Gene Therapy for Chinese Hemophilia A

Official title

Clinical Exploration of Clinical Exploration Adeno-associated Virus Vector Expression of Human Coagulation Factor VIII Gene Therapy for Hemophilia A

Overview

IHBDH-GTHA-2020 is an open- label, non- randomized study to evaluate the safety, tolerability and kinetics of a single intravenous infusion of GS001 in hemophilia A subjects with \<1 IU/dl residual FVIII levels.

Detailed description

IHBDH-GTHA-2020 is a open- label, non- randomized study to evaluate the safety, tolerability and kinetics of GS001 in hemophilia A subjects with residual FVIII levels\<1 IU/dl. The first patient will receive a single intravenous infusion of GS001 at a dose level of 2 x 10\^12 vg/kg body weight. After three weeks of follow-up for the first patient post infusion of GS001, the dose of GS001 can be adjusted for the other two patients based on the activity level of FVIII:C and safety assessment. Following completion of the first 3 patients received GS001 infusion at 2 x 10\^12 vg/kg dose level , the following 3 patients will continue to be enrolled to this dose group if there isn't any unexpected safety risk based on the assessments of FVIII expression and safety profile. The safety data and the activity level of FVIII:C from the first 6 subjects at 2 x 10\^12 vg/kg dose level will undergo review by an independent DMC prior to dosing the first subject in the next dose level, DMC may recommend dose escalation to 6 x 10\^12 vg/kg body weight or other recommended dose levels.

If the DMC recommends dose escalation to 6 x 10 \^12 vg/kg body weight or other recommended doses, at least 10 weeks of safety data and the activity level of FVIII:C post GS001 infusion from the first 3 subjects in this given dose level will undergo review by an independent DMC prior to dosing the following subjects. Based on the data from the first 3 subjects, DMC may recommend the dose adjustments for subsequent enrolled subjects, and expand the number of subject enrolled. Based on the safety, preliminary efficacy and vector kinetics profile of single intravenous infusions of GS001 at different dose levels in severe hemophilia A patients with endogenous factor FVIII activity levels ≤ 1% in this study, and based on the benefit-risk assessment of the subjects, the dose level to be administered for future larger clinical trial in patients with severe hemophilia A will be determined.

After all enrolled subjects have been followed for at least 12 weeks after intravenous infusion GS001, periodic analysis will be performed. Primary analysis of safety and efficacy will be performed 52 (± 2) weeks after intravenous infusion GS001, and all subjects will receive 52 (± 2) weeks of comprehensive safety and efficacy assessments. After completing the 52 (± 2) week visit (end-of-study visit), subjects will continue to be followed in this study for up to an additional 4 years for long-term safety and efficacy assessment to evaluate the long-term safety and efficacy of GS001 treatment.

A total of 12 to 15 subjects are expected to be enrolled in this study. Subjects will provide informed consent and then undergo screening assessments up to 4-8 weeks prior administration of GS001. All subjects will undergo 260 weeks (5 years) safety observation.

Interventions

• Genetic Injection of GS001
  Patients will be enrolled sequentially every 3 weeks or more between cohorts. Dose escalation may occur after a single patient has been safely dosed if the resulting FVIII activity at Week 3 is \< 5 IU/dL.The dose levels are as follows: 1. 2×10\^12 vg/kg 2. 6×10\^12vg/kg or other recommended doses 3. 2×10\^13 vg/kg or other recommended doses

Primary outcome measures

• Incidence of treatment- related adverse events [Time frame: From screening through up to the end of study (about 5 years).]
• Percentage of subjects in each dose group with newly occurred clinically significant abnormalities in physical examination compared to the baseline. [Time frame: From the start of study treatment (Day 1) through up to the end of study (about 5 years).]
• Changes of Weighted Mean of vital signs (systolic blood pressure [SBP] and diastolic blood pressure [DBP], pulse rate, temperature, respiratory rate) from baseline at each assessment time point for each dose group [Time frame: From the start of study treatment (Day 1) through up to the end of study (about 5 years).]
• Changes of Mean Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amio Transferase (AST) from baseline at each assessment time point for each dose group [Time frame: From the start of study treatment (Day 1) through up to the end of study (about 5 years).]
• Immune response to AAV capsid proteins [Time frame: From screening period through up to 5 years.]
• Immune response to FVIII transgene [Time frame: From screening period through up to 5 years.]
• Viral vector shedding of GS001 [Time frame: From date of infusion until the date of 3 consecutive documented negative results, assessed up to 1 year.]
• Thrombosis risk assessment [Time frame: From the start of study treatment (Day 1) through up to the end of study (about 5 years).]

