-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2141 Adults with Severe or Moderately Severe Hemophilia B Receiving Etranacogene Dezaparvovec in the HOPE-B Phase 3 Clinical Trial Continue to Experience a Stable Increase in Mean Factor IX Activity Levels and Durable Hemostatic Protection after 24 Months’ Follow-up

Program: Oral and Poster Abstracts
Session: 801. Gene Therapies: Poster I
Hematology Disease Topics & Pathways:
Bleeding and Clotting, Research, clinical trials, Biological therapies, adult, hemophilia, Clinical Research, Diseases, Gene Therapy, Therapies, Study Population, Human
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Steven W. Pipe, MD1, Frank W.G. Leebeek2, Michael Recht, MD, PhD, MBA3, Nigel S. Key4, Susan Lattimore3*, Giancarlo Castaman5*, Michiel Coppens6,7*, David Cooper8,9*, Robert Gut8,9*, Sergio Slawka8,9*, Stephanie Verweij8,9*, Ricardo Dolmetsch8,9*, Yanyan Li10*, Paul E. Monahan10* and Wolfgang A. Miesbach11*

1University of Michigan, Ann Arbor, MI
2Erasmus Medical Center, University Medical Center, Rotterdam, Netherlands
3Oregon Health & Science University, Portland, OR
4University of North Carolina, Chapel Hill, NC
5Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Florence, Italy
6Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, Netherlands
7Amsterdam UMC location, University of Amsterdam, Vascular Medicine, Amsterdam, Netherlands
8uniQure BV, Amsterdam, Netherlands
9uniQure Inc., Lexington, MA
10CSL Behring, King of Prussia, PA
11University Hospital Frankfurt, Frankfurt, Germany

Introduction: Etranacogene dezaparvovec (formerly AMT-061), an investigational gene therapy for hemophilia B, is an adeno-associated virus serotype 5 (AAV5) vector, containing a codon-optimized, highly active factor IX (FIX) Padua R338L transgene under the control of a liver-specific promoter. The Phase 3 HOPE-B clinical trial (NCT03569891) of etranacogene dezaparvovec met its primary efficacy endpoint, providing hemostatic protection superior to standard of care FIX prophylaxis over 52 weeks of follow-up after stable FIX Padua expression (defined as Months 7–18). However, the potential for liver-directed AAV to sustain long-term clotting factor expression remains unknown, with most human experience derived from early phase clinical trials.

Aim: Efficacy and safety data is provided from the pivotal Phase 3 HOPE-B clinical trial over a period of 24 months of gene expression.

Methods: In this open-label, single-arm study, adult male participants with severe or moderately severe hemophilia B (FIX≤2%), with or without pre-existing AAV5 neutralizing antibodies (NAbs), were infused with a single dose of etranacogene dezaparvovec (2x1013 gc/kg), following a ≥6-month lead-in period receiving FIX prophylaxis. FIX activity, annualized bleed rate (ABR), and FIX infusions were assessed frequently during the lead-in and first 12 months after receiving etranacogene dezaparvovec, then every 6 months during the long-term follow-up (Years 2–5). Adverse events (AEs) were recorded continuously.

Results: Of the 54 participants who received etranacogene dezaparvovec, 53 participants received the full dose and 52 completed 24 months of follow-up. At 464 days (~15 months) following infusion, one 75-year-old participant died from cardiogenic shock, preceded by a urinary tract infection, which was considered unrelated to treatment.

Of the 54 participants, 52 (96.3%) discontinued and remained free of continuous FIX prophylaxis from Day 21 to Month 24, including 20 participants with baseline AAV5 NAb titers up to 1:700. One participant with a markedly higher AAV5 NAbs titer (1:3212) and one participant who received only a partial vector dose (due to an infusion-related reaction) did not express FIX Padua or discontinue FIX prophylaxis.

Compared with the ≥6-month lead-in period (mean ABR 4.18), mean ABR for all bleeds during Months 7–24 post-treatment was significantly reduced by 64% (mean ABR 1.51; p=0.0002), sustaining the same bleed reduction that satisfied the primary endpoint of the trial during Months 7–18. The mean ABR for all other bleed types was also substantially reduced (Figure 1). The mean FIX activity level of participants was 39.0 IU/dL (standard deviation [SD]: ±18.7; min–max: 8.2–97.1) at Month 6 (n=51) and sustained at 36.7 IU/dL (±19.0; 4.7–99.2) at Month 24 post-treatment (n=50; Figure 2).

