase 3 HOPE-B trial included patients with hemophilia B with a wide range of pre-existing NAbs to AAV5 at baseline. The single-dose, open-label, single-arm, international trial observed adult males with severe or moderately severe hemophilia, as per FIX ≤2%.

Patients received routine FIX prophylaxis prior to the trial start, and entered a prospective lead-in period of ≥6 months during which bleeding and factor use were monitored. They were then treated with a single intravenous dose of etranacogene deaparvovec 2x1013 gc/kg.

Primary endpoint assessments include FIX activity at 26 and 52 weeks after dosing, and annualized bleeding rates at 52 weeks. Secondary endpoints include factor replacement use, adverse events, and reactive use of corticosteroids. Assessment is planned for 5 years. The newest data presented at ASH 2020 shows outcomes at the 26-week mark.

Investigators screened 75 patients, had 67 lead into the trial, then eventually dosed 54 patients who provided 26 weeks of follow-up data. Of the assessed patients, 44 had severe hemophilia B, while the other 10 had moderately severe disease. Mean patient age was 41.5 years old; bleeding was prevalent in 70.4% of patients during the lead-in despite prophylaxis, and 42.6% had AAV5 NAbs at baseline.

The Findings

After gene therapy treatment, FIX activity increased rapidly to a mean of 37.2% at week 26, representing a mean 36% change from baseline (±19.7; 95% CI, 0-96.1; P <.0001).

Investigators observed no correlation of pre-existing NAbs with FIX activity up to a titer of 678.2. One observed patient had a NAb titer of 3212.3 and did not respond.

Another patient received a partial gene therapy dose and remained on prophylaxis; all other patients (96.3%) successfully discontinued routine prophylaxis once administered etranacogene dezaparvovec.

Nearly three-fourths (72.2%) of patients reported 0 bleeds within 26 weeks. The remaining 15 patients reported a total of 21 bleeds.

Mean annualized FIX consumption dropped by 96% from lead-in to week 26, reported at just 12,622 at that time. Treatment-related adverse events were observed in 68.5% of patients, the majority (81.5%) being mild in severity. Investigators reported no patient deaths nor serious adverse events linked to etranacogene dezaparvovec.

As Piper and colleagues stressed, these findings are historical in the context of trial size and late-stage clinical value. What’s more, successes associated with the gene therapy include patients with varying rates of pre-existing AAV5 NAb titers.

“The safety profile was consistent with early phase AAV5 studies and together these data support a favorable safety and efficacy profile for etranacogene dezaparvovec,” they concluded.

The study, “First Data from the Phase 3 HOPE-B Gene Therapy Trial: Efficacy and Safety of Etranacogene Dezaparvovec (AAV5-Padua hFIX variant; AMT-061) in Adults with Severe or Moderate-Severe Hemophilia B Treated Irrespective of Pre-Existing Anti-Capsid Neutralizing,” was presented at ASH 2020.

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