TAK-754 / Takeda, Bayer - LARVOL DELTA

A Study of BAX 888 in Male Adults With Severe Hemophilia A (clinicaltrials.gov) - P1/2 | N=21 | Completed | Sponsor: Baxalta now part of Shire | Active, not recruiting ➔ Completed | Trial completion date: Apr 2025 ➔ Jul 2024 | Trial primary completion date: Apr 2025 ➔ Jul 2024

Trial completion • Trial completion date • Trial primary completion date • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases • F8

Preclinical development of TAK-754, a high-performance AAV8-based vector expressing coagulation factor VIII. (PubMed, Mol Ther Methods Clin Dev) - "Integration site analysis revealed minimal vector integration, with no observations of clonal outgrowth or preferred integrations in genes previously implicated in hepatocellular carcinoma formation within the observation period. These preclinical studies demonstrate a good safety and efficacy profile for TAK-754."

Journal • Preclinical • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Hepatocellular Cancer • Oncology • Rare Diseases • Solid Tumor

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, Haemophilia) - P1/2 | "Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow-up periods."

Gene therapy • Journal • P1/2 data • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases • Renal Disease

A Study of BAX 888 in Male Adults With Severe Hemophilia A (clinicaltrials.gov) - P1/2 | N=21 | Active, not recruiting | Sponsor: Baxalta now part of Shire | N=12 ➔ 21

Enrollment change • Hematological Disorders • Hemophilia • Rare Diseases

A Study of BAX 888 in Male Adults With Severe Hemophilia A (clinicaltrials.gov) - P1/2 | N=12 | Active, not recruiting | Sponsor: Baxalta now part of Shire | Trial completion date: Sep 2026 ➔ Apr 2025 | Trial primary completion date: Jul 2024 ➔ Apr 2025

Trial completion date • Trial primary completion date • Hematological Disorders • Hemophilia • Rare Diseases

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) - "No changes in cytokines were observed within 24 hours of infusion. Transaminase elevation and decline of FVIII expression occurred 4-9 weeks post-infusion despite use of glucocorticoids. No significant changes in complete blood count populations were observed."

Clinical • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases • IL6 • IRF7 • TLR9 • TNFA

A Study of BAX 888 in Male Adults With Severe Hemophilia A (clinicaltrials.gov) - P1/2; N=12; Active, not recruiting; Sponsor: Baxalta now part of Shire; Trial primary completion date: Sep 2021 ➔ Jul 2024

Clinical • Trial primary completion date • Hematological Disorders • Hemophilia • Rare Diseases

Co-Prevalence of Pre-Existing Immunity to Different Serotypes of Adeno-Associated Virus (AAV) in Adults with Hemophilia (ASH 2019) - P=N/A; "These include liver-directed recombinant AAV8 vectors BAX 888/SHP654/TAK‑754 factor VIII (FVIII) gene therapy (GT) for severe HA, and SHP648/TAK‑748 factor IX (FIX) GT for HB (Baxalta US Inc., a Takeda company, Lexington, MA, USA)... The findings from this ongoing study demonstrate that approximately 50% of patients with hemophilia have preexistent NAb responses to AAV2, AAV5 or AAV8 with 40% demonstrating co-prevalence to all 3 evaluated AAV serotypes. Similar percentages of patients exhibited a positive cellular response to AAV8 antigens. Further, patients with HB demonstrated a slightly higher co-prevalence and a higher cellular response than patients with HA."

Clinical

A Global, Open-Label, Multicenter, Phase 1/2 Study of the Safety and Dose Escalation of BAX 888, an Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing B-Domain Deleted Factor VIII (BDD-FVIII) in Severe Hemophilia A Subjects Administered a Single Intravenous Infusion (clinicaltrialsregister.eu) - P1/2; N=10; Terminated; Sponsor: BAXALTA INNOVATIONS GMBH

Clinical • New P1/2 trial • Hematological Disorders • Hemophilia • Rare Diseases • Thrombosis

A Study of BAX 888 in Male Adults With Severe Hemophilia A (clinicaltrials.gov) - P1/2; N=12; Active, not recruiting; Sponsor: Baxalta now part of Shire; Trial completion date: Sep 2024 ➔ Sep 2026

Clinical • Trial completion date • Hematological Disorders • Hemophilia • Rare Diseases

[VIRTUAL] 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 (EAHAD 2021) - P1/2 | "Introduction: TAK-754 (formerly BAX 888, SHP654; Baxalta US Inc., a Takeda company) is a modified adeno-associated virus serotype 8 (AAV8) capsid containing a codon-optimized B-domain–deleted coagulation factor VIII (FVIII) transgene with a liver-specific promoter... The TAK-754 safety profile was consistent with an AAV8-based gene therapy. The initial vector-derived FVIII expression showed a steady decline corresponding with transaminase elevation. Utilization of corticosteroids did not prevent loss of FVIII expression."

