FDA approves Casgevy, 1st CRISPR therapy for sickle cell disease

Gene-editing therapy indicated for patients 12 and older with recurrent VOCs

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Note: This story was updated Dec. 12, 2023, to clarify that Lyfgenia treats vaso-occlusive events, including painful vaso-occlusive crises (VOCs).

The U.S. Food and Drug Administration (FDA) has approved the gene-editing therapy exagamglogene autotemcel (exa-cel) — now known as Casgevy — for treating sickle cell disease (SCD).

The therapy from Vertex Pharmaceuticals and CRISPR Therapeutics is indicated for patients ages 12 and older who have recurrent vaso-occlusive crises (VOCs). With the decision, Casgevy has become the first cell-based gene therapy employing CRISPR/Cas9, a type of gene-editing technology, to win approval in the U.S.

The FDA also approved Lyfgenia (lovotibeglogene autotemcel), another cell-based gene therapy developed by Bluebird Bio, for sickle cell patients ages 12 and older with a history of vaso-occlusive events.

“These approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a press release.  “Today’s actions follow rigorous evaluations of the scientific and clinical data needed to support approval, reflecting the FDA’s commitment to facilitating development of safe and effective treatments for conditions with severe impacts on human health.”

The therapy earned conditional approval last month in the U.K., where it’s also marketed as Casgevy, for SCD patients 12 and older for whom a stem cell transplant is appropriate, but no donor is available.

The companies, which are jointly developing Casgevy, completed a rolling biologics license application to the FDA earlier this year. The agency agreed to a priority review of the therapy, which shortens the standard review time from a year to about eight months.

Casgevy is under standard review in the U.S. for transfusion-dependent beta thalassemia, a related disorder, and a decision is expected in March. Similar applications are being considered in the European Union.

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What is Casgevy and what does it do?

In both SCD and beta thalassemia, not enough functional hemoglobin is available to carry oxygen through the body. This leads to anemia, or a lack of healthy red blood cells. In SCD, genetic mutations result in a defective version of hemoglobin being produced that causes red blood cells to become misshapen, a process known as sickling. In beta thalassemia little to no hemoglobin is produced.

Formerly known as CTX001, Casgevy is a gene-editing therapy that aims to increase the production of fetal hemoglobin, a version of hemoglobin that carries oxygen during fetal development. It does so more effectively than its adult counterpart, which is switched on sometime after birth. SCD-causing mutations affect the adult version, but not the fetal form.

Casgevy uses a gene-editing tool called CRISPR/Cas9 to alter a specific point in the DNA sequence of a gene that encodes the BCL11A protein, which normally halts the production of fetal hemoglobin after birth. The modification prevents BCL11A production, enabling more fetal hemoglobin to be generated.

The procedure involves taking a patient’s own blood cell precursors and modifying them, then returning them via a stem cell transplant after a round of high-dose chemotherapy to kill off existing faulty cells. The modified cells should repopulate the blood with cells capable of producing healthy hemoglobin, thereby preventing red blood cell sickling.

Data from the ongoing Phase 2/3 CLIMB-121 clinical trial (NCT03745287) backed the applications. The results of the study, which enrolled people ages 12-35 with severe SCD, indicated a single infusion of Casgevy was sufficient to prevent any painful VOCs for at least a year in 29 of the 31 (93.5%) evaluated patients. Stem cell transplants were successful in all patients, with no cases of rejection reported.

An FDA advisory committee meeting ahead of the agency’s decision was completed last month. While the exact content of the discussion wasn’t disclosed, briefing documents indicate safety would be a major focus, especially the possibility that off-target genetic editing could lead to health problems for patients.

So far, the most common side effects associated with Casgevy in clinical trials have been those linked to busulfan, the chemotherapy agent given before the transplant, such as low platelet and white blood cell counts, nausea, vomiting, and abdominal pain. The therapy’s developers plan to work with ImmunoGen to develop more tolerable approaches to wipe out faulty cells.

To continue evaluating the long-term safety of Casgevy, CLIMB-121 patients can enter the ongoing CLIMB-131 extension study (NCT04208529), where they will continue to be monitored for up to 15 years.

An ongoing open-label Phase 3 trial called CLIMB-151 (NCT05329649) is evaluating the safety and efficacy of Casgevy in pediatric patients, ages 2-11, with severe SCD. The trial has similar goals as CLIMB-121 in adults and may still be recruiting up to 15 participants at sites in the U.S. and Europe.