U.S.-First Gene Therapies for Sickle Cell Disease Approved by FDA

Jeffrey S. Chamberlain, PhD - December 08, 2023

First-approved CRISPR therapeutic is one of the two products approved for clinical use in the United States.

In a historic move today, the FDA approved two cell-based gene therapies, Casgevy and Lyfgenia, to treat sickle cell disease (SCD) in patients 12 years and older. These treatments are the first gene therapies approved for SCD in the U.S. and Casgevy is the first approved therapy in the U.S. that uses CRISPR.

Casgevy, also known as exa-cel (exagamglogene autotemcel), is an ex vivo, autologous, CRISPR-Cas9 gene-edited therapy developed by CRISPR Therapeutics and Vertex to treat patients with severe SCD. The gene-editing tool CRISPR earned its inventors—ASGCT Member Jennifer A. Doudna, PhD, and Emmanuelle Charpentier, PhD—the Nobel Prize in 2020.

Lyfgenia, or lovo-cel, developed by Bluebird Bio, uses a lentiviral vector for genetic modification and is approved for the treatment of patients 12 years of age and older with SCD and a history of vaso-occlusive events (VOEs).  

Both products are made from the patients’ own blood stem cells, which are modified and given back to the patient as a one-time, single-dose infusion as part of a hematopoietic stem cell transplant.

The sickle cell community has waited so long for a lasting treatment option for this extremely debilitating disease. I’m very grateful that, moving forward, SCD patients will finally be able to experience some relief from pain crises and other serious complications that come with the disease.

People with SCD have inherited a faulty beta-globin gene, which means their bodies can’t make enough adult hemoglobin. This causes red blood cells to become stiff and unable to carry oxygen throughout the body, which leads to tissue and organ damage. Casgevy works by using a patient’s own hematopoietic stem cells, which are edited outside the body with CRISPR, to produce high levels of fetal hemoglobin. The modified cells are then returned to the body where they’re able to make healthy red blood cells.

With Lyfgenia, the patient’s blood stem cells are genetically modified to produce HbAT87Q, a gene-therapy-derived hemoglobin that functions similarly to hemoglobin A, which is the normal adult hemoglobin produced in people not affected by SCD. Red blood cells containing HbAT87Q have a lower risk of sickling and occluding blood flow. These modified stem cells are then delivered to the patient. 

SCD affects about 100,000 Americans, occurring most often in Black populations.

The safety and efficacy of Casgevy were evaluated in an ongoing single-arm, multi-center trial in adult and adolescent patients with SCD. A total of 44 patients were treated with Casgevy. Of the 31 patients evaluated, 29, or 93.5%, were free from severe vaso-occlusive crisis (VOC) episodes for at least 12 consecutive months during the 24-month follow-up period. No patients experienced graft failure or rejection.

For Lyfgenia, safety and effectiveness were based on data analysis from a single-arm, 24-month multicenter study in patients with SCD and history of VOEs between the ages of 12- and 50- years old. Twenty-eight (88%) of 32 patients achieved complete resolution of vaso-occlusive events during this time period.

Casgevy is also indicated to treat transfusion-dependent beta-thalassemia. FDA is expected to make an approval decision on the thalassemia indication by March 30, 2024.

The FDA granted approval of Casgevy to Vertex Pharmaceuticals Inc. and approval of Lyfgenia to Bluebird Bio Inc.

Jeffrey Chamberlain, PhD is president of ASGCT and a professor and McCaw Chair in Muscular Dystrophy at the University of Washington.