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Nearly all people with sickle cell disease (SCD) treated with the U.S.-approved gene-editing therapy Casgevy (exagamglogene autotemcel) were free of painful vaso-occlusive crises (VOCs) for at least one year, according to new data from a Phase 2/3 clinical trial.

These updated results were presented at the annual European Hematology Association (EHA) Congress, held June 13-16, in Spain, as announced by Vertex Pharmaceuticals, the company that co-developed the therapy along with CRISPR Therapeutics.

Data also showed that Casgevy sustainably improved quality of life, which included physical, emotional, and social/family factors, as well as functional well-being and overall health status.

“The transformative benefit seen in patients with sickle cell disease in the trial is impressive given the significant and cumulative burden of disease faced by people living with this blood disorder,” Haydar Frangoul, MD, medical director of pediatric hematology and oncology at the Sarah Cannon Research Institute and the TriStar Centennial Children’s Hospital, in Tennessee, said in a company press release.

“I am eager to offer this therapy and the opportunity of a potential functional cure to my eligible patients,” Frangoul added.

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Casgevy uses gene-editing tool CRISPR/Cas9 to modify red blood cells

Sickle cell disease, or SCD for short, is marked by the production of an abnormal version of the adult form of hemoglobin — the protein in red blood cells that carries oxygen through the body. Abnormal hemoglobin tends to form clumps, deforming red blood cells into a sickle-like shape. The misshaped cells die prematurely and can block blood vessels, driving VOCs and other disease symptoms.

Before birth, an alternative version of hemoglobin, called fetal hemoglobin, or HbF, is made by the human body. However, shortly after birth, HbF production stops in favor of the adult form of the protein. Casgevy uses the gene-editing tool CRISPR/Cas9 to increase HbF production in red blood cells, with the goal of reducing the frequency and severity of VOCs.

In an initial step, blood stem cells from a patient’s bone marrow are collected and edited in a lab to boost HbF production. Modified cells are then returned to the patient via a stem cell transplant. These cells are then expected to give rise to new red blood cells that are capable of producing HbF.

Before edited cells are returned to the patient’s body, the individual must complete a chemotherapy regimen that destroys existing stem cells, making room for the new ones to be taken in and grown.

In a Phase 2/3 trial called CLIMB-121 (NCT03745287), 46 SCD patients have now received Casgevy. Of these, 17 completed two years of follow-up and have enrolled in CLIMB-131 (NCT04208529), an extension study that will collect long-term data.

New data, described in an oral presentation titled “Exagamglogene Autotemcel For Severe Sickle Cell Disease,” were in line with previously reported published data.

Of the 39 evaluable patients with at least 16 months of follow-up, all but three — 36 or 92.3% — were free from VOCs for at least one year. The mean time without such crises was 27.9 months, or a little longer than two years, extending to a maximum of 54.8 months, or 4.6 years. Moreover, 38 patients (97.4%) were free from VOC-related hospitalizations for at least one year.

Blood tests also showed that total hemoglobin levels remained in the normal range, while HbF steadily rose to 40% or more at six months and was produced by more than 90% of red blood cells.

These results confirm the potential for [Casgevy] to provide a one-time functional cure to [patients] with severe SCD.

All treated patients had at least one adverse event after receiving Casgevy, most of which were mild or moderate, and all experienced serious side effects. The most common adverse events were nausea, mouth inflammation (stomatitis), vomiting, fever accompanied by low blood cell counts, headache, and itching. Most adverse events occurred within the first six months after treatment and were generally consistent with the chemotherapy regimen used before the transplant.

“These results confirm the potential for [Casgevy] to provide a one-time functional cure to [patients] with severe SCD,” the researchers wrote in the study abstract.