Summary Information For: AAVhu37, FVIII-BDD, DTX201, NCT03588299 *ˑ ²⁴ˑ ²⁵ˑ ⁵⁷
AAVhu37, FVIII-BDD, DTX201, NCT03588299 *ˑ ²⁴ˑ ²⁵ˑ ⁵⁷
Haemophilia A
Bayer/Ultragenyx
General Study Information
  • 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

 

Reference 

reported follow-up times by different publications

      25

52 weeks for Co. 1, 28 weeks for Co. 2 and 10 weeks for Co. 3

      57

up to 21 months for all dose cohorts

 

CH reported for all dose cohorts here 57

Efficacy details

 

FVIII activity for both first dose cohorts was reported by two different publications 24-25

 

steady-state FVIII activity


Reference

period of observation  

Co. 1
(0.5e13 gc/kg)

Co. 2
(1e13 gc/kg)

Co. 3
(2e13gc/kg)

      24

15 weeks

~ 5% - 17%

not reported

not reported

      25

Co. 1: 52 weeks /
Co. 2: 28 weeks

~ 5% - 20%

~8- 40%

not reported

     
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
Safety Details

Not reported

 

Reference

AEs were reported by different publications as follows

     24 -25

no SAEs, study-drug-related AEs or S/AE of special interest were reported 

        57

3/6 pts. in Co. 2 (1/2) and Co. 3 (2/2) developed AEs of special interest: asymptomatic elevations in ALT. No SAEs have been 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

References:

  *     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

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