FDA grants exa-cel priority review, with decision due by year’s end

Approval of CRISPR gene-editing therapy would be first for SCD in US

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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The U.S. Food and Drug Administration (FDA) is reviewing an application that seeks the approval of exagamglogene autotemcel, a CRISPR-based gene-editing therapy known as exa-cel, to treat sickle cell disease (SCD) and transfusion-dependent beta thalassemia.

The rolling biologics license application was completed by Vertex Pharmaceuticals and CRISPR Therapeutics earlier this year, and filed along with a request for a priority review that usually shortens the time to a decision from the standard one year to about eight months.

The application for beta thalassemia is under standard review and the FDA is expected to provide a ruling by March 30, 2024. Meanwhile, the FDA granted priority review to the application for SCD, with a decision for that indication due sooner — by Dec. 8.

Similar applications are under review in the European Union and the U.K.

“We are very pleased with the acceptance of the submissions and the priority review designation for SCD by the FDA, as well as the progress of the exa-cel filings in the EU and U.K.,” Reshma Kewalramani, MD, president and CEO of Vertex, said in a company press release.

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If the FDA issues a positive decision in December, exa-cel would be the first treatment of its type to win regulatory approval for SCD in the U.S., the company noted.

“This is an exciting milestone for the CRISPR platform, and we look forward to continuing the close collaboration with our partners at Vertex to bring this medicine to patients in need,” said Samarth Kulkarni, PhD, CEO of CRISPR Therapeutics.

Exa-cel holds the promise to be the first CRISPR gene-editing therapy to be approved, and we continue to work with urgency to bring this treatment with transformative potential to patients who are waiting.

SCD and beta thalassemia are diseases that occur when the body makes a faulty version of hemoglobin, or not enough of it. Hemoglobin is a protein that’s responsible for carrying oxygen throughout the body. When there isn’t enough hemoglobin, it can lead to anemia, or a low number of healthy red blood cells for transporting oxygen in the body.

Exa-cel, formerly known as CTX001, uses a gene-editing tool called CRISPR/Cas9. It alters a specific point in the DNA sequence of a gene coding for BCL11A, a protein that normally halts the production of fetal hemoglobin some time after birth. This version of hemoglobin is the main carrier of oxygen during fetal development and is more effective doing so than its adult counterpart.

The genetic modification prevents the production of BCL11A, allowing fetal hemoglobin to be produced.

This is done in a patient’s own blood cell precursors. After these cells are modified in the lab using exa-cel, they are given back to the patient through a stem cell transplant.

The modified cells are then expected to populate the blood with healthy hemoglobin-producing blood cells, which in turn is expected to reduce the need for regular blood transfusions and also lower the frequency of painful vaso-occlusive crises (VOCs) in SCD patients.

“Exa-cel holds the promise to be the first CRISPR gene-editing therapy to be approved, and we continue to work with urgency to bring this treatment with transformative potential to patients who are waiting,” Kewalramani said.

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Exa-cel Continues to Prevent VOCs in Sickle Cell Patients: New Trial Data

New trial data presented at hematology conference

The therapy is being tested in a number of ongoing clinical studies.

Earlier data from CLIMB–121 (NCT03745287), a Phase 2/3 study that enrolled people with severe SCD, showed that a single intravenous (into-the-vein) infusion of exa-cel increased fetal hemoglobin levels and prevented VOCs from occurring. That trial involved patients ages 12-35.

Now, updated data from a pre-specified interim analysis were presented at the 2023 European Hematology Association Congress, being held in person June 8-15 in Frankfurt, Germany, as well as virtually.

“This analysis confirms the potential of exa-cel to render patients transfusion-independent or VOC-free, with significant improvement in their quality of life and physical performance,” Franco Locatelli, MD, PhD, a professor of pediatrics at the Sapienza University of Rome, in Italy, said in another press release.

Locatelli, who also directs the department of pediatric hematology and oncology at Bambino Gesù Children’s Hospital, also in Rome, presented data from 17 of the 35 people with SCD who had received exa-cel at the time of the analysis.

All but one patient — 94% in total — remained free from VOCs for at least one year, which was one of the study’s primary endpoints. On average, patients remained free from VOCs for a mean of 18.7 months, or just longer than 1.5 years. The one patient who did not had a complex set of coexisting conditions, according to researchers.

Fully 100% of the participants remained free from hospitalizations related to severe VOCs for at least one year, which was one of the study’s secondary endpoints. Treatment with exa-cel also brought about clinically significant improvements in patient-reported outcomes.

Exa-cel led to an increase in fetal hemoglobin within the first few months, and its levels were maintained over time. By the third month, fetal hemoglobin made up more than 30% of the total hemoglobin, and it remained at around 40% as time went on.

There were no serious side effects related to exa-cel.

All patients who participated in CLIMB-121 had the chance to roll over into CLIMB-131 (NCT04208529), an ongoing study that’s evaluating how safe exa-cel is, and how well it works, for up to 15 years.