There was an overall 96% reduction in mean unadjusted annualized FIX consumption from the lead-in period (257,339 IU/year/participant) to Months 19–24 (9751 IU/year/participant; p<0.0001).

During the 24 months post-dose, all participants experienced at least one treatment-emergent AE (TEAE); of the 557 events, 424 (76%) were mild, 115 (21%) were moderate, and 18 (3%) were severe. A total of 38 participants (70.4%) experienced 93 treatment-related TEAEs, with only one occurring during Months 18–24. There was an increase in alanine transaminase (with or without increased aspartate transaminase) in eleven participants (20.4%). Nine participants (16.7%) received supportive care with reactive corticosteroids for a mean duration of 79.8 days (SD: 26.6; range: 51–130 days). There were no serious AEs related to treatment; a serious AE of hepatocellular carcinoma was determined by independent molecular genomic and integration analysis to be unrelated to treatment.

Conclusions: Demonstrating durability of disease correction with acceptable safety is the next major hurdle for gene therapy in people with hemophilia B. After 24 months’ follow-up, single-dose etranacogene dezaparvovec resulted in stable FIX Padua expression in participants with AAV NAb undetected or <1:700 titer; reduction in ABR remained durable and superior to FIX prophylaxis. This outcome was achieved with limited early reactive corticosteroid exposure in a minority of participants, allowing all participants who discontinued prophylaxis to remain off prophylaxis at Month 24.

Disclosures: Pipe: Siemens: Research Funding; Freeline: Consultancy; Takeda: Consultancy; Spark Therapeutics: Consultancy; Sangamo Therapeutics: Consultancy; Sanofi: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; BioMarin Pharmaceutical Inc.: Consultancy; Apcintex: Consultancy; ASC Therapeutics: Consultancy; Bayer: Consultancy; UniQure: Consultancy; Regeneron/Intellia: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy; Yewsavin: Research Funding. Leebeek: Biomarin: Consultancy; uniQure: Consultancy, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; CSL Behring: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. Recht: American Thrombosis and Hemostasis Network; Yale University School of Medicine: Current Employment; Oregon Health & Science University: Ended employment in the past 24 months; Catalyst Biosciences, Biomarin, CSL Behring, Genentech, Hema Biologics, Kedrion, Novo Nordisk, Pfizer, Sanofi, Takeda, uniQure: Consultancy; Bayer, Biomarin, CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark Therapeutics, Takeda, uniQure: Research Funding; Foundation for Women and Girls with Blood Disorders; Partners in Bleeding Disorders: Thrombosis and Hemostasis Societies of North America: Membership on an entity's Board of Directors or advisory committees. Key: uniQure / CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Lattimore: uniQure: Honoraria, Membership on an entity's Board of Directors or advisory committees. Castaman: CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ablynx: Membership on an entity's Board of Directors or advisory committees; Kedrion: Consultancy, Honoraria, Speakers Bureau; Werfen: Consultancy, Honoraria, Speakers Bureau; Grifols: Consultancy, Honoraria, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; uniQure: Membership on an entity's Board of Directors or advisory committees. Coppens: Bayer: Other: Consulting fee, Research Funding; Alexion: Other: Consulting fee; CSL Behring: Other: Consulting fee, Research Funding; Daiichi Sankyo: Other: Consulting fee, Research Funding; Novo Nordisk: Other: Consulting fee, Research Funding; Roche: Research Funding; UniQure: Research Funding; Sobi: Other: Consulting fee; Viatris: Other: Consulting fee. Cooper: uniQure: Current Employment. Gut: uniQure: Current Employment. Slawka: uniQure: Current Employment. Verweij: uniQure: Current Employment. Dolmetsch: uniQure: Current Employment. Li: CSL Behring: Current Employment. Monahan: CSL Behring: Current Employment. Miesbach: Takeda: Consultancy; Chugai: Consultancy; Alnylam: Consultancy; Bayer: Consultancy; Freeline: Consultancy; Sobi: Consultancy; Biomarin: Consultancy; Biogen: Consultancy; CSL Behring: Consultancy; Novo Nordisk: Consultancy; Octapharma: Consultancy; Roche: Consultancy; Pfizer: Consultancy; LFB: Consultancy; uniQure: Consultancy.

*signifies non-member of ASH