First-in-human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A

Abstract

Background: Gene therapy for hemophilia A has the potential to reduce the treatment burden for care-providers and patients, by eliminating the need for regular factor VIII (FVIII) prophylaxis through the long-term expression of endogenous FVIII at levels sufficient to provide bleed protection. BAY 2599023 (AAVhu37FVIII) is a non-replicating adeno-associated virus (AAV) vector, based on the AAV serotype hu37, which contains a single-stranded DNA genome encoding a B-domain deleted FVIII, under the control of a liver-specific promotor/enhancer combination optimized for transgenic expression. The AAVhu37 capsid is a member of the hepatotropic Clade E family and has been selected based on nonclinical studies demonstrating efficient liver-directed FVIII gene transfer, favorable biodistribution as well as durable FVIII expression. BAY 2599023 is the first clinical-stage AAV gene therapy vector based on the AAVhu37 serotype. This analysis reports safety and FVIII activity following a single intravenous infusion of BAY 2599023 in the first-dose cohort of a phase I/II open-label, first time in human dose-finding study (NCT03588299) of previously treated, severe hemophilia A patients. Patients/Methods: Two participants were enrolled sequentially; each received a single infusion of AAVhu37 (0.5 x 1013 GC/kg). Patients were males ≥18 years with no history of FVIII inhibitor development, no detectable immunity to the AAVhu37 capsid, and >150 exposure days to FVIII products. Primary endpoints were adverse events (AEs), serious AEs and AEs/SAEs of special interest (S/AESI); the secondary endpoint was change in FVIII activity from baseline. Informed patient consent, and ethics committee approval at each local site, were obtained. Results: Following more than 15 weeks of safety observation, no SAEs, AEs related to study drug, nor S/AESI were reported. Liver enzymes (alanine aminotransferase and aspartate aminotransferase) remained <1.5 of baseline. Corticosteroids were not used in either patient. Clear evidence of FVIII expression was observed in both patients with stable values of ~5% and ~17% in the first and second patient, respectively. An early read-out also indicated hemostatic efficacy in both; the first patient had successfully halted prophylaxis for 6 weeks, while the second one, treated on-demand with 99 bleeds recorded in the 12 months prior to gene transfer, has been bleed free for over 5.5 months to date. Conclusions: BAY 2599023 was previously shown in non-clinical studies to have a good safety profile, with the potential to achieve endogenous expression of FVIII at therapeutic levels, over an extended period of time. In this first-in-human clinical study with BAY 2599023, two patients have been treated with BAY 2599023 at the starting dose of 0.5 x 1013 GC/kg and no safety concerns have been reported to date. Measurable expression of endogenous FVIII and an early read-out of hemostatic efficacy have been demonstrated in both patients. Overall, data generated from this first dose cohort demonstrate that successful translation from pre-clinical to clinical development and proof-of-mechanism for BAY 2599023 was achieved. Disclosures Pipe: HEMA Biologics: Consultancy; Shire: Consultancy; Roche/Genentech: Consultancy; Sanofi: Consultancy; Freeline: Consultancy; Apcintex: Consultancy; Novo Nordisk: Consultancy; Catalyst Bioscience: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; uniQure: Consultancy; BioMarin: Consultancy; Pfizer: Consultancy; Spark Therapeutics: Consultancy. Becka:Bayer: Employment. Detering:Bayer: Employment. Vanevski:Bayer: Employment. Lissitchkov:Octapharma: Equity Ownership, Research Funding; Bayer: Consultancy, Equity Ownership, Honoraria, Other: Principal investigator for clinical trials, Research Funding; Sobi: Consultancy, Equity Ownership, Honoraria; Sanofi: Equity Ownership, Research Funding; Roche: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Shire: Consultancy, Equity Ownership, Honoraria, Speakers Bureau. OffLabel Disclosure: Gene therapy for haemophilia treatment.

Current Clinical Applications of In Vivo Gene Therapy with AAVs

“…As outlined in Tables 2 and 3 , there are 20 clinical trials approaching, including a handful of pivotal trials and the first pending licensing application (Harrington et al., 2020, WFH Virtual Summit, conference). 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 The field has largely converged on the use of systemically administered AAV vectors for hepatocyte expression of coagulation factors VIII (FVIII) and IX (FIX). 144 Although AAV efforts predominate, lentiviral vectors for either systemic infusion 157 , 158 or ex vivo transduction of hematopoietic stem cells 159 , 160 , 161 or induced pluripotent stem cells 162 are being pursued preclinically or as a phase I clinical trial.…”

“… 144 , 145 , 149 , 152 Unlike FVIII-SQ, FIX-R338L differences are not gene-therapy specific, suggesting the assay discrepancies are related to FIX-R338L biochemistry. 192 , 201 , 211 , 212 The understanding of which assay best predicts in vivo hemostatic function of hepatocyte-derived FVIII/FIX-R338L is relevant to guide clinical management because sustained FVIII:C/FIX:C, depending on the assay used, crosses clinical thresholds of mild/moderate hemophilia, 152 , 155 normal FVIII:C/FIX:C (Harrington et al., 2020, WFH Virtual Summit, conference), 145 , 146 and supratherapeutic FVIII:C/FIX:C (Harrington et al., 2020, WFH Virtual Summit, conference). 145 Preliminary FVIII antigen data correlate with CSA-determined FVIII:C, 153 whereas preliminary phenotypic data supporting OSA-determined FVIII:C correlate with hepatocyte-derived FVIII in vivo function, 152 suggesting that hepatocyte-derived FVIII may be more easily converted from its procofactor to cofactor state.…”

Gene therapy in haemophilia: literature review and regional perspectives for Turkey

“…Preliminary report of the phase I/II open-label, first time in human dose-finding study (NCT03588299) showed that two patients had measurable expression of endogenous FVIII and an early read-out of haemostatic efficacy at the starting dose of 0.5 × 10 13 vg/kg. 53 …”

Haemophilia: factoring in new therapies

“…AAVhu37 (BAY 2599023, Bayer) is being studied in a Phase I study. Thus far, two patients with severe HA without inhibitors have been treated with a dose of 0.5E13 gc/kg with no AEs and have achieved FVIII levels of 5–15% (NCT0358829) 61 …”