CRISPR Therapy (CTX001) for Thalassemia

Recruiting at 11 trial locations

Overseen By Medical Information

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Vertex Pharmaceuticals Incorporated

Disqualifiers: Prior HSCT, Sickle cell variant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to test a new treatment called CTX001 for individuals with thalassemia, specifically targeting those with a severe form requiring regular blood transfusions. The treatment employs a cutting-edge gene editing tool, CRISPR, to modify certain blood cells and enhance their function. Suitable participants have a history of frequent blood transfusions and meet specific genetic criteria related to thalassemia. The goal is to determine the safety and effectiveness of this single-dose treatment in improving health and reducing the need for transfusions. As a Phase 3 trial, this represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

Is there any evidence suggesting that CTX001 is likely to be safe for humans?

Research has shown that CTX001, a treatment using CRISPR technology, was safe in earlier studies with patients who have transfusion-dependent thalassemia (TDT). In these studies, all 15 patients who received CTX001 no longer needed regular blood transfusions.

Most patients handled the treatment well. Reports indicate that 91% of patients became independent of transfusions after the therapy, suggesting its safety. Additionally, in a group of patients with sickle cell disease, a related condition, all remained free of severe complications after treatment.

Although the treatment remains under study, these results are promising for its safety. CTX001's presence in a later stage of clinical trials indicates it has already passed earlier safety tests. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for thalassemia, which often involve regular blood transfusions and iron chelation therapy, CTX001 offers a groundbreaking approach by using CRISPR-Cas9 gene-editing technology. This treatment works by modifying the patient's own hematopoietic stem cells to boost fetal hemoglobin production, potentially reducing or even eliminating the need for transfusions. Researchers are excited because this approach targets the underlying genetic cause of the disease rather than just managing symptoms, offering hope for a more permanent solution.

What evidence suggests that CTX001 might be an effective treatment for thalassemia?

Research has shown that CTX001, the treatment under study in this trial, offers promising results for people with transfusion-dependent thalassemia (TDT). In earlier studies, many patients treated with CTX001 no longer required regular blood transfusions. CTX001 employs a technique called CRISPR-Cas9 gene editing to increase fetal hemoglobin levels in the blood, addressing the genetic issue causing thalassemia. Studies have consistently found the treatment to be safe and effective, making it a potentially life-changing option for those with this condition. ^{3 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for children with Transfusion-Dependent β-Thalassemia (TDT) who need regular blood transfusions and are suitable for a stem cell transplant. They must have specific genetic forms of TDT confirmed by the study's lab. Those with a perfect match donor, previous transplants, certain sickle cell disease variants, or active infections can't participate.

Inclusion Criteria

I have needed regular blood transfusions for at least 6 months.

I have been diagnosed with Thalassemia and my condition is confirmed by genetic testing.

I am considered a good candidate for a stem cell transplant using my own cells.

Exclusion Criteria

I have had a stem cell transplant before.

I have the sickle cell β-thalassemia variant.

I have a healthy, fully matched donor for my treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of CTX001 through a central venous catheter

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• CTX001

Trial Overview The trial tests CTX001, which involves editing patients' own stem cells using CRISPR-Cas9 technology to potentially treat TDT. It's an open-label study where all participants receive one dose of the modified cells after a conditioning regimen.

How Is the Trial Designed?

Group I: CTX001 Experimental Treatment 1 Intervention

CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Participants will receive single infusion of CTX001 through central venous catheter.

CTX001 is already approved in European Union, United States for the following indications:

Approved in European Union as CTX001 for:

• Transfusion-dependent β-thalassemia (TDT)
• Severe sickle cell disease (SCD)

Approved in United States as CTX001 for:

• Transfusion-dependent β-thalassemia (TDT)
• Severe sickle cell disease (SCD)

Who Is Running the Clinical Trial?

