CRISPR-Cas9 Gene Editing for Beta Thalassemia

Not currently recruiting at 22 trial locations

Overseen By Medical Information

Age: < 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Vertex Pharmaceuticals Incorporated

Disqualifiers: Prior allo-HSCT, Sickle cell, others

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

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: 25

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called CTX001 for individuals with transfusion-dependent beta thalassemia (TDT), a blood disorder requiring regular red blood cell transfusions. The goal is to assess the safety and effectiveness of this gene-editing therapy in potentially reducing or eliminating the need for these transfusions. Participants will receive a single infusion of their own modified stem cells, altered to improve blood production. This trial suits those diagnosed with TDT who have required regular transfusions over the past two years. As a Phase 2, Phase 3 trial, it measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the trial team for guidance.

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

Research has shown that CTX001, a gene editing treatment using CRISPR-Cas9, offers promising safety results for individuals with transfusion-dependent beta thalassemia. In earlier studies, most patients no longer required blood transfusions after receiving CTX001, indicating the treatment's effectiveness and providing insight into its safety.

Reports from these studies indicate that patients generally tolerated the treatment well. Although specific side effects were not detailed, the high success rate of patients becoming independent of transfusions suggests that serious side effects are likely uncommon. However, as with any medical treatment, potential risks exist, so discussing these with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for beta thalassemia?

Unlike the standard treatments for beta thalassemia, which often involve regular blood transfusions and iron chelation therapy, CTX001 represents a groundbreaking approach by using CRISPR-Cas9 gene editing technology. This treatment modifies the patient's own stem cells to reactivate fetal hemoglobin production, potentially reducing or eliminating the need for transfusions altogether. Researchers are excited about CTX001 because it targets the root cause of the disease at the genetic level, offering a one-time treatment with the potential for a lasting cure, rather than just managing symptoms.

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

Research has shown that CTX001, the treatment under study in this trial, offers promising results for treating individuals with transfusion-dependent beta thalassemia. In one study, 91% of patients who received this treatment no longer required regular blood transfusions. This therapy employs a tool called CRISPR-Cas9 to modify genes in patients' stem cells, aiming to address the root cause of the disease. The goal is to increase fetal hemoglobin, potentially improving patients' health. These findings suggest that CTX001 could effectively manage beta thalassemia. ^{2 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for individuals with transfusion-dependent β-thalassemia, which means they need regular blood transfusions due to their condition. They should have a history of significant blood transfusion needs and be suitable for an autologous stem cell transplant. People with certain genetic variations of thalassemia or active infections, low white blood cell or platelet counts can't participate.

Inclusion Criteria

I've had significant blood transfusions in the last 2 years.

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

I have been diagnosed with transfusion-dependent β-thalassemia.

Exclusion Criteria

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

White blood cell (WBC) count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism

I have had a stem cell transplant from a donor.

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

24 months

Regular visits (in-person and virtual) over 24 months

What Are the Treatments Tested in This Trial?

Interventions

• CTX001

Trial Overview The study is testing CTX001, which involves modifying the patient's own stem cells using CRISPR-Cas9 technology to potentially treat β-thalassemia. It's a single-dose study looking at both safety and how well it works in improving the condition.

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 a single infusion of CTX001 through a 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

Using a combination of single-strand oligodeoxynucleotides and high-fidelity CRISPR/Cas9, researchers achieved a highly efficient and seamless correction of the β-thalassemia mutation in patient-specific induced pluripotent stem cells (iPSCs).

The corrected iPSCs showed minimal off-target effects and expressed normal β-globin transcripts when differentiated into hematopoietic progenitor cells, indicating a safe and effective approach for potential cell therapy in treating β-thalassemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection. Liu, Y., Yang, Y., Kang, X., et al.[2020]

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]

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]

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]

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]

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… “This therapy offers the potential of a functional cure for patients with transfusion-dependent beta thalassemia or severe sickle cell disease ...

2. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2309673

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.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05477563

Study Details | NCT05477563 | Evaluation of Efficacy and ... The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 modified CD34+ human hematopoietic stem and progenitor cells (hHSPCs) using CTX001.

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

5612617 EFFICACY AND SAFETY OF A SINGLE DOSE ... Elevated fetal hemoglobin(HbF) is associated with improved outcomes in patients(pts) with transfusion-dependent β-thalassemia(TDT) and sickle cell disease(SCD).

6. 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.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03655678?term=CTX001&spons=CRISPR%20Therapeutics,%20Vertex&viewType=Table&rank=4

A Safety and Efficacy Study Evaluating CTX001 in ... Data collected at the beginning of a clinical study for all participants and for each arm or comparison group. These data include demographics, such as age, sex ...

8. 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 ...