Clinical Study of BRL-101 in the Treatment of Sickle Cell Disease

• ClinicalTrials.gov Identifier: NCT06287099
• Recruitment Status: Not yet recruiting
• First Posted: February 29, 2024
• Last Update Posted: March 19, 2024
• Sponsor: Bioray Laboratories
• Collaborator: Nanfang Hospital, Southern Medical University
• Information provided by (Responsible Party): Bioray Laboratories

Tracking Information

• First Submitted Date: February 23, 2024
• First Posted Date: February 29, 2024
• Last Update Posted Date: March 19, 2024
• Estimated Study Start Date: April 20, 2024
• Estimated Primary Completion Date: October 20, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 17, 2024)

• Proportion of stem cell engrafted subjects [ Time Frame: Within 42 Days After BRL-101 Infusion ]
  Stem cell engraftment was defined as an absolute peripheral blood neutrophil count of ≥ 0.5 × 109/L for 3 consecutive days following BRL-101 intravenous infusion.
• Time to neutrophil engraftment [ Time Frame: Within 42 Days After BRL-201 Infusion ]
  Defined as Day 1 of absolute peripheral blood neutrophil count ≥ 0.5 × 109/L for 3 consecutive days
• Frequency, severity, and relationship to BRL-101 of adverse events over 12 months following BRL-101 infusion. [ Time Frame: Within 12 Months After BRL-101 Infusion ]
  Adverse events assessed according to NCI-CTCAE v5.0 criteria

Original Primary Outcome Measures (submitted: February 23, 2024)

• Proportion of stem cell engrafted subjects [ Time Frame: Within 42 Days After BRL-101 Infusion ]
  Stem cell engraftment was defined as an absolute peripheral blood neutrophil count of ≥ 0.5 × 109/L for 3 consecutive days following BRL-101 intravenous infusion.
• Time to neutrophil engraftment [ Time Frame: Up to 12 Months After BRL-201 Infusion ]
  Defined as Day 1 of absolute peripheral blood neutrophil count ≥ 0.5 × 109/L for 3 consecutive days
• Frequency, severity, and relationship to BRL-101 of adverse events over 12 months following BRL-101 infusion. [ Time Frame: Up to 12 Months After BRL-101 Infusion ]
  Adverse events assessed according to NCI-CTCAE v5.0 criteria

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Clinical Study of BRL-101 in the Treatment of Sickle Cell Disease
• Official Title: Clinical Study on the Safety and Efficacy of a Single Intravenous Dose of CRISPR/Cas9-Edited Autologous CD34+ Hematopoietic Stem/Progenitor Cells (BRL-101) in the Treatment of Sickle Cell Disease
• Brief Summary: This is a single center, non-randomized, open label, single-dose study in subjects with Sickle Cell Disease (SCD). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 modified CD34+ human hematopoietic stem and progenitor cells (hHSPCs) (BRL-101).
• Detailed Description: This clinical trial is a single-arm, single-dose, single center, open-label study without dose escalation. The primary objective is to explore the safety of the study drug in SCD. Myeloablative conditioning and administration for the remaining subjects can only be started after the first subject completes dosing and safety observation and assessment.
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Sickle Cell Disease

Intervention

Drug: BRL-101

Subjects will receive a single infusion of BRL-101.

Other Name: Autologous hematopoietic stem and progenitor cells injection

Study Arms

Experimental: BRL-101

Autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the BCL11A gene. Subjects will receive a single infusion of BRL-101.

Intervention: Drug: BRL-101

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: February 23, 2024): 5
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 10, 2026
• Estimated Primary Completion Date: October 20, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Fully understood this study and voluntarily signed the written informed consent form.
2. Aged between 3 and 35 years.
3. Be diagnosed with Sickle Cell Disease (SCD), with a genotype of βS/βS, βS/β+ or βS/β0.
4. A Lansky/Karnofsky Performance Status (LPS) score of ≥80.
5. Suitable for autologous hematopoietic stem cell transplantation.
6. Have good compliance and are willing to adhere to visit schedules, trial protocols, laboratory tests, and other trial procedures.
7. Agree to participating in long-term follow-up studies.
8. Subjects of childbearing potential must use effective contraception for at least 6 months following cell reinfusion during the study.

