First-in-Human Dose-Finding Study of AAVhu37 Vector-Based Gene Therapy: BAY 2599023 Has Stable and Sustained Expression of FVIII over 2 Years

Abstract

▪BackgroundGene therapy for hemophilia A has the potential to reduce the treatment burden for patients and their care providers by eliminating the need for regular factor VIII (FVIII) prophylaxis through long-term expression of endogenous FVIII at levels sufficient to provide bleed protection. Ongoing phase 3 gene therapy trials for hemophilia A show promise but can result in unpredictable FVIII expression of uncertain durability. Gene therapy must evolve to meet patient expectations of a durable, efficacious and safe treatment.BAY 2599023 (AAVhu37.hFVIIIco) is the first, clinical stage adeno-associated virus (AAV) gene therapy vector, based on the AAVhu37 serotype. BAY 2599023 is a non-replicating AAV vector and contains a single-stranded DNA genome encoding a B-domain-deleted FVIII, under the control of a liver-specific promoter/enhancer combination, optimized for transgenic expression. The AAVhu37 capsid is a member of the hepatotropic clade E family and was selected based on preclinical studies demonstrating efficient, liver-directed FVIII gene transfer, favorable biodistribution and durable FVIII expression. Here, we report safety and FVIII activity levels achieved to date in this first-in-human, dose-finding study of BAY 2599023.MethodsThe ongoing BAY 2599023 phase 1/2, open-label, dose-finding study (NCT03588299) included male patients aged ≥18 years with severe hemophilia A, no history of FVIII inhibitors, no detectable neutralizing immunity against AAVhu37 (neutralizing antibody titer ≤5), and ≥150 exposure days to FVIII products. Patients received a single intravenous infusion of BAY 2599023 and were enrolled sequentially into three dose cohorts (0.5 × 10 13 GC/kg, 1.0 × 10 13 GC/kg and 2.0 × 10 13 GC/kg), each comprising at least two patients. Patients to be enrolled in a fourth cohort will receive a single infusion of 4 × 10 13 GC/kg (Figure 1). Primary endpoints were adverse events (AEs), serious AEs (SAEs) and AEs/SAEs of special interest (S/AESIs). The secondary endpoint was FVIII activity over time. Informed patient consent and ethics committee approval were obtained.ResultsThree cohorts of ≥2 patients each (N = 9) were enrolled sequentially (Figure 1). At the data cutoff (May 2021), FVIII activity data were available for the first eight patients.BAY 2599023 delivered sustained FVIII expression levels for up to >23 months, with evidence of bleed protection. Patients in Cohorts 2 and 3 have all been off prophylaxis with FVIII products since approximately 6-12 weeks after gene transfer. To date, it has been observed that no spontaneous bleeds requiring treatment have been reported once FVIII levels >11 IU/dL were achieved. Of the 9 patients treated, 5 patients developed an AESI: mild/moderate alanine aminotransferase (ALT) elevations observed in Cohort 2 (n =1) and Cohort 3 (n = 3) were managed with corticosteroid treatment; another ALT elevation was reported as study-drug-related SAE in Cohort 3 (n = 1) but returned to normal a few weeks after interruption of the H2 blocker famotidine. The latest follow-up data for up to 28 months will be presented.ConclusionsBAY 2599023 was designed to enhance efficacy and durability of FVIII expression with a favorable safety profile. Sustained FVIII levels allowed suspension of FVIII prophylaxis in the majority of patients, with asymptomatic ALT elevations that respondedto corticosteroids, making BAY 2599023 a key candidate in the evolution of gene therapy in hemophilia A. [Display omitted] DisclosuresPipe: Genventiv: Consultancy; Regeneron/ Intellia: Consultancy; uniQure: Consultancy, Other; Spark Therapeutics: Consultancy; Takeda: Consultancy; Sanofi: Consultancy, Other; Sangamo Therapeutics: Consultancy; Roche/Genentech: Consultancy, Other; Pfizer: Consultancy; Novo Nordisk: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; HEMA Biologics: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy. Sheehan: BioMarin: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Coppens: Portola/Alexion: Research Funding; CSL Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Roche: Research Funding; Daiichi Sankyo: Research Funding; Sanquin Blood Supply: Research Funding; uniQure: Research Funding; Medcon International: Consultancy; MEDtalks: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Sobi: Consultancy. Eichler: Takeda: Consultancy, Honoraria; BioMarin: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Pfizer: Research Funding; Novo Nordisk: Consultancy, Research Funding; Biotest: Consultancy, Honoraria; Bayer: Consultancy, Research Funding. Linardi: Bayer: Current Employment. Wiegmann: Bayer: Current Employment. Hay: Pfizer: Consultancy, Research Funding; Inspiration: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Spark Therapeutics: Consultancy, Research Funding. Lissitchkov: Bayer: Other: Principal Investigator of Clinical Trials; Catalist: Other: Principal Investigator of Clinical Trials; Grifols: Other: Principal Investigator of Clinical Trials.