Conference Coverage

SCD, beta-thalassemia: CRISPR-based gene therapy `transformative’


 

FROM EHA 2023

The investigational gene therapy exagamglogene autotemcel (exa-cel) shows encouraging efficacy, safety, and patient-reported outcomes for transfusion-dependent beta-thalassemia and sickle cell disease (SCD), in findings that could lead to the first-ever approval of a therapy that utilizes CRISPR-Cas9 gene-editing.

Results from the prespecified interim analyses of the phase 3 CLIMB THAL-111 and CLIMB SCD-121 studies, presented at the European Hematology Association annual congress, show that patients with beta-thalassemia who received exa-cel were able to remain transfusion-free for up to 40.7 consecutive months, while in patients with sickle cell disease, the treatment likewise provided up to 36.5 months of freedom from vaso-occlusive crises.

The findings underscore that “exa-cel can provide a one-time, functional cure to patients with beta-thalassemia and sickle cell disease,” said coauthor Franco Locatelli, MD, of Catholic University of the Sacred Heart, Bambino Gesù Children’s Hospital, Rome.

In a comment, senior investigator Haydar Frangoul, MD, noted that, “with almost 4 years of follow-up on patients with beta-thalassemia and sickle cell disease, it appears that the benefit is holding.”

“The engraftment of our edited cells appears very stable over time. There is no reason to believe it will change,” said Dr. Frangoul, who is medical director of pediatric hematology/oncology, Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial, Nashville, Tenn.

Burden is high; current curative options have caveats

Patients with transfusion-dependent beta-thalassemia may require blood transfusions as often as every 2-5 weeks because of genetic mutations causing the absence of functional hemoglobin and subsequent depletions in red blood cells. And with hemoglobin being an iron-rich protein, patients are also at risk of an iron accumulation in the body, adding the possible need for uncomfortable iron chelation therapy to prevent organ damage.

The measures are burdensome, but the need is dire. Life expectancy in beta-thalassemia without them is only about 5 years.

With SCD, patients can face severe pain from vaso-occlusive crises as sickled red blood cells block blood flow, potentially causing hospitalization and complications including kidney failure or stroke.

A cure does already exist for both genetic disorders in the form of allogeneic stem cell transplantation. However, that option requires a matched related stem cell donor, and fewer than 20% of patients have accessibility to such donors.

Gene therapy

Gene therapy offers a potentially ideal alternative, providing a possible “functional cure” without the need for a donor, by instead harvesting patients’ cells, fixing the mutation and transferring them back to the patient.

The Food and Drug Administration already approved a first gene therapy, betibeglogene autotemcel (beti-cel), for children and adults with transfusion dependent beta-thalassemia, in August 2022.

While beti-cel utilizes a viral vector to insert functional copies of a modified gene into patients’ extracted hematopoietic stem cells before transfusing them back, exa-cel instead uses CRISPR-CAS9 technology to edit the gene, allowing the body to produce fetal hemoglobin, in an approach believed to be more precise and efficient.

“As we explain to patients, it’s a difference between gene addition, which is what beti-cel is, or gene editing, which is what exa-cel is,” Dr. Frangoul explained.

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