• ClinicalTrials.gov Identifier: NCT03370172¹
• Phase I/II, dose escalation, dose expansion
• Non-randomized, open label trial¹

• Completed
• Last Update Posted: 2025-09-11¹

• Male, aged 18 to 75 years at the time of screening
• Confirmed diagnosis of hemophilia A (FVIII:C <1%, measured following >=5 days without FVIII treatment) 
• And/or documented intron 1 inversion or intron 22 inversion mutation in the F8 gene, consistent with severe hemophilia A
• History of > 150 EDs to exogenously administered FVIII   concentrates or cryoprecipitate

• Anti-Adeno-associated virus, serotype 8 (AAV8) neutralizing antibody titer >= 1:5
• Received an AAV vector previously or any other gene transfer agent in the previous 12 months prior to Study Day 0

Modified AAV8 capsid^{2, 3} / HEK 293 cells⁴

Key characteristics of the FVIII transgene in the TAK-754 (BAX 888) vector include:

• Codon-optimized, B-domain–deleted FVIII (Orth04) transgene (Refs #2, #3, #4)
• Reduced CpG motifs (Ref #4) to limit innate immune activation, linked to expression loss in a hemophilia B trial with the same capsid (BAX-335; Ref #5)

    The expression cassette in the AAV vector includes the following regulatory elements: ^{2, 3}

• Liver-specific transthyretin (TTR) enhancer/promoter
• Synthetic polyadenylation (pA) signal

    Single peripheral intravenous infusion²

    Dose-cohorts^{2, 3} were reported as follows: 

• Co. 1: 2e12 (2)
• Co. 2: 6e12 (2)

Up to 2 years²

    OS^1, 2

Follow-up data regarding FVIII activity levels were reported in References #2 and #4 and are summarized below:

According to Figure 1 shown in Reference #4:

• Participants P1, P2, and P3 lost FVIII transgene expression within 9 months post-infusion
• Participant P4 resumed prophylaxis at study month 28

    Peak FVIII activity occurred 4-9 weeks after infusion²

    Not reported

ABR was not reported after vector infusion, possibly because the achieved transgene expression was of a short duration, rendering ABR assessment impractical^{2, 3}

No pts. developed infusion reactions and no changes in serum cytokines were observed at the time of TAK-754 infusion as reported in the poster at the ISTH 2022 Congress³

TAK-754–related Treatment-Emergent Adverse Events (TEAEs), as presented in Table 1 of Reference #4, are summarized below:

    * Hypophosphatemia SAE occurred in one participant at multiple study visits. Classified as both an AE and SAE at different time points during the study

Glucocorticoid-related Treatment-Emergent Adverse Events (TEAEs), as presented in Table 1 of Reference #4, are summarized below:

    According to the posters presented at the EAHAD 2021² and the ISTH 2022 Congress³, the following observations were made:

• All pts. developed minor ALT elevations (30 - 90 IU/ml) and received corticosteroids (3/4 pts.) or corticosteroid prophylaxis (1/4pts) 
• First peaks were observed between  3 - 6 weeks post infusion
• The  minor ALT elevations were maintained for up 16 months post infusion 

    Not reported

    According to Figure 5 presented in the poster at the ISTH 2022 Congress³, the following observations were made:

• All patients in both dose-cohorts exhibited weak signals ranging from 350 to >500 SFU per million cells with at least one of the three AAV8 peptide pools
• The peak values were observed between 6 and 12 weeks after the infusion
• Positive samples were defined as those with a signal ≥3 times the background and >60 cells per million
• The same data were also presented in the poster at the EAHAD 2021 Congress²

 Based on Figure 3 presented in the poster at the ISTH 2022 Congress³, the following observations were made:

• The minor elevations in ALT levels that were observed did not respond to steroid treatment.
• There was no correlation found between the elevation of transaminase levels and cell-mediated cytotoxic T cell responses.

Based on Figure 3 presented in the poster at the ISTH 2022 Congress³, the following observations were made:

• In the low-dose cohort, the FVIII activity levels were too low to establish a correlation between them and the elevations in ALT levels 
• In the high-dose cohort, an increase in ALT levels was observed, which was associated with a decline in FVIII transgene expression

Subsequently, findings regarding the decline or loss of FVIII expression were reported in Reference #4 as follows:

• Although ELISpot assays did not correlate with the loss of FVIII transgene expression or transaminase elevations in this study,
  • positive responses against the AAV capsid were observed at various time points in all four participants (Figure S2)

As reported in Reference #4, no malignancies were observed during the study period

1. A Study of BAX 888 in Male Adults With Severe Hemophilia A. Available at: Study Details | A Study of BAX 888 in Male Adults With Severe Hemophilia A | ClinicalTrials.gov
2. Chapin, J., et al., RESULTS FROM A PHASE 1/2 SAFETY AND DOSE ESCALATION STUDY OF TAK-754, AN AAV8 VECTOR WITH A CODON-OPTIMIZED B-DOMAIN–DELETED FACTOR VIII TRANSGENE IN SEVERE HEMOPHILIA A. Haemophilia, 2021. 27(S2): p. p. 18-181. Abstract - 2021 - Haemophilia - Wiley Online Library
3. Chapin, J., et al., A translational analysis of immune components in peripheral blood from severe hemophilia A patients treated with TAK-754, an AAV8 vector with a codon-optimized B-domain–deleted factor VIII transgene. ISTH 2022 Congress, 2022. PB0211.
4. Chapin J, Álvarez Román MT, Ayash-Rashkovsky M, Diogo D, Kenniston J, Lopez-Jaime FJ, Maggiore C, Mingot-Castellano ME, Rajavel K, Rauch A, Susen S, von Grotthuss M, Wagoner M, Wang Q. A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials. Haemophilia. 2025 Jan;31(1):108-117. doi: 10.1111/hae.15121. Epub 2024 Dec 23. PMID: 39716875; PMCID: PMC11780198. A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials - PubMed
5. Konkle, B.A., et al., BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood, 2021. 137(6): p. 763-774. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression | Blood | American Society of Hematology (ashpublications.org)

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