Vertex Pharmaceuticals Incorporated

Lead Sponsor

Trials

267

Recruited

36,100+

Dr. David Altshuler

Vertex Pharmaceuticals Incorporated

Chief Medical Officer since 2020

MD, PhD

Dr. Reshma Kewalramani

Vertex Pharmaceuticals Incorporated

Chief Executive Officer since 2020

MD, trained in internal medicine and nephrology

CRISPR Therapeutics

Industry Sponsor

Trials

7

Recruited

630+

Published Research Related to This Trial

A CRISPR/Cas9 genome-editing approach successfully targeted the HBG promoters to mimic a natural mutation that increases fetal hemoglobin (HbF) levels, showing promise for treating β-thalassemia.

In experiments with hematopoietic stem and progenitor cells from β0-thalassemia patients, a 20% editing efficiency led to a corresponding 20% increase in HbF, indicating the potential for this method to induce therapeutic levels of HbF across various β-thalassemia types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of therapeutic levels of HbF in genome-edited primary &#946;0 39-thalassaemia haematopoietic stem and progenitor cells. Mingoia, M., Caria, CA., Ye, L., et al.[2021]

CRISPR/Cas9 gene editing technology shows promise as a curative treatment for β-thalassemia by enabling precise genome editing, which can help patients avoid complications associated with traditional treatments like graft-versus-host disease (GVHD) and graft rejection.

Current clinical trials are focusing on strategies to reactivate γ-globin and increase fetal hemoglobin production in hematopoietic stem cells, highlighting the potential of CRISPR-based therapies to address the underlying genetic causes of β-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR/Cas-based gene editing in therapeutic strategies for beta-thalassemia. Zeng, S., Lei, S., Qu, C., et al.[2023]

A novel CRISPR/Cas9-based gene-editing strategy targeting the HBB gene for beta-thalassemia showed approximately 50% efficiency in co-transfecting CRISPR and donor template plasmids in HEK293 cells, with a subsequent HDR efficiency of about 37.5%.

The study successfully isolated HDR-positive cells using a combination of selection markers and negative selection methods, indicating that this approach could be a promising avenue for developing effective gene therapies for beta-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design Principles of a Novel Construct for HBB Gene-Editing and Investigation of Its Gene-Targeting Efficiency in HEK293 Cells. Lotfi, M., Ashouri, A., Mojarrad, M., et al.[2023]

CRISPR-Cas9 gene editing shows promise in correcting β-thalassemia mutations and enhancing the production of adult hemoglobin (HbA), which could significantly benefit patients with this hereditary disease.

The review suggests combining CRISPR-Cas9 gene editing with pharmacological methods to induce fetal hemoglobin (HbF) as a safer alternative to reduce potential genotoxicity associated with multiplex gene editing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined approaches for increasing fetal hemoglobin (HbF) and de novo production of adult hemoglobin (HbA) in erythroid cells from &#946;-thalassemia patients: treatment with HbF inducers and CRISPR-Cas9 based genome editing. Finotti, A., Gambari, R.[2023]

A novel genome editing strategy using Cas9 and AAV6 successfully introduced natural mutations that increase γ-globin expression, which is beneficial for treating β-thalassemia, in both cell lines and primary cells from patients.

The edited hematopoietic stem and progenitor cells (HSPCs) not only showed increased γ-globin levels but also retained their ability to reconstitute blood cell production long-term in a mouse model, indicating potential for effective and lasting treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of Fetal Hemoglobin by Introducing Natural Hereditary Persistence of Fetal Hemoglobin Mutations in the γ-Globin Gene Promoters for Genome Editing Therapies for β-Thalassemia. Lu, D., Xu, Z., Peng, Z., et al.[2023]

The DARE (disruption of aberrant regulatory elements) technique effectively corrected β-globin expression in IVSI-110(G>A) β-thalassemia transgenic cells, showing potential for targeted repair of various disease-causing mutations.

