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

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.

Pipe:Apcintex: Consultancy; CSL Behring: Consultancy; Sangamo Therapeutics: Consultancy; Freeline: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; BioMarin Pharmaceutical Inc.: Consultancy; HEMA Biologics: Consultancy; Spark Therapeutics: Consultancy; Regeneron/Intellia: Consultancy; UniQure: Consultancy; Bayer: Consultancy; ASC Therapeutics: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. 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; 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; Bayer, Biomarin, CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark Therapeutics, Takeda, uniQure: Research Funding; Catalyst Biosciences, CSL Behring, Genentech, Grifols, Hema Biologics, Novo Nordisk, Pfizer, Sanofi, Takeda, uniQure: Consultancy; Oregon Health & Science University: Ended employment in the past 24 months. 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.