Hematological Diseases, Hemoglobinopathies, Sickle Cell Disease
Conditions
Brief summary
This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in participants with severe 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) using CTX001.
Interventions
BIOLOGICALExa-cel
Administered by IV infusion following myeloablative conditioning with busulfan.
Sponsors
Vertex Pharmaceuticals Incorporated
CRISPR Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosis of severe sickle cell disease as defined by: * Documented severe sickle cell disease genotype * History of at least two severe vaso-occlusive crisis events per year for the previous two years prior to enrollment * Eligible for autologous stem cell transplant as per investigators judgment Key
Exclusion criteria
* An available 10/10 human leukocyte antigen (HLA)-matched related donor * Prior hematopoietic stem cell transplant (HSCT) * Clinically significant and active bacterial, viral, fungal, or parasitic infection Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Have Not Experienced Any Severe Vaso-occlusive Crisis (VOC) for at Least 12 Consecutive Months (VF12) After Exa-cel Infusion | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | A VOC is a condition of SCD characterized by vaso-occlusion presenting as recurrent pain episodes. The percentage of participants who remain VOC free after achieving VF12 were data reported in the outcome measure. |
| Percentage of Participants Who Achieve Neutrophil Engraftment | Up to 24 months post exa-cel infusion. | Neutrophil engraftment is defined as the first day of 3 consecutive measurements of absolute neutrophil count (ANC)≥500/μL on 3 different days, within 42 days after exa-cel infusion without the use of unmodified CD34+ cells after reaching the nadir, defined as ANC \<500/µL. |
| Time to Neutrophil Engraftment for Participants Who Achieve Neutrophil Engraftment | Up to 24 months post exa-cel infusion. | Neutrophil engraftment is defined as the first day of 3 consecutive measurements of absolute neutrophil count (ANC)≥500/μL on 3 different days, without use of the unmodified CD34+ cells after reaching the nadir, defined as ANC\<500/μL. Time to neutrophil engraftment was calculated by the neutrophil engraftment date subtract exa-cel infusion date +1. |
| Time to Platelet Engraftment for Participants Who Achieve Platelet Engraftment | From Exa-cel infusion up to 2 years after exa-cel infusion | Platelet engraftment is defined as the first day of 3 consecutive measurements of unsupported (no platelet transfusions for the last 7 days) platelet ≥50,000/μL on 3 different days after Exa-cel infusion. For participants discharged early day 7 after the last platelet transfusion will be the day of platelet engraftment, as long as 3 subsequent and consecutive unsupported measurements on 3 different days are \>50,000/μL. For participants who have been discharged prior to platelet engraftment, it is recommended to collect blood every 2 to 3 days to obtain an accurate assessment of platelet engraftment. Time to platelet engraftment was defined as first of 3 consecutive measurements on 3 different days with platelet ≥50 × 109/L without a platelet transfusion for 7 consecutive days. |
| Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From receiving exa-cel infusion up to 2 years | — |
| Transplant-related Mortality (TRM) Within 100 Days After Exa-cel Infusion | Within 100 days after exa-cel infusion | The transplant-related mortality is defined as death related to Busulfan and/or exa-cel infusion. The number and proportion of TRM participants who have died within 100 days, or with at least 100 days post exa-cel infusion. |
| Transplant-related Mortality Within 12 Months Post Exa-cel Infusion | Within 12 months post exa-cel infusion | The transplant-related mortality is defined as death related to Busulfan and/or exa-cel infusion. The number and proportion of TRM within 12 months will be summarized for participants who have died within 12 months, or with at least 12 months post exa-cel infusion. |
| All-cause Mortality | From exa-cel infusion up to 2 years | All-cause mortality from exa-cel infusion up to 2 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Free From Inpatient Hospitalization for Severe VOCs Sustained for at Least 12 Months (HF12) | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | The HF12 means Free from inpatient hospitalization for severe vaso-occlusive crises (VOCs) and sustained for at least 12 months after exa-cel infusion. |
| Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | The VF12 defines absence of any severe vaso-occlusive crises (VOCs) for at least 12 consecutive months after exa-cel infusion. Only severe VOCs adjudicated by an outcome measure adjudication committee as meeting the protocol definition of severe VOCs were included in the analysis. Relative reduction from baseline was calculated as 100 % × (Baseline value - post-baseline value) / Baseline value. Annualized rate is calculated by the Total number of events/number of years. |
| Percentage of Participants With at Least 90% Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | Percentage of participants with at least 90% relative reduction from baseline was reported. The percentages were calculated relative to the number of participants who did not achieve VF12. |
| Percentage of Participants With at Least 80% Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | Percentage of participants with at least 80% relative reduction from baseline was reported. The percentages were calculated relative to the number of participants who did not achieve VF12. |
