New Study Shows Potential of Gene Therapy for Hemophilia B

May 14, 2021
Kenny Walter

Kenny Walter is an editor with HCPLive. Prior to joining MJH Life Sciences in 2019, he worked as a digital reporter covering nanotechnology, life sciences, material science and more with R&D Magazine. He graduated with a degree in journalism from Temple University in 2008 and began his career as a local reporter for a chain of weekly newspapers based on the Jersey shore. When not working, he enjoys going to the beach and enjoying the shore in the summer and watching North Carolina Tar Heel basketball in the winter.

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

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.

Endpoints

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.

Results

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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