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Evolution of AAV Vector Gene Therapy is Ongoing In Hemophilia. Will the Unique Features of BAY 2599023 Address the Outstanding Needs?

1University of Michigan, Ann Arbor, United States, 2Manchester University Dept. of Haematology, Manchester, United Kingdom, 3University of Wisconsin–Madison, Madison, United States, 4National Specialized Hospital for Active Treatment of Haematologic Diseases, Sofia, Bulgaria, 5Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands, 6Institute of Clinical Haemostaseology and Transfusion Medicine, Saarland University, Homburg, Germany, 7Bayer, Wuppertal, Germany, 8Bayer, Basel, Switzerland

Abstract Number: PB0652

Meeting: ISTH 2021 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia Gene Therapy

Background: Ongoing phase 3 gene therapy trials for hemophilia A show promise but unpredictable factor (F)VIII expression of uncertain durability. Gene therapy must evolve to meet patient expectations of a durable, efficacious and safe treatment. Thus, BAY 2599023 (AAVhu37.hFVIIIco) comprises an adeno-associated virus vector with capsid serotype hu37 (AAVhu37) and codon-optimized, B-domain-deleted human FVIII (hFVIIIco), with packaging and expression driven by a transthyretin promoter/enhancer combination.

Aims: Report safety and FVIII activity achieved to date in this first-in-human, dose‑finding study of BAY 2599023.

Methods: This phase 1/2, open-label study (NCT03588299) includes males aged ≥18 years with severe hemophilia A, >150 exposure days to FVIII products, no history of FVIII inhibitors, and no detectable pre-existing neutralizing antibodies to AAVhu37. Patients received a single intravenous infusion of BAY 2599023. Primary endpoints were adverse events (AEs), serious AEs (SAEs) and AEs/SAEs of special interest (S/AESIs). Secondary endpoint was FVIII activity over time. Informed patient consent and ethics committee approval were obtained. 

Results: Three cohorts of ≥2 patients each (N=8) were enrolled sequentially (Figure 1).

Figure 1. BAY 2599023 dose escalation

At data cutoff (January 2021), FVIII activity data were available for the first 6 patients (Figure 2). BAY 2599023 delivered sustained FVIII expression levels for up to 21 months, with evidence of bleed protection. Of these 6 patients, 3 (Cohorts 2 [n=1] and 3 [n=2]) developed AESIs: asymptomatic elevations in alanine aminotransferase, managed reactively with corticosteroids. No SAEs have been reported. Two additional patients recently enrolled in Cohort 3 are being treated prophylactically with corticosteroids. Data from all 8 patients, up to 27 months, will be presented.
Figure 2. FVIII levels (chromogenic* [BDD plasma]) by patient over time† in Cohorts 1, 2 and 3 (n=6‡) 

Conclusions: BAY 2599023 was designed to enhance efficacy and durability of FVIII expression with a favorable safety profile. All patients with evaluable data have shown effective, sustained FVIII levels, with no SAEs, making BAY 2599023 a key candidate in the evolution of gene therapy in hemophilia A.

To cite this abstract in AMA style:

Pipe SW, Hay C, Sheehan J, Lissitchkov T, Coppens M, Eichler H, Weigmann S, Ferrante F. Evolution of AAV Vector Gene Therapy is Ongoing In Hemophilia. Will the Unique Features of BAY 2599023 Address the Outstanding Needs? [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/evolution-of-aav-vector-gene-therapy-is-ongoing-in-hemophilia-will-the-unique-features-of-bay-2599023-address-the-outstanding-needs/. Accessed November 30, 2023.

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