| Percentage of Participants With at Least 75% Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | Percentage of participants with at least 75% relative reduction from baseline was reported. The percentages were calculated relative to the number of participants who did not achieve VF12. |
| Percentage of Participants With at Least 50% Relative Reduction From Baseline in Annualized Rate of Severe VOCs for Participants Who do Not Achieve VF12 up to 24 Months After Exa-cel Infusion | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | Percentage of participants with at least 50% relative reduction from baseline was reported. The percentages were calculated relative to the number of participants who did not achieve VF12. |
| Duration of Severe VOC Free in Participant Who Have Achieved VF12 | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | The VF12 means the absence of any severe VOC for at least 12 consecutive months after exa-cel infusion. The evaluation of the severe VOC free duration in participants who achieved VF12 started 60 days after the last RBC transfusion for post transplant support or SCD management. |
| Relative Reduction From Baseline in Annualized Rate of Inpatient Hospitalizations for Severe VOCs Up to 24 Months After Exa-cel Infusion | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | The HF12 means Free from inpatient hospitalization for severe vaso-occlusive crises (VOCs) and sustained for at least 12 months after exa-cel infusion. Relative reduction from baseline is calculated as 100% × (Baseline value - post-baseline value) / Baseline value. Annualized rate is calculated by the Total number of events/number of years. Only severe VOCs adjudicated by an outcome measure adjudication committee as meeting the protocol definition of severe VOCs are included in the analysis. |
| Relative Reduction From Baseline in Annualized Duration of Hospitalization for Severe VOCs Who Did Not Achieve HF12 Up to 24 Months After Exa-cel Infusion | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | The HF12 means Free from inpatient hospitalization for severe vaso-occlusive crises (VOCs) and sustained for at least 12 months after exa-cel infusion. Relative reduction from baseline is calculated as 100% × (Baseline value - post-baseline value) / Baseline value. Annualized rate is calculated by the Total number of events/number of years. Only severe VOCs adjudicated by an outcome measure adjudication committee as meeting the protocol definition of severe VOCs are included in the analysis. |
| Percentage of Participants With Sustained Fetal Hemoglobin (HbF) Greater Than or Equal to (≥) 20% for at Least 3 Months | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | The HbF evaluation started 60 days after the last RBC transfusion for post transplant support or SCD management. The last RBC transfusion refers to that in the period of the initial RBC transfusions for post transplant support or SCD management. |
| Percentage of Participants With Sustained HbF ≥ 20% for at Least 6 Months | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | The HbF evaluation started 60 days after the last RBC transfusion for post transplant support or SCD management. The last RBC transfusion refers to that in the period of the initial RBC transfusions for post transplant support or SCD management. |
| Percentage of Participants With Sustained HbF ≥20% for at Least 12 Months | From 60 days after last RBC transfusion up to 2 years after exa-cel infusion | The HbF evaluation started 60 days after the last RBC transfusion for post transplant support or SCD management. The last RBC transfusion refers to that in the period of the initial RBC transfusions for post transplant support or SCD management. |
| Number of Annualized Red Blood Cells (RBC) Units Transfused After Exa-cel Infusion | 2 years after exa-cel infusion | The evaluation of the number of annualized RBC units transfused after exa-cel infusion started 12 months after exa-cel infusion. |
| Participants With Relative Reduction From Baseline in Number of Annualized Units of Red Blood Cells Transfused | 2 years after exa-cel infusion | Relative reduction from baseline = 100% × (Baseline value - post baseline value)/Baseline value. The evaluation of the number of annualized RBC units transfused after exa-cel infusion started 12 months after exa-cel infusion. |
| Total Fetal Hemoglobin (HbF) Concentration Over Time | 2 years after exa-cel infusion | — |
| Total Hemoglobin (Hb) Concentration Over Time | 2 years after exa-cel infusion | — |
| Change From Baseline in Reticulocyte Count Over Time | 2 years after exa-cel infusion | — |
| Change From Baseline in Indirect Bilirubin Over Time | 2 years after exa-cel infusion | — |
| Percentage of Participants With Detectable Haptoglobin Over Time | 2 years after exa-cel infusion | — |
| Percentage of Participants With Lactate Dehydrogenase (LDH) Level <300 Units Per Liter (U/L) Over Time | 2 years after exa-cel infusion | — |
| Percentage of Alleles With Intended Genetic Modification Present in Peripheral Blood Leukocytes Over Time | 2 years after exa-cel infusion | — |
| Percentage of Alleles With Intended Genetic Modification Present in CD34+ Cells of Bone Marrow Over Time | 2 years after exa-cel infusion | — |
| Change in Patient-reported Outcome (PRO) Over Time Assessed Using on a 11-point Numerical Rating Scale [NRS]) for Participants ≥12 and <18 Years of Age | 2 years after exa-cel infusion | The 11-point pain numerical rating scale (NRS) is used to measures pain intensity on a 1-dimensional score ranging from 0 (no pain) to 10 (worst possible pain). |
