New Study Shows Potential of Gene Therapy for Hemophilia B


FIX activity was similar in participants without and with pre-existing neutralizing antibodies.

Michael Recht, MD, PhD

Michael Recht, MD, PhD

In data presented at the American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting, a team, led by Michael Recht, MD, PhD, The Hemophilia Center at Oregon Health & Science University, tested a promising new gene therapy for patients with hemophilia B with pre-existing neutralizing antibodies (NAb).

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

While the majority of clinical trials for gene therapies exclude patients with pre-existing neutralizing antibodies to capsid serotype, early clinical trials, as well as non-human primate data suggests that generally prevalent titers of anti-AAV5 NAbs may not preclude successful transduction with etranacogene dezaparvovec.

The Study

The researchers established the phase 3 study, dubbed Health Outcomes with Padua gene; Evaluation in Hemophilia B, to assess the efficacy and safety of etranacogene dezaparvovec in adults with hemophilia B.

The open-label, single-dose, single-arm, multinational study included adult male patients with severe or moderate-severe HB (FIX≤2%) on prior routine FIX prophylaxis.

The research team assessed pre-existing Nabs to AAV5, but not exclusionary. Each patient entered at least a 6-month lead-in period, then received a single dose of etranacogene dezaparvovec (2x1013 gc/kg) without prophylactic immunosuppression.


The investigators sought co-primary endpoints of the change infix activity at 26 and 52 weeks and 52-week annualized bleeding rate when compared to the lead-in.

They analyzed the outcomes at 26 weeks in 54 participants with and without pre-existing NAbs to AAV5 using descriptive statistics and a correlation analysis.

Each patient was doses and completed the 26 weeks of follow-up, with 57.4% (n = 31) showing no AAV5 NAbs. Of this group, 42.6% (n = 23) with AAV5 at baseline, the median titer was 56.9 (1st-3rd quartile 23.3-282.5) with a distribution representative of the general population.


The max neutralizing antibody titer was 3212 and 1 individual with a NAb titer of 198 received a partial dose and was ultimately excluded from the final assessment of NAb’s impact on efficacy.

The remaining 52 participants discontinued prophylaxis and remained prophylaxis-free at 26 weeks.

There was no correlation between pre-existing NAbs with FIX activity observed up to a titer of 678 (n = 52; r = -0.28; 95% CI, -0.51 to 0.00; R2 = 0.078) and mean FIX activity at 26 weeks was 32.7 IU/dl (min <2; max 90.4; 1st-3rd quartile, 16.3-42.6; n = 22) in participants with NAbs compared to 41.3 IU/dl (min 8.4; max 97.1; 1st-3rd quartile 31.3-52.7, n = 31) in those without.

There were trends in adverse events in the safety profile of the treatment, with the most common treatment-related adverse events being transient transaminitis requiring corticosteroids (n = 2 with NAbs; n = 7 without), infusion-related reactions (n = 5 with NAbs; n = 2 without), headache (n = 2 with NAbs; n = 5 without), and influenza-like illness (n = 4 with NAbs; n = 3 without). There were no deaths or inhibitors to FIX reported in the study.

“FIX activity was similar in participants without and with pre-existing NAbs to AAV5 up to a titer of 678; there were insufficient data to assess a relationship with higher titer NAbs,” the authors wrote. “No relationship between AAV5 NAbs and safety was observed. This study demonstrates for the first-time successful treatment of patients with pre-existing NABs at generally prevalent levels with an AAV5 construct, supporting broad eligibility for AAV5-based therapies.”

The study, “Clinical Outcomes in Patients with and without Pre-Existing Neutralizing Antibodies to the Vector: 6 Month Data from the Phase 3 HOPE-B Gene Therapy Trial of Etranacogene Dezaparvovec,” was published online in Molecular Therapy.

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