• ClinicalTrials.gov Identifier: NCT03588299¹
• Phase I/II, open-label, dose finding study

• Ongoing development, Recruiting¹
• Last Update Posted: 2023-12-13¹
• 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 line²

Codon-optimized B-domain-deleted human factor VIII (hFVIIIco)³

• Liver-specific promotor/enhancer combination^3-4
• Transthyretin promoter/enhancer combination ⁵

Systemic⁴

• Co. 1: 0.5e13 (2)^3-4
• Co. 2: 1e13 (2)³
• Co. 3: 2e13 (2)³
• Subsequently, 2 additional pts. were enrolled in Co. 3, that are being treated prophylactically with corticosteroids⁵

CH reported for all dose cohorts here⁵

     
According to Fig. 2⁵ 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. 2⁵ , 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 reference⁵ 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 ³ 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 baseline⁴
• Co. 2: one mild elevation in ALT levels was recorded^{3, 5}
• Co. 3: mild-to-moderate elevation in ALT levels was recorded in 2/2 pts.^{3, 5}

• Co. 1: AST levels remained <1.5 times of baseline⁴
• Co. 2: one mild elevation in ALT levels was recorded^{3, 5}
• Co. 3: mild-to-moderate elevation in AST levels were recorded in 2/2 pts.^{3, 5}

Not reported

Co. 2 - Co. 3: all (3/3) ALT/AST elevations responded to short corticosteroid treatment^{3, 5}

• Co. 2: 1/2 pts. with mild elevation in ALT levels responded to short corticosteroid treatment without loss of FVIII activity³
• Co. 3: Not applicable, due to missing timings of the ALT elevations⁵

Not reported

1. Study to Test the Safety and How Well Patients With Severe Hemophilia A Respond to Treatment With BAY 2599023 (DTX 201), a Drug Therapy That Delivers a Healthy Version of the Defective Factor VIII Gene Into the Nucleus of Liver Cells Using an Altered, Non-infectious Virus (AAV) as a "Shuttle". Available at: Study Details | Study to Test the Safety and How Well Patients With Severe Hemophilia A Respond to Treatment With BAY 2599023 (DTX 201), a Drug Therapy That Delivers a Healthy Version of the Defective Factor VIII Gene Into the Nucleus of Liver Cells Using an Altered, Non-infectious Virus (AAV) as a "Shuttle". | ClinicalTrials.gov
2. 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)
3. 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
4. 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)
5. 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; 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