Background: Previously, we reported data from a first-in-human, dose-escalation, Phase 1 gene therapy trial demonstrating a dose-dependent increase in transgenic factor IX (FIX) expression in 10 adults with severe hemophilia B (FIX activity ≤1%). This was achieved following a single intravenous infusion of a self-complementary adeno-associated virus (scAAV) vector containing the wild-type FIX gene (codon-optimized), under the control of a synthetic liver-specific promoter and pseudotyped AAV8 capsid (scAAV2/8-LP1-hFIXco; ClinicalTrials.gov:NCT00979238). We now report durable efficacy and long-term safety over at least 10 years of follow-up in these participants.

Methods: FIX activity, annualized bleeding rate (ABR), use of FIX concentrates, safety (specifically transaminitis and oncogenesis), and FIX expression kinetics were evaluated in the 10 participants following a bolus infusion of scAAV2/8-LP1-hFIXco at a dose of 2x10 11vg/kg (N=2), 6x10 11vg/kg (N=2), or 2x10 12vg/kg (N=6), between 2010 and 2012.

Results: As of December 31, 2022, the median follow-up was 10.7 years (range 4-12 years). A total of 11 treatment-related adverse events occurred in 10 participants, including transient elevation of liver transaminases within 3 months of vector infusion in 4 of 6 patients treated with the high vector dose, without any recurrence. Two new serious adverse events were reported: (1) non-mucinous lung adenocarcinoma in situ, identified incidentally following a bullectomy for spontaneous pneumothorax 5 years after gene therapy in a 48-year-old participant considered not related to gene therapy following molecular studies, and (2) adenocarcinoma of the prostate in a 72-year-old participant 12 years after gene therapy. Tissue evaluation of the latter case is ongoing. No FIX inhibitors, thrombosis, persistent transaminitis or deaths were observed. Transgenic FIX expression has remained stable, with mean (±SD) FIX activity (one-stage) for the three dose cohorts of 1.7±0.9, 2.3±0.9 and 4.9±2.2 IU/dL, respectively (Figure 1). The mean and median ABR over the 10-year period following gene therapy of all 10 participants were 1.95 and 1.6 compared to 16.5 and 14, respectively, before gene therapy. This represents an 8.5-fold reduction in bleeding events (Wilcoxon signed rank test p=0.002). In the 6 high-dose participants, the ABR was 21-fold lower (mean=1.16, median 1, paired t-test, p<0.008). Mean and median FIX concentrate usage before gene therapy in the 10 participants were 2869 and 2526 IU/kg dropping to 945 and 274 IU/kg, respectively, over a 10-year period after gene therapy (p=0.0003). All participants developed a persistent, high-titer polyclonal anti-AAV8 capsid-specific antibody response after administration of scAAV2/8-LP1-hFIXco.

Conclusion: Expression of transgenic FIX has remained stable over a period of 10 years following systemic administration of scAAV2/8-LP1-hFIXco resulting in sustained clinical benefit, with substantial reduction in ABR and FIX concentrate use.

Davidoff:Uniqure: Patents & Royalties; BioMarin: Patents & Royalties. Chowdary:Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Apcintex: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees; Freeline: Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: 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; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Spark: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. McIntosh:BioMarin: Patents & Royalties; Freeline: Current equity holder in publicly-traded company. Batty:BioMarin Pharmaceutical: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Pfizer: Honoraria; Institute for Nursing and Medication Education (IMNE): Honoraria. Mahlangu:Novo Nordisk: Research Funding; Pfizer: Research Funding; Sandoz: Research Funding; Spark Therapeutics: Research Funding; Roche: Research Funding; Sanofi: Research Funding; BioMarin Pharmaceutical Inc.: Research Funding; Catalyst: Research Funding. Recht:Partners in Bleeding Disorders: 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, Takeda, uniQure: Research Funding; CSL Behring, Genentech, Hema Biologics, Pfizer, Sanofi, Takeda, uniQure: Consultancy. Shen:Apellis: Honoraria; Sanofi: Honoraria; Alexion: Speakers Bureau. Nathwani:MRC: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BioMarin: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; NovalGen Ltd: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Freeline: Consultancy, Current equity holder in private company, Patents & Royalties; LifeArc: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Genethon: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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2023
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