• 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
• 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 combination⁵

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

Follow-up time points were reported as summarized below:

CH, as reported for all dose cohorts in reference #5

Steady-state FVIII activity levels were reported for both initial dose cohorts in References #3 and #4, and are summarized below:

According to Figure 2 in reference #5, the first two patients in Co. 3 (2e13 vg/kg) had FVIII activity levels of approximately 20% and 50%
at 11- and 12-months post–gene transfer, respectively

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 publication (Reference #5) stated that BAY 2599023 delivered sustained FVIII expression levels for up to 21 months, with evidence of bleed protection for the first treated 6 participants

Data regarding FVIII infusion prophylaxis were taken from reference #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

Adverse events reported across different publications are summarized in the table below:

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 participants^{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 participants ^{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 participants 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”. ClinicalTrials.gov identifier: NCT03588299. Link
2. Peyvandi F, Garagiola I. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia. 2019 Sep;25(5):738-746. doi: 10.1111/hae.13816. Epub 2019 Jul 8. PMID: 31282050. Link
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. Link
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. Link
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]. ISTH 2021 Congress, 2021. Link

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