Abstract Number: OC 09.4
Meeting: ISTH 2020 Congress
Background: BAY 2599023 (AAVhu37.hFVIIIco) comprises an adeno-associated virus vector with capsid serotype hu37 (AAVhu37), and a genome that directs expression of a codon-optimized B-domain-deleted human factor VIII (hFVIIIco) under the control of a liver-specific promoter/enhancer combination.
Aims: We report safety and FVIII activity in this first-in-human study.
Methods: This phase 1/2, open-label, dose‑finding study (NCT03588299) included male patients aged ≥18 with severe hemophilia A, receiving a single intravenous infusion of BAY 2599023. Patients had no history of FVIII inhibitors, no detectable immunity to the AAVhu37 capsid and >150 exposure days to FVIII products. Primary endpoints were adverse events (AEs), serious AEs (SAEs) and AEs/SAEs of special interest (S/AESIs). Secondary endpoint was change in FVIII activity from baseline. Informed patient consent and ethics committee approval were obtained.
Results: Three cohorts of two patients were enrolled sequentially. Following 52 weeks of safety observation of the first cohort (0.5 × 1013 GC/kg), no SAEs, study-drug-related AEs or S/AESIs were reported. Despite the low dose, clear evidence of FVIII coagulant activity was observed (~5- 20%). One patient was off prophylaxis for ~7 months. After ~28 weeks of follow-up of the second cohort (1.0 × 1013 GC/kg), both patients have FVIII activity (~8- 40%) and are off prophylaxis. One AESI, mild elevation in alanine aminotransferase/aspartate aminotransferase, was recorded (responded to short corticosteroid treatment without loss of FVIII activity). Following safety review, escalation to 2.0 × 1013 GC/kg was recommended. Currently, two patients have been treated for ~10 weeks and off prophylaxis for ~4 weeks. AESIs of mild-to-moderate elevation in alanine aminotransferase/aspartate aminotransferase were recorded for both patients (responded to corticosteroid treatment).
Conclusions: Six patients were treated with BAY 2599023 at doses of 0.5, 1.0 and 2.0 × 1013 GC/kg. Successful proof-of-concept has been achieved with measurable, stable expression of endogenous FVIII and indications of hemostatic efficacy in all treated patients.
To cite this abstract in AMA style:Pipe SW, Hay CRM, Sheehan J, Lissitchkov T, Leebeek FWG, Coppens M, Detering E, Ribeiro S, Vanevski KM. First-in-Human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A: Safety and FVIII Activity Results [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/first-in-human-gene-therapy-study-of-aavhu37-capsid-vector-technology-in-severe-hemophilia-a-safety-and-fviii-activity-results/. Accessed December 2, 2022.
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