Casgevy (exagamglogene autotemcel) for sickle cell disease
Fact-checked by What is Casgevy for sickle cell disease?
Casgevy (exagamglogene autotemcel) is an approved gene-editing therapy used for people with sickle cell disease (SCD) who experience recurrent vaso-occlusive crises (VOCs). It is designed to reduce the frequency and severity of these painful events.
Mutations in the HBB gene cause SCD by leading to the production of a faulty version of hemoglobin (the protein that helps red blood cells transport oxygen), which tends to clump inside red blood cells, deforming them into a sickle-like shape. These sickled red blood cells can block blood vessels, leading to VOCs and other symptoms.
Casgevy uses a gene-editing technology called CRISPR/Cas9 to increase the production of fetal hemoglobin. This alternative version of hemoglobin is produced during early fetal development and is more effective transporting oxygen than its adult counterpart. However, shortly after birth, a protein called BCL11A instructs the body to slow fetal hemoglobin production and make more of the adult type, which is susceptible to sickle cell mutations.
The treatment involves collecting a patient’s hematopoietic stem cells, the precursors that give rise to all blood cell types. These cells are edited in a lab to reduce the activity of BCL11A, then returned to the patient via a stem cell transplant.
Once in the body, the edited stem cells can engraft, or survive and multiply, in the bone marrow, giving rise to healthy blood cells that produce fetal hemoglobin. This is expected to help prevent red blood cell sickling and reduce VOC frequency and severity.
CRISPR Therapeutics and Vertex Pharmaceuticals collaborated to develop Casgevy, which is administered via a one-time intravenous or into-the-vein infusion. In addition to SCD, Casgevy also is approved to treat a related condition called transfusion-dependent beta thalassemia.
Therapy snapshot
| Brand name | Casgevy |
| Chemical name | Exagamglogene autotemcel |
| Usage | Used to reduce the frequency and severity of vaso-occlusive crises in sickle cell disease |
| Administration | Intravenous infusion |
Who with sickle cell disease can take Casgevy?
In the U.S., Casgevy is approved for the treatment of people with SCD, ages 2 and older, who experience recurrent VOCs. The therapy earned similar approvals in other regions, including conditional approvals in U.K. and the European Union, although age ranges vary.
Casgevy’s prescribing information doesn’t list any contraindications to its use. However, it shouldn’t be used in people with active human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus infections. It is also not recommended for people who have previously received a stem cell transplant.
How is Casgevy administered in sickle cell disease?
Manufacturing and administering Casgevy requires several steps:
- Deciding if Casgevy is appropriate: Professionals at an authorized treatment center work with patients and families to determine if a patient is eligible for treatment.
- Discontinuing other disease-modifying therapies: This typically occurs at least eight weeks before starting the rest of the process. Patients may receive extra blood transfusions during this period to maintain hemoglobin levels within a safe threshold.
- Stem cell collection: Over two or three consecutive days, patients will receive a medication like plerixafor, which causes hematopoietic stem cells to move into the bloodstream, where they can be collected via a process called apheresis. Some patients may need to have another round of cell collection at least two weeks later.
- Casgevy manufacturing: A laboratory edits the stem cells, freezes them, and then ships them to the patient’s healthcare provider. This may take up to six months.
- Conditioning: About two to seven days before the Casgevy infusion, patients receive a round of high-dose chemotherapy to destroy unhealthy blood stem cells and make room for the new modified ones.
- Casgevy infusion: The edited stem cells are returned to the patient via an intravenous infusion. Dosing is based on body weight, with a minimum recommended dose of 3 million cells per kilogram of body weight.
- Inpatient recovery: Patients typically stay in the treatment center for about four to six weeks while recovering from the procedure.
While the timeline can vary, the entire process may take up to one year.
Casgevy in sickle cell disease clinical trials
Two clinical studies, the Phase 2/3 CLIMB-121 trial (NCT03745287) and the Phase 3 CLIMB-151 (NCT05329649), supported Casgevy’s regulatory approval for SCD in the U.S.:
- CLIMB-121 included adults and adolescents, ages 12 to 35, with severe SCD, who had at least two VOCs each year in the two years before screening. In total, 44 participants went through conditioning and received a single dose of Casgevy. The main goal was to determine the proportion of participants who went at least 12 consecutive months without experiencing VOCs in the two years after receiving Casgevy. Data showed that 93.5% of the 31 participants with evaluable follow-up data achieved this outcome. Additionally, none of the evaluable patients required hospitalization for VOCs for at least 12 months in a row after receiving Casgevy.
- CLIMB-151 had a similar design and included 11 children, ages 5 to 11, with severe sickle cell and recurrent VOCs who received a one-time Casgevy infusion. Eight of them were followed for at least 16 months after receiving Casgevy and comprised the trial’s main efficacy population. Data showed that all eight children remained free of VOCs for at least 12 consecutive months. None had to be hospitalized for severe VOCs for 12 months in a row.
Casgevy side effects
The most common side effects of Casgevy in people with SCD include:
- inflammation of the mucous membranes lining the mouth and gastrointestinal tract, known as mucositis
- decreased appetite
- low counts of immune neutrophils accompanied by fever, called febrile neutropenia
- low counts of other blood cell types, including platelets, white blood cells, and red blood cells
The therapy carries warnings for other potentially serious side effects, including:
- allergic reactions, including a life-threatening reaction called anaphylaxis
- complications with engraftment, the process through which infused stem cells take hold and begin producing new blood cells
- off-target gene editing
Engraftment issues are especially concerning for platelets, the small cell fragments that promote blood clotting, so patients should be monitored for bleeding. Failure of engraftment is also possible, which could affect production of neutrophils and other white blood cells, so regular blood tests are important during follow-up.
It is also possible that gene-editing therapies like Casgevy may mistakenly edit portions of DNA other than those intended. While this hasn’t been observed with Casgevy, the risk cannot be ruled out, and the potential clinical significance of this off-target editing remains unclear.
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