| Change in Patient-reported Outcome (PRO) Over Time Assessed Using on a 11-point Numerical Rating Scale [NRS]) for Participants ≥18 and ≤35 Years of Age | 2 years after exa-cel infusion | The 11 point pain numerical rating scale (NRS) is used to measures pain intensity on a 1 dimensional score ranging from 0 (no pain) to 10 (worst possible pain). |
| Change in PRO Over Time Assessed Using EuroQol Quality of Life Scale (EQ-5D-Y)Visual Analogue Scale (VAS) for Participants ≥12 and <18 Years of Age | 2 years after exa-cel infusion | The EQ-5D VAS is a version of the EQ-5D designed for children and adolescents S). The EQ VAS records the subject's self-rated health on a 100-point VAS scale that ranged from 0 (worst imaginable health) to 100 (best imaginable health) points. |
| Change in PRO Over Time Assessed Using EuroQol Quality of Life Scale (EQ-5D-5L) for Participants ≥18 and ≤35 Years of Age | 2 years after exa-cel infusion | The EQ-5D VAS is a version of the EQ-5D designed for children and adolescents S). The EQ VAS records the subject's self-rated health on a 100-point VAS scale that ranged from 0 (worst imaginable health) to 100 (best imaginable health) points. |
| Change in PRO Over Time Assessed Using Functional Assessment of Cancer Therapy-bone Marrow Transplant (FACT-BMT) Score for Participants ≥18 and ≤35 Years of Age | 2 years after exa-cel infusion | The Functional Assessment of Cancer Therapy-Bone Marrow Transplant scale (FACT-BMT) is a quality of life instrument that assesses the effects of bone marrow transplantation (BMT) on a patient's physical, social/family, emotional, and functional well-being while taking into consideration BMT-specific concerns. The assessment has different questions, each scored on a Likert scale from 0-4. The overall score is computed by adding scores of the questions and falls in the range 0-148, with higher scores indicating higher levels of overall well-being. |
| Change in PRO Over Time Assessed Using Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me) Score on Different Domains for Participants ≥18 and ≤35 Years of Age | 2 years after exa-cel infusion | ASCQ-Me is a disease-specific HRQoL questionnaire for adults with sickle cell disease that assesses Emotional Impact, Pain Impact, Social Functioning Impact, Stiffness Impact, Sleep Impact, Pain Episode Frequency, and Pain Episode Severity. Domain scores are reported as T-scores standardized to a reference population where mean = 50, and SD = 10. A change of approximately 5 points (1/2 SD) is considered clinically meaningful. An increase of 5 points indicates improvement for the impact domains, whereas a decrease of 5 points indicates improvement for the Pain Episode Frequency and Pain Episode Severity domains. For impact domain items higher score indicates better HRQoL and lower disease burden. For Pain items lower score indicates a better outcome. Scores are interpreted relative to the reference population mean of 50, taking into account the direction of scoring for each domain. |
| Change in PRO Over Time Assessed Using Pediatric Quality of Life Inventory (PedsQL) for Participants Greater Than or Equal to (≥) 12 and Less Than (<) 18 Years of Age | 2 years after Exa-cel infusion | PedsQL scores were used to assess quality of life of participants. It is a standardized, generic instrument for measuring health related quality of life (HRQoL) in children and adolescents. It includes different domains (Psychosocial health, physical functioning, emotional functioning, social functioning, and school functioning). When completing the PedsQL questionnaires, respondents were asked to provide a response on a 5-point scale ranging from 0 (never a problem) to 4 (almost always a problem). Responses were then transformed to a 0 to 100 score, with higher scores reflecting better quality of life. |
| Change in PRO Over Time Assessed Using Pediatric Quality of Life Inventory (PedsQL) Sickle Cell Disease Module (SCD) for Participants Greater Than or Equal to (≥) 12 and Less Than (<) 18 Years of Age | 2 years after exa-cel infusion | The PedsQL Sickle Cell Disease Module (PedsQL SCD) is a disease-specific module of the PedsQL. The tool measures self-reported health-related quality of life in participants with SCD across 9 domains: pain and hurt, pain impact, pain management (mgmt), worry I, worry II, emotions, treatment, communication I, and communication II. When completing the PedsQL SCD Module questionnaires, respondents were asked to provide a response on a 5-point scale ranging from 0 (never a problem) to 4 (almost always a problem). Responses were then transformed to a 0 to 100 score, with higher scores reflecting better quality of life. |
Countries
Belgium, Canada, France, Germany, Italy, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 63 participants were enrolled in the clinical trial after providing written informed consent and meeting the inclusion/exclusion criteria. Of these, 58 participants were initiated in the mobilization regimen, of which 46 participants proceeded to receive the exa-cel (exagamglogene autotemcel) infusion, forming the Full Analysis Set (FAS). The results are presented based on the FAS population.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 21.4 Years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 39 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 46 |
| other Total, other adverse events | 46 / 46 |
| serious Total, serious adverse events | 22 / 46 |
Outcome results
None listed