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

• Active, not recruiting,
• Last Update Posted: April 10, 2023¹

• 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} / vector manufacturing platform not reported

    Codon-optimized B-domain–deleted FVIII (Orth04) transgene^{2, 3} with reduced CpG motifs in order to reduce innate immunogenicity based on previous reports⁴

    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

Early follow-up data on FVIII activity was reported in reference #2 as follows:

   
    According to Figure 3 presented in the poster³ at the ISTH 2022 Congress, all pts. experienced a loss
    of transgene expression of FVIII within 9 months post infusion.
 

    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

   Reported AEs were presented in reference #8 and are summarized as follows:

 ^a  1 case of elevated liver enzymes is currently in recovery and 1 has not been resolved
 ^b  Hypophosphatemia event progressed from non-severe AE to severe SAE 
     All other TAK-754–related AEs have been resolved

Data on prednisolone-related AEs were extracted from the poster presented at EAHAD 2021 meeting, corresponding to the abstract of reference².
In this regard each of the following 14 prednisolone-related AEs occurred once as follows:

• Hyperphagia 
• Somnolence
• Increased appetite
• Night sweats
• Rash in back
• Rash in upper extremities
• Facial erythrose
• Irritability
• Difficulty falling asleep
• High blood pressure
• Tachycardia
• Rash acneform
• Weight gain
• Vitamin D deficiency

    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

    Not reported

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. 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