Secondary outcome measures (4)

• Vector- derived FVIII:C and FVIII antigen levels [Time frame: From pre-dose phase through up to 1 years post-dose]
• FVIII usage within 1 year after GS001 infusion [Time frame: From week 3 to week 52 post GS001 infusion.]
• Number of bleeding events requiring exogenous FVIII replacement therapy within 1 year after GS001 infusion [Time frame: Week 3 to Week 52 post GS001 Infusion]
• Number of bleeding events within 1 year after GS001 infusion [Time frame: Week 3 to Week 52 post GS001 infusion]

Eligibility criteria

Inclusion criteria

• Be able to understand the purpose and risks of the study and provide informed consent according to national and local privacy laws;
• Male subjects and ≥ 18 years of age;
• Have hemophilia A with ≤1 IU/dL (≤1%) endogenous FVIII activity levels at the time of screening. If the screening result is >1% due to previous treatment with FVIII product, then it may be confirmed by documented historical evidence from a certified clinical laboratory demonstrating ≤1% FVIII activity levels ;
• No history of hypersensitivity or anaphylaxis associated with FVIII product administration;
• Have no measurable FVII inhibitor as assessed by laboratory two times that were at least one week apart; or documented no prior history of FVIII inhibitor after 150 EDs and no clinical signs or symptoms of decreased response to FVIII infusion ;
• Have acceptable laboratory values sampled at screening and repeated prior to Day 0; A. Hemoglobin ≥ 11 g/dL; B. Platelets ≥ 100 x 10\^9/L; C. AST, ALT, alkaline phosphatase ≤ 1.25 upper limit of normal (ULN); D. Bilirubin ≤ 1.25 ULN; E. Creatinine ≤ 2 mg/dL.
• Agree to use reliable barrier contraception until the end of the 52 weeks observation period, and three consecutive semen samples are negative for vector sequences after GS001 infusion.

Exclusion criteria

• Have Hepatitis B, hepatitis C or HBsAg, HCVAb, HBV-DNA, HCV-RNA are positive and have clinical significance. Both natural clearers and those who have cleared HCV on antiviral therapy are deemed eligible;
• Currently Receiving antiviral therapy for hepatitis B and C;
• Have history of chronic infections or other chronic diseases that may pose a risk to the study participation;
• Have participated in a previous gene therapy research trial within the last 52 weeks or in a clinical study with an investigational drug within the past 30 days;
• The subject has any concurrent diseases that cannot tolerate treatments of prednisone or prednisolone as judged by the investigator;
• History of arterial or venous thromboembolic events (e.g., deep vein thrombosis, non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolism);
• Known inherited or acquired thrombophilia, including conditions associated with increased risk of thromboembolism, such as atrial fibrillation;
• Major surgery planned in 1 year period following the infusion with GS001;
• Hypersensitivity to the study vector;
• Have clinically major diseases or any other unspecified conditions that, in the opinion of the Investigator, makes the subject unsuitable for participating in the study;
• Patients who are unable or unwilling to comply with the schedule of visits and study assessments described in the clinical protocol;
• Evidence of other bleeding disorders not associated with hemophilia A.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Chinese Academy of Medical Science and Blood Disease Hospital — Tianjin

Publications

• Liu W, Pei X, Yu T, Xu B, Dai X, Xue F, Chen L, Wang X, Wang Y, Chen Y, Liu X, Fu R, Wang W, Chi Y, Li HY, Yang R, Zhang L. Phase 1 pilot study for hemophilia-A: AAV8 vector with prophylactic tacrolimus-glucocorticoid achieves therapeutic FVIII activity. Signal Transduct Target Ther. 2026 Mar 11;11(1):88. doi: 10.1038/s41392-026-02599-3. PMID 41813646

Identifiers

NCT: NCT04728841 · IIT2020030

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