Clinical • P1/2 data • Cardiovascular • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases • Renal Disease • Thrombosis

Safety and Dose Escalation Study of an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia A Participants (clinicaltrials.gov) - P1/2; N=12; Active, not recruiting; Sponsor: Baxalta now part of Shire; Trial completion date: May 2023 ➔ Sep 2024; Trial primary completion date: May 2023 ➔ Sep 2021

Clinical • Trial completion date • Trial primary completion date • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Safety and Dose Escalation Study of an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia A Participants (clinicaltrials.gov) - P1/2; N=12; Active, not recruiting; Sponsor: Baxalta now part of Shire; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Rare Diseases

Takeda demonstrates its long-standing commitment to advancing treatments for rare bleeding disorders with studies highlighting real-world evidence and investigational gene therapy at ASH 2019 (Businesswire) - "Real-world evidence from studies across many of Takeda’s portfolio of treatments for hemophilia demonstrate the cost savings and patient benefits resulting from ongoing personalized treatment....The poster 'Real-World Clinical Management of Patients with Hemophilia and Inhibitors: Effectiveness and Safety of aPCC in Patients with >18 Months’ Follow-up in the FEIBA Global Outcome Study (FEIBA GO)'...Takeda also presented data from preclinical scientific studies...These studies will inform Takeda's approach to its own investigational AAV gene therapy programs; TAK-754, an investigational AAV gene therapy for hemophilia A is currently in Phase 1 clinical study, soon to be followed by other potential gene therapies including TAK-748, an investigational gene therapy for hemophilia B."

Clinical data • Preclinical

Safety and Dose Escalation Study of an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia A Participants (clinicaltrials.gov) - P1/2; N=12; Recruiting; Sponsor: Baxalta now part of Shire; Trial completion date: Jun 2022 ➔ May 2023; Trial primary completion date: Jun 2022 ➔ May 2023

Clinical • Trial completion date • Trial primary completion date

Nonclinical Efficacy and Toxicology Evaluation of a Human FVIII Gene Therapy Vector (TAK-754/SHP654) in Mice (ISTH 2019) - "Treatment with TAK-754/SHP654 was shown to be efficacious in mice at doses ≥1.2x10 12 cp/kg and the No-Observed-Adverse-Effect-Level in mice was considered to be 5x10 13 cp/kg, the highest dose tested."

Preclinical

Prevalence of Preexisting Immunity to Adeno-associated Virus (AAV) in Adults with Hemophilia: Interim Results from an International Epidemiology Study (ISTH 2019) - "Background: Recombinant adeno-associated virus (AAV) serotype 8 vectors are in development for liver-directed gene transfer in patients with hemophilia, including TAK-754/SHP654/BAX 888 factor VIII (FVIII) gene therapy for severe hemophilia A (HA) and TAK-748/SHP648 factor IX (FIX) gene therapy for hemophilia B (HB)... Insights into preexisting AAV immunity from this study will increase understanding of anti-AAV responses that currently restrict patient eligibility for gene therapy trials."

Clinical

Factor VIII Clotting and Chromogenic Activities for TAK-754 / SHP654, a Clinical Hemophilia A Gene Therapy Candidate, Using in vitro and in vivo Assays (ISTH 2019) - "AAV8 vector-mediated expression of BDD-FVIII in the mouse liver resulted in a FVIII clotting to chromogenic activity ratio of about 2, whereas no assay discrepancy was noted in vitro for the HepG2 liver cell line. Blood matrix effects and specific FVIII protein activity secreted by hepatocytes need to be further analyzed to identify the root cause of this phenomenon observed in multiple studies and using different AAV serotypes."

Takeda to demonstrate global leadership in hematology at ISTH 2019 (Businesswire) - "Takeda Pharmaceutical Company Limited...will present research covering a broad range of rare bleeding disorders at the 27th Annual International Society on Thrombosis and Haemostasis Congress (ISTH), July 6-10, 2019 in Melbourne, Australia. Showcased in 10 oral presentations and 38 poster presentations, these data underscore Takeda’s pursuit of treatment innovation to achieve optimized and personalized patient care in hematology."

Clinical data • P3 data