A Phase 3b Study to Evaluate Efficacy and Safety of a Single Dose of Autologous CRISPR Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (CTX001) in Subjects with Transfusion-Dependent β-Thalassemia or Severe Sickle Cell Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vertex Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

26 Oct 2022 → ongoing

Decision date (initial)

2024-07-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-514641-12-00

EudraCT number

2021-006390-37

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To assess HbF levels over time, after a single dose of autologous CRISPR/Cas9 modified CD34+ human hematopoietic stem and progenitor cells (hHSPCs)(CTX001) in adolescent and adult subjects with either Transfusion dependent β-Thalassemia (TDT) or severe sickle cell disease (SCD)

Secondary objectives 3

1. To evaluate efficacy and safety of a single dose of CTX001 in adolescent and adult subjects with either TDT or severe SCD
2. Assess the effects of infusion of CTX001 on disease-specific events and clinical status
3. Quantify gene editing efficiency

Conditions and MedDRA coding

Transfusion-dependent β-thalassemia (TDT)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. Participants with TDT and SCD: Eligible for autologous stem cell transplant as per investigator's judgment.
2. Participants with TDT: Diagnosis of TDT as defined by: Documented homozygous β-thalassemia or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE). Participants can be enrolled based on historical data, but a confirmation of the genotype using the study central laboratory will be required before busulfan conditioning History of at least 100 milliliter (mL)/kilograms (kg)/year or 10 units/year of packed red blood cells (RBC) transfusions in the prior 2 years before signing the consent or the last rescreening for patients going through re-screening
3. Participants with SCD: Diagnosis of severe SCD as defined by: Documented SCD genotypes History of at least two severe VOCs events per year for the previous two years prior to enrollment

Exclusion criteria 3

1. Participants with TDT and SCD: A willing and healthy 10/10 human leukocyte antigen (HLA)-matched related donor is available per investigator's judgement Prior hematopoietic stem cell transplant (HSCT) Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator
2. Participants with TDT: Participants with associated α-thalassemia and >1 alpha deletion, or alpha multiplications Participants with sickle cell β-thalassemia variant
3. Participants with SCD: History of untreated moyamoya syndrome or presence of moyamoya syndrome at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. HbF and Hb levels over time. The evaluation will start 60 days after last RBC transfusion for post-transplant support or disease management.

Secondary endpoints 9

1. TDT and SCD: Safety and tolerability of CTX001 based on adverse events (AEs), clinical laboratory values, neutrophil engraftment, platelet engraftment, transplant-related mortality (TRM), and all-cause mortality.
2. TDT and SCD: Relative reduction from baseline in annualized volume of RBC transfusions
3. TDT and SCD: Proportion of alleles with intended genetic modification present in peripheral blood over time
4. TDT and SCD: Proportion of alleles with intended genetic modification present in CD34+ cells of the bone marrow over time
5. TDT: Duration transfusion free
6. SCD: Relative reduction from baseline in annualized rate of severe vaso-occlusive crises (VOCs) up to 12 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management.
7. SCD: Relative reduction from baseline in annualized rate of inpatient hospitalizations for severe VOCs up to 12 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management.
8. SCD: Relative reduction from baseline in annualized duration of hospitalization for severe VOCs up to 12 months after CTX001 infusion. The evaluation starts 60 days after last RBC transfusion for post-transplant support or SCD disease management.
9. SCD: Relative reduction from baseline in markers of hemolysis up to 12 months after CTX001 infusion.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vertex Pharmaceuticals Inc.

Sponsor organisation

Vertex Pharmaceuticals Inc.

Address

50 Northern Avenue

City

Boston

Postcode

02210-1862

Country

United States

Scientific contact point

Organisation

Vertex Pharmaceuticals Inc.

Contact name

Clinical Trials and Medical Info

Public contact point

Organisation

Vertex Pharmaceuticals Inc.

Contact name

Clinical Trials and Medical Info

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 58 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications