CASGEVY™ Gene Therapy for Sickle Cell Disease and Beta Thalassemia

CASGEVY™ (exagamglogene autotemcel) is a one-time gene therapy treatment for people age 12 years or older with sickle cell disease or beta thalassemia. It uses a gene editing technology called CRISPR/Cas9 to modify patients’ own blood-forming stem cells. The treated cells then begin making new, healthy red blood cells.

CASGEVY works by enabling people to make a fetal form of hemoglobin that normally stops being made after birth. It does this by suppressing a gene that shuts off fetal hemoglobin production. This enables people to make healthy, functioning red blood cells, which has benefits for both sickle cell disease and beta thalassemia:

• In sickle cell disease, CASGEVY prevents red blood cells from sickling and clogging blood vessels. This reduces or eliminates serious pain crises and decreases or eliminates the anemia.
• In beta thalassemia, CASGEVY increases people’s overall hemoglobin levels. This improves oxygen delivery and decreases the severity of anemia, reducing or eliminating the need for red blood cell transfusions.

The U.S. Food and Drug Administration has approved CASGEVY — the first treatment to utilize CRISPR editing technology — for two conditions:

• In December 2023, CASGEVY was approved for people with sickle cell disease 12 years and older with recurring vaso-occlusive pain crises.
• In January 2024, CASGEVY was approved for people age 12 and older with beta thalassemia who require red blood cell transfusions.

CASGEVY is a custom treatment, made from each person’s own blood stem cells. It involves multiple steps that may take up to nine months to a year to complete. The treatment process is similar for sickle cell disease and beta thalassemia.

Blood transfusions

Beginning two months before stem cell collection, you will start or continue to receive regular red blood cell transfusions.

Stem cell collection

Before you receive CASGEVY, you will be admitted to the hospital for collection of stem cells from your blood. First, a special catheter will be placed in one of your veins under sedation. You will receive a medication to “mobilize” your blood stem cells, moving them from your bone marrow to your bloodstream. The stem cells will then be collected from your blood using a process called apheresis. This can take up to two to three days. Then the catheter will be removed.

You can return home while your stem cells are edited in a special manufacturing lab to make the CASGEVY product. This will take several months. Sometimes one or more additional rounds of cell collection are required.

Conditioning treatment and CASGEVY infusion

When the treated cells are ready, you will undergo several days of testing to make sure you are ready to receive it. Once that testing is complete, you will be admitted to the hospital for four to six weeks. You will first receive “conditioning” chemotherapy. The powerful conditioning drug eliminates the stem cells in your bone marrow to make room for the new, treated cells. This can cause short-term side effects due to temporarily low numbers of platelets and white blood cells. About a week later, you will receive your treated cells as a one-time infusion.

Monitoring and follow-up

After your infusion, you will remain in the hospital while your treated stem cells take hold (engraft) in your bone marrow and start making new blood cells. Our team will watch you for any side effects. Once you return home, we will continue to follow you with regular check-ups for 15 years.

Sickle cell disease

CASGEVY was tested in a multi-center clinical trial in adults and adolescents with sickle cell disease and a history of severe vaso-occlusive pain crises. The study was open-label, meaning that everyone knew they were receiving CASGEVY.

Of 30 people who were followed for a sufficient length of time (average follow up was 19 months), 29 were free of severe pain episodes for at least 12 months in a row after treatment. None of the 30 rejected their treated cells or needed to be hospitalized for pain crises.

This trial is still continuing. To date, the 29 people who stopped having pain crises have remained free of them for an average of 22.2 months. One patient did have a severe pain crisis that required hospitalization.

Beta thalassemia

A multi-national clinical trial tested CASGEVY in people with transfusion-dependent beta thalassemia, age 12 to 35. The study was open-label, so participants knew they were receiving CASGEVY.

Of 35 people who were followed for at least 16 months, 32 went without needing a red blood cell transfusion for 12 months in a row. CASGEVY increased amounts of both total hemoglobin and fetal hemoglobin, and no one rejected their treated cells.

To date, the 32 people who became transfusion-independent have remained so for an average of 20.8 months. The clinical trial is still ongoing.

CASGEVY appears to be very safe. However, the conditioning chemotherapy needed before you receive CASGEVY will temporarily leave you with fewer blood cells while treated stem cells engraft into your bone marrow. Until this happens, you may have low levels of platelets (the cells that make your blood clot), red blood cells, and white blood cells (which fight infection). You will also lose your hair temporarily.

After your infusion, you will stay in the hospital until your blood counts build up to the necessary levels. Your care team will be watching for these side effects:

• Abnormal bruising, bad headaches, prolonged bleeding, or bleeding from the gums or in urine or stool (signs of a low platelet count)
• Fever, chills, or infections (signs of a low white-cell count)

Other side effects of the chemotherapy may include severe, painful mouth sores, nausea, muscle or bone pain, abdominal pain, vomiting, headache, and itching. These symptoms are temporary and your care team can treat these as needed.

Because CASGEVY is still new, we don’t yet have information about long-term side effects. After any gene therapy or bone marrow transplant there is a very small risk of developing a blood cancer. We will follow you for at least 15 years after your treatment to ensure that you remain healthy.

As in cancer treatment, the conditioning chemotherapy drug used before CASGEVY treatment may prevent you from being able to become pregnant or father a child. Your care team will offer referral to our Fertility Preservation Program before you start treatment. This program provides counseling, sperm banking, egg freezing, and other options for preserving fertility.

The clinical trials of CASGEVY for sickle-cell disease and beta thalassemia are not yet complete. While CASGEVY may not technically cure these conditions, most patients have found the results to be life-changing. So far, the data indicate that:

• In people with sickle cell disease, CASGEVY can eliminate or greatly reduce the severity of pain crises, making it a milder disease in most people.
• In beta thalassemia, CASGEVY seems to enable most people to avoid transfusions.

Because CASGEVY has only recently become available, it’s not yet clear to what extent insurance providers will cover it. We encourage you to talk with your health insurance company and medical team. Boston Children’s Financial Services staff will guide you through the insurance approval process.

Contact the Blood Disorders Center:

Phone: 617-355-8246
Email: hemeclinic-dl@childrens.harvard.edu