Casgevy markedly reduced rates of VOCs in SCD patients: Trial data

Now-approved gene-editing therapy was tested in Phase 2/3 clinical study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with the gene-editing therapy Casgevy (exagamglogene autotemcel) substantially decreased the rates of painful vaso-occlusive crises (VOCs) among people with sickle cell disease taking part in a Phase 2/3 clinical trial.

Full results from the trial, which supported the recent approvals of Casgevy in the U.S., the U.K., and the European Union, were detailed in “Exagamglogene Autotemcel for Severe Sickle Cell Disease,” a study published in The New England Journal of Medicine.

“Treatment with [Casgevy] eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more,” the researchers wrote.

The work was funded by Casgevy’s co-developers Vertex Pharmaceuticals and CRISPR Therapeutics. The companies last month received priority review for an application seeking the approval of Casgevy in Canada.

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Sickle cell is caused by mutations that lead to the production of an abnormal version of the adult form of hemoglobin — the protein red blood cells use to carry oxygen through the body. The abnormal version of adult hemoglobin tends to form clumps inside red blood cells, deforming them into the sickle-like shape that gives the disease its name. Sickled red blood cells can obstruct blood vessels, driving VOCs and leading to other disease symptoms.

An alternative version of hemoglobin, called fetal hemoglobin, or HbF, is usually made in early fetal development, but stops being produced shortly after birth. Casgevy is a gene-editing therapy that uses a technology called CRISPR/Cas9 to increase the production of HbF in blood cells, thereby counteracting the disease-driving effects of the mutated version of the adult form of the protein.

Essentially, treatment with Casgevy entails collecting hematopoietic stem cells, or blood cell precursors, from a patient’s bone marrow, engineering them in the lab to boost the production of HBF, and then returning them to the patient via a stem cell transplant. The modified stem cells can then give rise to new blood cells capable of producing HBF.

As part of the procedure, patients need to undergo a chemotherapy conditioning regimen that basically works to destroy existing stem cells in the bone marrow, making room for the engineered stem cells to grow.

Approvals of Casgevy for sickle cell were based on data from a Phase 2/3 trial called CLIMB-121 (NCT03745287), conducted at sites in North America and Europe. As of the analysis for this study, a total of 44 patients had been treated with Casgevy in the trial and had been followed for a median of slightly longer than 19 months, or about 1.5 years.

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.

Prior to receiving Casgevy, the study participants had experienced a mean of four severe VOCs per year, spending nearly three weeks each year in the hospital due to pain crises.

The study’s main goal was to see if Casgevy could prevent severe VOCs for at least one consecutive year. The data showed that, of the 30 patients who had been followed long enough to be evaluated, 29 or 97% were completely free from severe VOCs in the first year. The exception was a patient who had a history of chronic pain related to sickle cell. However, while the patient was not completely free from pain crises, there were no VOCs that required hospitalization.

Patients who met the study’s main goal remained free of VOCs for a mean period of 22.4 months, or nearly two years.

Moreover, all 30 patients included in the analysis were free from hospitalization due to VOCs for at least one consecutive year, meeting the study’s key secondary goal.

“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,” Stephan Grupp, MD, PhD, study co-author at the Children’s Hospital of Philadelphia, said in a press release.

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Biomarker data from the trial indicated that Casgevy increased HBF levels as expected. Data from patients on measures of pain and quality of life also tended to improve following treatment with Casgevy.

“Patient-reported outcome measures supported clinically meaningful improvements in pain, health and disease status, and general well-being,” the researchers wrote.

All of the patients in the study experienced at least one side effect after receiving Casgevy, and nearly all experienced serious side effects, including inflammation in the mouth (stomatitis), severely decreased appetite, fever, and low blood cell counts. These usually occurred soon after receiving the therapy, and were generally linked to the chemotherapy conditioning regimen, and not to Casgevy itself.

Overall, the researchers said the safety profile of Casgevy was consistent with what would be expected in the context of a conditioning regimen and a bone marrow transplant.

One participant in the study died from COVID-19 a few months after receiving Casgevy. This death was deemed to be unrelated to Casgevy, though investigators said the chemotherapy conditioning regimen likely weakened the patient’s immune system, setting the stage for a severe infection.

An extension study called CLIMB-131 (NCT04208529), slated to continue through 2039, is collecting long-term data on patients who received Casgevy in this study.

“Data from the follow-up studies may provide insight into the proportion of patients who continue to have vaso-occlusive crises after treatment and the long-term safety of the treatment,” the researchers wrote.