CTX001: CRISPR Therapeutics and Vertex Present Positive Clinical Data for Investigational Gene-Editing Therapy CTX001™ in Severe Hemoglobinopathies

  Highlights 

- CTX001 is an investigational ex vivo CRISPR gene-edited therapy that is being evaluated for patients suffering from TDT or severe SCD
- CTX001 is being developed under a co-development and co-commercialization agreement between - CRISPR Therapeutics and Vertex.
- Received Fast Track Designation from FDA
- Clinical studies showed positive results with increased HbF & free of vaso-occlusive crises (Date presented in ASH 2020)


CTX001 is an investigational ex vivo CRISPR gene-edited therapy that is being evaluated for patients suffering from TDT or severe SCD in which a patient’s hematopoietic stem cells are engineered to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is a form of the oxygen-carrying hemoglobin that is naturally present at birth, which then switches to the adult form of hemoglobin. The elevation of HbF by CTX001 has the potential to alleviate transfusion requirements for TDT patients and reduce painful and debilitating sickle crises for SCD patients.

Platform 
Patients who enroll in these trials will have their own hematopoietic stem and progenitor cells collected from peripheral blood. The patient’s cells will be edited using the CRISPR/Cas9 technology. The edited cells, CTX001, will then be infused back into the patient as part of a stem cell transplant, a process which involves, among other things, a patient being treated with myeloablative busulfan conditioning. Patients undergoing stem cell transplants may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of CTX001. Patients will initially be monitored to determine when the edited cells begin to produce mature blood cells, a process known as engraftment. After engraftment, patients will continue to be monitored to track the impact of CTX001 on multiple measures of disease and for safety.

Regulatory Status: 
CTX001 has been granted Regenerative Medicine Advanced Therapy (RMAT) from the U.S. FDA, Orphan Drug Designation from both the FDA and the European Medicines Agency (EMA), and Fast Track Designation from the FDA for both SCD and TDT.

CLIMB-121 for Sickle Cell Disease (NCT03745287)
The ongoing Phase 1/2 open-label trial, CLIMB-SCD-121, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 18 to 35 with severe SCD. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.

Primary Outcome Measures :
  • Proportion of subjects with HbF ≥20%, sustained for at least 3 months at the time of analysis, starting 6 months after CTX001 infusion [ Time Frame: 6 months up to 2 years after CTX001 infusion ]
  • Proportion of subjects with engraftment (absolute neutrophil count [ANC] ≥500/µL for three consecutive days) [ Time Frame: Within 42 days after CTX001 infusion ]
  • Time to engraftment [ Time Frame: From CTX001 infusion up to 2 years after CTX001 infusion ]
  • Frequency and severity of collected adverse events (AEs) [ Time Frame: From screening to 2 years after CTX001 infusion ]
  • Incidence of transplant-related mortality (TRM) within 100 days after CTX001 infusion [ Time Frame: Within 100 days after CTX001 infusion ]
  • Incidence of TRM within 1 year after CTX001 infusion [ Time Frame: Within 1 year after CTX001 infusion ]
  • All-cause mortality [ Time Frame: 2 years after mobilization ]
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

Efficacy Outcome
  • Increased HbF was observed in all subjects treated with CTX001 infusion
  • One Patient is free of vaso-occlusive crises up to  9 months after CTX001 infusion

Safety Outcome
  • The majority of AEs occurred within the first 60 days after CTX001 infusion 
  • 1 patient experienced SAEs related to plerixafor: chest pain, neck pain, headache, and abdominal pain; all resolved 
  • Post-CTX001, only 1 patient experienced SAEs: sepsis (relatedto busulfan), cholelithiasis, and abdominal pain (both unrelated to any study drug); all resolved 
  • There were no SAEs related to CTX001



CLIMB-111 for Severe Thalassemia (NCT03655678)
The ongoing Phase 1/2 open-label trial, CLIMB-Thal-111, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 18 to 35 with TDT. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.

Primary Outcome Measures :
  • Proportion of subjects achieving transfusion reduction for at least 6 months (TR6) [ Time Frame: From 3 to 24 months post-CTX001 infusion ]
  • Proportion of subjects with engraftment (absolute neutrophil count [ANC] ≥500/µL for three consecutive days) [ Time Frame: Within 42 days after CTX001 infusion ]
  • Time to neutrophil and platelet engraftment [ Time Frame: Days post-infusion to engraftment ]
  • Frequency and severity of collected adverse events (AEs) [ Time Frame: Signing of informed consent through Month 24 visit ]
  • Incidence of transplant-related mortality (TRM) [ Time Frame: Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion ]
  • All-cause mortality [ Time Frame: Signing of informed consent through Month 24 visit ]
Criteria
Key Inclusion Criteria:
  • Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by:
    • Documented homozygous β-thalassemia or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE). Subjects 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 mL/kg/year or ≥10 units/year of packed RBC transfusions in the prior 2 years before signing the consent or the last rescreening for patients going through re-screening.
  • Eligible for autologous stem cell transplant as per investigator's judgment.

Key Exclusion Criteria:

  • An available 10/10 Human Leukocyte Antigen (HLA)-matched related donor.
  • Prior allo-HSCT.
  • Subjects with associated α-thalassemia and >1 alpha chain deletion or alpha multiplications.
  • Subjects with sickle cell beta thalassemia variant.
  • Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator.
  • White blood cell (WBC) count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism.

Efficacy Outcome
  • Increased HbF levels in TDT subjects after infusion of CTX001
  • The first 10 patients treated with CTX001 have been followed for 3.8 to 21.5 months and have stopped transfusions (TDT) and are VOC-free (SCD)
Increased HbF in TDT subjects after infusion of CTX001

Safety Outcome
  • Majority of AEs occurred within first 60 days after CTX001 infusion 
  • 2 patients experienced a combined total of 5 SAEs related or possibly related to busulfan only: venoocclusive liver disease (in both patients), febrile neutropenia (2 events in 1 patient), and colitis; all resolved 
  • One patient experienced 4 SAEs related or possibly related to CTX001: headache, haemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, and idiopathic pneumonia syndrome (latter also related to busulfan). All SAEs occurred in the context of HLH and have resolved. 
  •  No CTX001-related SAEs were reported in the other patients
Source
Clinicaltrials.gov
CRISPR Therapeutics/ Vertex (ASH2020 Presentation)

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