Session: 801. Gene Therapies: Advances in Clinical Gene Therapy for Hematological Disorders
Hematology Disease Topics & Pathways:
Research, clinical trials, Bleeding and Clotting, bleeding disorders, Biological therapies, hemophilia, Clinical Research, Genetic Disorders, Diseases, Gene Therapy, Therapies
Methods: This Phase I/II trial (NCT03003533/NCT03432520) of SPK-8011 is an open-label, multicenter, non-randomized trial, the full methodology of which has been reported previously (George et al. N Engl J Med 2021). Eligible participants were males ≥18 years of age, with FVIII levels ≤2%, >150 exposure days to FVIII concentrates, and no FVIII inhibitors. All participants were negative for neutralizing antibodies to SPK200. Participants were enrolled into four dose cohorts receiving a single IV dose of either 5×1011, 1×1012, 2×1012, or 1.5×1012 vector genomes (vg) per kilogram of body weight, with a maximum dose based on a BMI of 30 kg/m2. Several immunomodulation (IM) approaches were evaluated. Trial objectives included evaluation of the safety and efficacy of SPK-8011 and the extent and durability of FVIII expression.
Results: At data cut-off (30 June 2022), 23 participants were included across dosing cohorts of 5×1011 vg/kg (n=2), 1×1012 vg/kg (n=3), 1.5×1012 vg/kg (n=9), or 2×1012 vg/kg (n=9). Median (range) observation time was 159.3 (6.9–259.9) weeks, based on both the primary study 8011-101 and the long-term follow-up study. A total of 49 treatment-related adverse events (AEs) were reported; 23 were considered vector-related, including one serious adverse event (Grade 2 alanine transaminase [ALT] elevation resulting in elective hospitalization for IV corticosteroid administration), and 26 were related to IM therapies. No FVIII inhibitors or thrombotic events were reported. Transient non-sustained asymptomatic ALT elevation occurred in 11 participants during the expected window of presumed capsid immune response and resolved with use of IM agents.
In 16 participants with ≥1 year follow-up, a one-stage FVIII assay showed no apparent decrease in FVIII activity over time, with a majority expressing in the mild HA range (Table). Sustained expression of FVIII was maintained in 21/23 participants with several methods of IM; two participants lost FVIII expression following a presumed capsid immune response (George et al. N Engl J Med 2021).
Across all 21 participants with sustained FVIII expression, a 91% (95% CI: 78–97%) reduction in annualized bleeding rate (ABR) for all bleeds was observed, with all-bleed ABR of 11.59 (7.39–18.17) before infusion vs. 0.99 (0.46–2.14) after infusion (Figure). The 16 participants on prophylactic treatment before gene therapy had an 82% (95% CI: 53–93%) reduction in ABR for all bleeds; 6.88 (4.16–11.36) before vs. 1.26 (0.57–2.77) after infusion. ABRs for spontaneous bleeds were 5.20 (2.99–9.04) and 0.52 (0.19–1.39) before and after infusion, respectively. The five participants using on-demand treatment before infusion had a 99% (95% CI: 98–100%) reduction in all-bleed ABR; 27.26 (18.80–39.53) vs. 0.20 (0.09–0.45) before and after infusion, respectively, and 20.98 (12.29–35.82) vs. 0.05 (0.01–0.29) for spontaneous bleeds. In total, 17/21 (81%) participants had an ABR of <1 for treated bleeds and 20/21 (95%) had an ABR of <1 for spontaneous treated bleeds following infusion of SPK-8011.
Median (IQR) annualized FVIII infusion rates (AIRs) of 0.2 (0.0–1.2) were reported across all participants 28 days post vector infusion vs. 82.0 (36.0–106.0) before vector administration.
Conclusions: With up to 5 years of follow-up, a single infusion of SPK-8011 resulted in durable year-to-year FVIII expression and clinically meaningful reductions in ABR and AIR. No major safety signals were reported, indicating SPK-8011 was well tolerated in this population of people with HA.
Disclosures: Croteau: Bayer, Pfizer: Honoraria; Spark Therapeutics, Genentech, Sanofi: Research Funding; Bayer, Pfizer, Sanofi, BioMarin, HemaBiologics: Consultancy; ATHN, Hemophilia Alliance, THSNA: Membership on an entity's Board of Directors or advisory committees. Eyster: SPARK/Roche, Novo Nordisk and Baxalta: Research Funding; PennState Hershey Medical Center: Current Employment. Tran: Sanofi: Research Funding; AstraZeneca, CSL Behrig: Honoraria; Pfizer, Takeda: Speakers Bureau. Ragni: Takeda: Honoraria, Other: Provided study (rVWF) drug for trial; BioMarin: Honoraria. Samelson‑Jones: Spark Therapeutics, Pfizer, Accugen, Cabaletta, Uniqure, Frontera: Research Funding. George: Avrobio: Other: Data safety monitoring committee; Intellia: Consultancy; STRM.Bio: Other: Scientific advisory board; Pfizer: Consultancy; AskBio Therapeutics: Other: Receives licensing fees ; Bayer: Consultancy; Spark: Consultancy; Biomarin: Consultancy. Sullivan: Bayer: Consultancy; Genentech: Consultancy; Pfizer: Consultancy; Biomarin: Consultancy, Speakers Bureau; Octapharma: Consultancy; Mississippi Center for Advanced Medicine: Current Employment; Make-A-Wish Mississippi: Membership on an entity's Board of Directors or advisory committees. Rasko: Gilead, Roche, Novartis, Bluebird Bio, SPARK therapeutics, Cynata, Pfizer Inc: Consultancy; Rarecyte: Current equity holder in private company; Genea: Current equity holder in publicly-traded company. Moormeier: University Health Physicians, University of Missouri-Kansas City: Current Employment. Angchaisuksiri: Ramathibodi Hospital: Current Employment. Teitel: Regeneron, Bayer, Takeda, Novo Nordisk, Pfizer, Roche, Sanofi, BioMarin: Consultancy; Pfizer, Spark, Bayer: Research Funding; Regeneron, Bayer, Takeda, Novo Nordisk, Pfizer, Roche, Sanofi: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Kenet: Novo Nordisk: Consultancy, Honoraria; BioMarin Pharmaceutical Inc.: Consultancy, Honoraria; UniQure, SPark, Sobi, CSL: Honoraria; Roche: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Opko Biologics: Consultancy, Research Funding; Shire: Research Funding; Alnylam: Research Funding; BPL: Consultancy, Research Funding; ASC Therapeutics: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi-Genzyme: Consultancy, Honoraria. Wynn: Novartis Pharmaceuticals: Current Employment; Takeda: Research Funding; Sanofi: Research Funding; AMAG: Research Funding; Dova: Research Funding; Spark: Research Funding. Jaworski: Spark Therapeutics: Current Employment. Macdougall: Spark Therapeutics: Current Employment; Roche: Current equity holder in publicly-traded company. Jaeger: Spark Therapeutics: Current Employment; BioNTech: Ended employment in the past 24 months. Trivedi: Spark Therapeutics: Current Employment; Roche: Current equity holder in publicly-traded company. Mingozzi: Roche pharma: Current equity holder in publicly-traded company; American Society of Gene and Cell Therapy: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Current Employment. Chang: F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Spark Therapeutics: Current Employment. Levy: Spark Therapeutics, Inc Board of Directors (Non-voting): Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Current equity holder in publicly-traded company; Genentech, Inc: Ended employment in the past 24 months; Spark Therapeutics Inc: Current Employment.
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