A Phase 3 Study to Evaluate Efficacy and Safety of a Single Dose of Exa-cel in Subjects with Severe Sickle Cell Disease, βS/βC Genotype

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]

Decision date (initial)

2024-03-11

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Vertex Pharmaceuticals Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Evaluate efficacy of a single dose of exa-cel in adolescent and adult subjects with severe sickle cell disease (SCD), βS/βC genotype (HbSC).

Secondary objectives 3

1. To evaluate safety of a single dose of exa-cel in adolescent and adult subjects with severe SCD, HbSC genotype
2. Assess the effects of infusion of exa-cel on disease-specific events and clinical status
3. Quantify gene editing efficiency

Conditions and MedDRA coding

Sickle cell anaemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Documented βS/βC (HbSC) genotype. Subject can be enrolled based on historical genotype results, but confirmation of genotype is required before start of busulfan conditioning.
2. Subjects with severe SCD. Severe SCD is defined by the occurrence of at least 2 of the following events per year during the 2-year period before screening, while receiving appropriate supportive care: • Acute pain event that requires a visit to a medical facility and administration of pain medications or RBC transfusions • Acute chest syndrome, as indicated by the presence of a new pulmonary infiltrate associated with pneumonia-like symptoms, pain, or fever • Priapism lasting >2 hours and requiring a visit to a medical facility • Splenic sequestration, as defined by an enlarged spleen, left upper quadrant pain, and an acute decrease in Hb concentration of ≥2 g/dL.
3. Karnofsky performance status of ≥80% for subjects ≥16 years of age or Lansky performance status of ≥80% for subjects <16 years of age.
4. Eligible for autologous stem cell transplant as per investigator’s judgment.
5. Willing to participate in either a long-term follow-up study (VX18-CTX001- 131) or registry study (if available) for a total of 15 years follow-up post-exa-cel infusion.

Exclusion criteria 11

1. A willing and healthy 10/10 Human Leukocyte Antigen (HLA)-matched related donor is available per investigator’s judgement.
2. Prior hematopoietic stem cell transplant (HSCT).
3. Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator.
4. White blood cell (WBC) count <3 × 109 /L or platelet count <50 × 109 /L, not related to hypersplenism per investigator judgment.
5. Subjects with history of alloimmunization to RBC antigens and for whom the investigator anticipates that there will be insufficient RBC units available for the duration of the study.
6. HbF level >15.0%, irrespective of concomitant treatment with HbF-inducing treatments such as HU.
7. History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk to the subject.
8. Any prior or current malignancy or myeloproliferative disorder or a significant immunodeficiency disorder.
9. Advanced liver disease (as defined in the protocol)
10. Intolerance, contraindication, or known sensitivity to plerixafor or busulfan. Subject must not have any risk factors in the opinion of the investigator that would increase the likelihood of busulfan-related toxicities.
11. Pregnancy or breastfeeding

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of subjects who have not experienced any severe vaso-occlusive crises (VOCs) for at least 12 consecutive months (VF12). The duration of VF12 will start 60 days after last red blood cell transfusion for post-transplant support or sickle cell disease management.

Secondary endpoints 19

1. Safety and tolerability of exa-cel based on adverse events (AEs), clinical laboratory values, neutrophil engraftment, platelet engraftment, transplant-related mortality (TRM), and allcause mortality.
2. Proportion of subjects with HbF level ≥20% at Month 6.
3. Proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months (HF12) after exa-cel infusion. The evaluation of HF12 starts 60 days after last RBC transfusion for post-transplant support or SCD disease management.
4. Relative reduction from baseline in annualized rate of severe VOCs up to 24 months after exa-cel infusion.
5. Duration of severe VOC free in subjects who have achieved VF12
6. Relative reduction from baseline in rate of inpatient hospitalizations for severe VOCs up to 24 months after exa-cel infusion.
7. Relative reduction from baseline in annualized duration of hospitalization for severe VOCs up to 24 months after exa-cel infusion.
8. Proportion of subjects with sustained HbF ≥20% at the time of analysis for at least 3 months, 6 months, or 12 months.
9. Relative reduction from baseline in annualized volume of RBC transfusions
10. Fetal hemoglobin (HbF) concentration over time
11. Hemoglobin (Hb) concentration over time
12. Proportion of subjects with detectable haptoglobin over time
13. Proportion of alleles with intended genetic modification present in peripheral blood over time
14. Proportion of alleles with intended genetic modification present in CD34+ cells of the bone marrow over time
15. Change in patient reported outcomes (PROs) over time in adults (≥18 years) using; o Pain scale: 11-point numerical rating scale (NRS) o Functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) o Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me) o EuroQol Quality of Life Scale (EQ 5D 5L)
16. Change in PROs over time in adolescents (12 to <18 years of age) using; o Pain-scale: 11-point NRS o Pediatric Quality of Life Inventory (PedsQL) Generic Core self-report and parent proxy versions o PedsQL SCD module (self-report and parent proxy versions) o EQ-5D-Youth (EQ-5D-Y self-report and parent proxy versions)
17. Change from baseline in reticulocyte count (percent reticulocytes and absolute reticulocyte count) over time
18. Change from baseline in hemolysis biomarker concentrations over time: indirect bilirubin, haptoglobin, and lactate dehydrogenase (LDH)
19. Proportion of subjects with normalized LDH

Investigational products

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

Test 1

Auxiliary 2

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

Application history

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