CRISPR, Vertex’s Gene Editing Based Therapy, CTX001 Prospers in Hemoglobinopathy Trials

By T. Chakraborty, Ph.D.

On June 12th, at the 25th Annual European Hematology Association (EHA) Congress, both companies presented updates from CLIMB-111 and CLIMB-121 trials that evaluated CTX001 in patients suffering from transfusion-dependent β-thalassemia and sickle cell disease respectively.

Genetic Blood Disorders

Beta-thalassemia and sickle cell disease (SCD) are both severe genetic blood disorders that have affected humans throughout the ages. β-thalassemia is characterized by little to no production of β-globin as a result of mutations in the beta-globin (HBB) gene, while SCD is an inherited disease where the red blood cells (RBCs) look like a “sickle.”

It is estimated that β-thalassemia will affect approximately 1 in 100,000 individuals and is most prevalent in the Mediterranean, Middle East, Africa, Central Asia, India, and the Far East [1]. The most severe form is termed as transfusion-dependent β-thalassemia (TDT), which is synonymous with severe anemia and permanent dependence on RBC transfusion.

The death rate for SCD in the U.S., as estimated by the Centre of Disease Control (CDC) is approximately 100,000 and is particularly common in African American and Hispanic-American of this region [2]. For patients living with SCD, bone marrow transfer, blood transfer is mandatory for survival. In both diseases, patients require extensive care and require frequent blood transfusions to survive. This can be very challenging with severe complications associated with blood transfusions, including an exact donor match.

Investigational CRISPR Based Therapy, CTX001

Both TDT and SCD are caused by a gene mutation that reduces hemoglobin amounts. CRISPR-Cas9 has been gaining a lot of attention in recent years as a probable tool for the treatment of genetic diseases. CTX001 is an investigational CRISPR based therapy resulting from a collaboration between CRISPR and Vertex. In this therapy, patient hematopoietic stem cells are isolated and genetically modified ex vivo using CRISPR technology to produce a high level of hemoglobin in RBCs. They are then re-introduced into the patients. Pre-clinical studies have shown that even though 5% of these cells can be retained, that is enough to produce normal levels of hemoglobin. In early 2019, CTX001 was fast-tracked for treating severe cases of TDT and SCD, which prompted the start of two clinical trials, namely CLIMB-111 and CLIMB-121 [3].

CLIMB-111 and CLIMB-121 Trials

The CLIMB-111 trial is an open-label Phase1/2 clinical trial for severe TDT patients and currently has five enrolled patients. The update provided on the first two patients to receive this therapy showed promising results. Prior to CTX001 therapy, the patients suffered from severe TDT and required 34 and 61 units of packed RBCs yearly. Post CTX001 infusion, the patients are transfusion free, and their hemoglobin levels are 14.2g/dL and 12.5g/dL, respectively. Though for both the patients, two adverse events were reported, none of those events were related to the therapy suggesting that this CRISPR-based system is well tolerated.

Samarth Kulkarni, Ph.D., CEO of CRISPR Therapeutics, said, “With these new data, we are beginning to see early evidence of the potential durability of benefit from treatment with CTX001, as well as consistency of the therapeutic effect across patients. These highly encouraging early data represent one more step toward delivering on the promise and potential of CRISPR/Cas9 therapies as a new class of potentially transformative medicines to treat serious diseases.” in patients.

The CLIMB-121 trial is an open-label Phase1/2 clinical trial for severe SCD patients and currently has two enrolled patients. The update was only provided for the first patient. Prior to CTX001 therapy, the patients suffered from severe SCD, experienced seven vaso-occlusive crises (VOCs), and required four packed red blood cell transfusions per year. Post CTX001 infusion, the patients are transfusion free experienced no VOCs, and the hemoglobin levels have reached 11.8 g/dL. There were no safety issues related to therapy.

Reshma Kewalramani, M.D., CEO and President of Vertex, said, “The data announced today are remarkable, including the demonstration of a clinical proof-of-concept in TDT. While these are still early days, these data mark another important milestone for this program and for the field of gene editing. The results presented at this medical conference add to results previously shared, demonstrating that CRISPR/Cas9 gene editing has the potential to be a curative therapy for severe genetic diseases like sickle cell and beta-thalassemia.”

This CRISPR-based therapy gives hope to thousands of patients suffering from these diseases. However, it is to be noted that CRISPR is reported to have off-target effects. Also, the long-term safety and efficacy of this type of therapy are still under research. Further, other strategies are being utilized to treat these diseases. Earlier this year, researchers from Boston Children’s Hospital used a lentiviral approach to knockdown a protein for the treatment of SCD, which is also currently under clinical trial [3,4].

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: Successful Gene-Editing to Reverse Deafness Scores Another Win for Gene Therapy

References

1. https://pubmed.ncbi.nlm.nih.gov/31882227/
2. https://www.cdc.gov/ncbddd/sicklecell/treatments.html
3. http://www.crisprtx.com/about-us/press-releases-and-presentations/crispr-therapeutics-and-vertex-announce-new-clinical-data-for-investigational-gene-editing-therapy-ctx001-in-severe-hemoglobinopathies-at-the-25th-annual-european-hematology-association-eha-congress
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150438/

Author

Tulip Chakraborty