Exclusion Criteria:

-

Subjects meeting any of the following criteria are not eligible for enrolment in the study:

1. Known contraindications, intolerance, or hypersensitivity to hematopoietic stem cell mobilizers, busulfan injection, or dimethyl sulfoxide (DMSO) or study drug-related components.
2. Eligible for allogeneic hematopoietic stem cell transplantation and have found HLA-identical donors.
3. Prior allo-HSCT, gene therapy or gene editing therapy.
4. Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator.
5. HbF level >15.0%, irrespective of concomitant treatment with HbF inducing treatments such as HU.
6. Treatment with regular RBC transfusions that, in the opinion of the investigator, cannot be interrupted after engraftment.
7. More than 10 unplanned hospitalizations or emergency department visits related to SCD in the 1 year before screening and the investigator considered this to be a significant chronic pain rather than an acute pain crisis.
8. A history of clinically significant transcranial Doppler (TCD) test abnormalities or test abnormalities in the opinion of the investigator.
9. History of untreated Moyamoya disease or presence of Moyamoya disease at screening that in the opinion of the investigator puts the subjects at the risk of bleeding.
10. The subject has participated in other clinical studies and used drugs within 3 months before screening.
11. White blood cell count < 3 × 109/L and/or platelet count < 100 × 109/L not due to hypersplenism as judged by the investigator.
12. INR > 1.5×ULN, APTT > 1.5×ULN.
13. Creatinine > 1.5 × ULN or endogenous creatinine clearance < 60 ml/min (calculated according to the Cockcroft-Gault formula, see Appendix 3).
14. ALT or AST> 3×ULN, or direct bilirubin value > 2.5×ULN.
15. Severe iron overload with serum ferritin ≥ 5000 ng/ml, liver iron > 15 mg Fe/g dry weight (or liver MRIT2* < 1.4 ms or > 588 Hz), or heart MRI-T2* < 10 ms.
16. LVEF < 50%.
17. DLco < 50% predicted (corrected haemoglobin or/and alveolar volume) or forced vital capacity (FVC) (measured/predicted) < 60% (For children for whom DLco could not be determined), or abnormal blood gas analysis (for younger children with undetectable ventilatory function only).
18. Hepatitis B virus surface antigen (HBsAg) positive or HBV-DNA positive; hepatitis C virus (HCV) antibody positive; human immunodeficiency virus (HIV) antibody positive; syphilis (TP) -specific antibody positive; Epstein-Barr virus EBV-DNA positive; cytomegalovirus CMV-DNA positive.
19. History of a significant bleeding disorder.
20. History or family history of malignancy or myeloproliferative disorder.
21. Any prior or current cardiovascular system diseases, such as congestive heart failure, arrhythmia, myocardial disease, valvular heart disease or pulmonary hypertension; cirrhosis, liver fibrosis or active hepatitis; central nervous system diseases or mental illness.
22. Presence of immune dysfunction or endocrine disorders, such as insulin-dependent diabetes mellitus, hyperthyroidism, or insufficiency.
23. Pregnant or breastfeeding females.
24. Any condition that, in the opinion of the investigator, would make participation in this clinical study inappropriate.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 3 Years to 35 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Xiaoqin Feng, PhD; 020-61641921; fxq126126@126.com

• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT06287099
• Other Study ID Numbers: 2023-BRL-101-SCD
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Bioray Laboratories
• Original Responsible Party: Same as current
• Current Study Sponsor: Bioray Laboratories
• Original Study Sponsor: Same as current
• Collaborators: Nanfang Hospital, Southern Medical University

Investigators

• Study Chair: Xiaoqin Feng, PhD; Nanfang Hospital, Southern Medical University

• PRS Account: Bioray Laboratories
• Verification Date: February 2024