• ClinicalTrials.gov Identifier: NCT03588299
• Phase I/II, open-label, dose finding study

• Ongoing development, Recruiting ^*
• Last Update Posted: 2023-08-14 ^*
• ENROLLMENT (ACTUAL): 11

• Male ≥18 years of age with plasma FVIII activity levels < 1% of normal     or at screening
• Have >150 EDs to FVIII concentrates (recombinant or plasma-derived)
• Have >150 exposure days (EDs) to FVIII concentrates (recombinant or plasma-derived)

• Detectable antibodies reactive with AAVhu37capsid
• Participated in a gene transfer trial within the last 52 weeks or in a clinical trial with an investigational product within  the last 12 weeks

AAVhu37, Plamid/DNA, HeLa cell line ⁴³

Codon-optimized B-domain-deleted human factor VIII (hFVIIIco) ²⁵

• Liver-specific promotor/enhancer combination ^24-25
• Transthyretin promoter/enhancer combination ⁵⁷

Systemic ²⁴

• Co. 1: 0.5e13 (2) ^24-25
• Co. 2: 1e13 (2) ²⁵
• Co. 3: 2e13 (2) ²⁵
• Subsequently, 2 additional pts. were enrolled in Co. 3, that are being treated prophylactically with corticosteroids ⁵⁷

CH reported for all dose cohorts here ⁵⁷

     
According to Fig. 2 ⁵⁷ the first two pts. in Co. 3 had an FVIII activity at 11 and 12 months post gene transfer of around 20% and 50%. 

Based on the individual FVIII levels over time shown in Fig. 2 ⁵⁷ , the first two pts.included in Co. 3 achhieved the peak of FVIII response at 7 and 8 months post gene transfer
 - These observations were not mentioned in the publication referred to above -

ABR was not explicitly reported. However, the authors in this reference ⁵⁷ stated that BAY 2599023 delivered sustained FVIII expression levels for up to 21 months, with evidence of bleed protection for the first treated 6 pts.

Data regarding FVIII infusion prophylaxis were taken from here ²⁵ and summarized as follows^:

• Co. 1 (0.5e13 GC/kg): 1/2 pts. was off prophylaxis for approx. 7 months
• Co. 2 (1.0e13 GC/kg): after W28 of follow-up 2/2 pts. were off prophylaxis

Not reported

Not reported

• Co. 1: ALT levels remained <1.5 times of baseline ²⁴
• Co. 2: one mild elevation in ALT levels was recorded ^{25, 57}
• Co. 3: mild-to-moderate elevation in ALT levels was recorded in 2/2 pts. ^{25, 57}

• Co. 1: AST levels remained <1.5 times of baseline ²⁴
• Co. 2: one mild elevation in ALT levels was recorded ^{25, 57}
• Co. 3: mild-to-moderate elevation in AST levels were recorded in 2/2 pts. ^{25, 57}

Not reported

Co. 2 - Co. 3: all (3/3) ALT/AST elevations responded to short corticosteroid treatment ^{25, 57}

• Co. 2: 1/2 pts. with mild elevation in ALT levels responded to short corticosteroid treatment without loss of FVIII activity ²⁵
• Co. 3: Not applicable, due to missing timings of the ALT elevations ⁵⁷

Not reported

  *     ClinicalTrials.gov
24. Pipe, S., et al., First-in-human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A. Blood, 2019. 134(Suppl. 1): p. 4630.
       First-in-human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A | Blood | American Society of Hematology (ashpublications.org)
25. Pipe, S., et al., First-in-human gene therapy study of AAVHU37 capsid vector technology in severe haemophilia A: safety and FVIII activity results. Haemophilia, 2020. 26(S2): p. 124.
       First-in-Human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A: Safety and FVIII Activity Results - ISTH Congress Abstracts
43. Peyvandi, F. and I. Garagiola, Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia, 2019. 25(5): p. 738-746.
       Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia - PubMed (nih.gov)
57. Pipe, S., et al. Evolution of AAV Vector Gene Therapy is Ongoing In Hemophilia. Will the Unique Features of BAY 2599023 Address the Outstanding Needs? [abstract]. in ISTH 2021 Congress. 2021.
       Evolution of AAV Vector Gene Therapy is Ongoing In Hemophilia. Will the Unique Features of BAY 2599023 Address the Outstanding Needs? - ISTH Congress Abstracts

AAV, Adeno-associated virus; AEs, Adverse events; ABR, Annualized bleeding rate; AEs: adverse events; AIR, Annualized FVIII/FIX infusion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CH, Chromogenic Assay; Co., cohort; DOACs, Direct oral anticoagulants; D, days; EDs, exposure days; FIX, factor IX; FIX-Padua, gain of function FIX variant; FVIII, factor VIII; gc, genome copies; HEK cells, human embryonic kidney cells; IQR, interquartile range; IRR, Infusion-related reaction; NAbs, neutralizing antibodies; OS, One-stage clotting assay; Pop., population; pt., patient/participant; pts., patients/participants; P1, Participant 1; PI, phase I; PBGD, porphobilinogen deaminase; PBMC, peripheral blood mononuclear cells; SAEs, serious adverse events; SFU, spot-forming units; TAC, tacrolimus; ULN, upper limit of normal; VCN, vector copy number; vg, vector genomes; W, weeks; WT, wild type; Y, year