This method demonstrated high efficiency and flexibility, suggesting it could be applied to at least 14 known thalassemia mutations and other inherited diseases, paving the way for personalized therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Scope for Thalassemia Gene Therapy by Disruption of Aberrant Regulatory Elements. Patsali, P., Mussolino, C., Ladas, P., et al.[2020]

The study demonstrates that targeting specific mutations in thalassemia, such as IVS1-110G>A and IVS2-654C>T, using advanced gene-editing techniques (Cas9 and Cas12a/Cpf1) in hematopoietic stem cells can effectively restore normal gene function.

This approach shows high efficiency in correcting mutations and reversing abnormal splicing in blood cells, suggesting it could significantly benefit patients with transfusion-dependent β-thalassemia by potentially reducing their need for transfusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Editing aberrant splice sites efficiently restores β-globin expression in β-thalassemia. Xu, S., Luk, K., Yao, Q., et al.[2022]

Using CRISPR-Cas9 to edit the BCL11A enhancer in CD34+ cells from two patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) resulted in over 80% successful gene modification without off-target effects.

Both patients showed significant clinical improvements, including high levels of fetal hemoglobin, transfusion independence, and elimination of vaso-occlusive episodes in the SCD patient, more than a year after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. Frangoul, H., Altshuler, D., Cappellini, MD., et al.[2021]

CRISPR/Cas9 successfully corrected β-thalassemia mutations in patient-specific induced pluripotent stem cells (iPSCs), promoting the development of healthy hematopoietic stem cells (HSCs) in laboratory mice.

The corrected HSCs expressed normal β-globin (HBB) without causing tumors in various organs after implantation, indicating a safe and effective approach for personalized treatment of β-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Combination of CRISPR/Cas9 and iPSC Technologies in the Gene Therapy of Human β-thalassemia in Mice. Ou, Z., Niu, X., He, W., et al.[2018]

Citations

1. crisprtx.com crisprtx.com/about-us/press-releases-and-presentations/positive-results-from-pivotal-trials-of-exa-cel-for-transfusion-dependent-beta-thalassemia-and-severe-sickle-cell-disease-presented-at-the-2023-annual-european-hematology-association-eha-congress

Positive Results From Pivotal Trials of exa-cel… All patients treated with exa-cel demonstrated clinical benefit, and these data continue to demonstrate the potentially transformative profile ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2031054

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β ... Safety and efficacy of CTX001 in patients with transfusion-dependent β-thalassemia or sickle cell disease: early results from the CLIMB THAL ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10112499/

5612617 EFFICACY AND SAFETY OF A SINGLE DOSE ... Exagamglogene autotemcel(exa-cel; formerly known as CTX001) is a cell therapy designed to reactivate HbF via non-viral, ex vivo CRISPR/Cas9 gene-editing at the ...

4. ashpublications.org ashpublications.org/ashclinicalnews/news/8012/Full-Results-of-Exa-Cel-Study-Show-Continued

Full Results of Exa-Cel Study Show Continued Safety, Efficacy ... The study met both its primary and secondary endpoints: of the 30 evaluable patients, 97% were free from VOCs for at least 12 consecutive months, and 100% were ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05477563

Study Details | NCT05477563 | Evaluation of Efficacy and ... Evaluation of Efficacy and Safety of a Single Dose of CTX001 in Participants With Transfusion-Dependent β-Thalassemia and Severe Sickle Cell Disease.

6. ir.crisprtx.com ir.crisprtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-present-new-data-22-patients

Press Release Beta thalassemia: All 15 patients were transfusion independent after CTX001 infusion - - Sickle cell disease: All seven patients were free of vaso-occlusive ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38657265/

Exagamglogene Autotemcel for Transfusion-Dependent β- ... Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent β-thalassemia.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118692341

Safety and Efficacy of CTX001 in Patients with Transfusion- ... All 5 patients with TDT have been transfusion-free since ~2 months after CTX001 infusion and the 2 patients with severe SCD have had no VOCs ...