Researchers Publish Final Results of Key Clinical Trial for Gene Therapy for Sickle Cell Disease

Rare Daily Staff

A study of the gene therapy Casgevy for the treatment of sickle cell disease found that 96.7 percent of patients in the study did not have any blockages known as vaso-occlusive crises—painful hallmarks of the condition—for at least one year, and all were able to avoid hospitalization during that time.

A Children’s Hospital of Philadelphia-led international consortium published the final results of a key clinical trial of Casgevy for the treatment of sickle cell disease in patients 12 years and older with recurrent vaso-occlusive crises (VOCs). The study, published today in the New England Journal of Medicine, provide the complete details of the critical clinical trial that led to the FDA approval of Casgevy in December 2023.

SCD is an inherited blood disorder that affects the red blood cells, which are essential for carrying oxygen to all organs and tissues of the body. SCD causes severe pain, organ damage and shortened life span due to misshapen or “sickled” blood cells. People with SCD can experience painful blood vessel blockages, also known as vaso-occlusive crises (VOCs), that can lead to acute chest syndrome, stroke, jaundice, and symptoms of heart failure. Individuals may also experience anemia, which can result in end-organ damage and premature death. Most often, treatment is focused on relieving pain, minimizing organ damage, maintaining hydration, and addressing fevers, requiring medication and sometimes monthly blood transfusions and frequent hospital visits.

Casgevy, a cell-based gene therapy, uses CRISPR/Cas9, a type of genome editing technology. Patients’ hematopoietic stem cells are modified by genome editing using the technology. CRISPR/Cas9 can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. The modified blood stem cells are transplanted back into the patient where they engraft (attach and multiply) within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery. In patients with sickle cell disease, increased levels of HbF prevent the sickling of red blood cells.

“In this clinical trial, sickle cell patients who were having significant issues with their disease began to see their problems resolve within months and improve their quality of life significantly,” said senior study author Stephan Grupp, section chief of the Cellular Therapy and Transplant Section at CHOP and one of the principal investigators in the clinical trials that led to the approval of Casgevy.

The researchers conducted the CLIMB SCD-121 trial, a phase 3, single-arm, open-label study of Casgevy in patients between 12 and 35 years old with sickle cell disease and at least two severe VOCs in each of the two years before screening. The key primary endpoint of the study was a proportion of patients without severe VOCs for at least 12 consecutive months, with a secondary endpoint of patients who were free from inpatient hospitalization for severe VOCs for at least 12 consecutive months.

A total of 44 patients received treatment with a median follow up of 19.3 months. In a total of 30 patients with sufficient follow-up data to be evaluated, 29 were free of VOCs for at least 12 consecutive months. The safety of treatment was comparable to treatment with hematopoietic and progenitor stem cells, and no malignancies were reported as a result of treatment.

The study was supported by Vertex Pharmaceuticals and CRISPR Therapeutics, which market Casgevy.

Photo: Senior study author Stephan Grupp, section chief of the Cellular Therapy and Transplant Section at CHOP and one of the principal investigators in the clinical trials that led to the approval of Casgevy