FDA Sets PDUFA Dates for First CRISPR Gene Edited Therapy

The FDA has accepted Vertex Pharmaceuticals’ biologics license applications (BLAs) for the investigational treatment exagamglogene autotemcel (exa-cel) for severe sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). The FDA has granted priority review for the sickle cell indication and standard review for the beta thalassemia indication.

The agency has assigned Prescription Drug User Fee Act (PDUFA) target action dates of Dec. 8, 2023, for the sickle cell application and March 30, 2024, for the beta thalassemia application.

The beta thalassemia and sickle cell disease result from mutations in a gene that encodes a key component of hemoglobin, the oxygen carrying molecule in blood. Both diseases require regular transfusions and result in painful symptoms and chronic hospitalizations. Both result in reduced life expectancy.

Exa-cel is a one-time therapy that uses a patient’s own hematopoietic stem cells that are edited to produce high levels of fetal hemoglobin in red blood cells. Increasing fetal hemoglobin has the potential to reduce or eliminate vaso-occlusive crisis — a condition tissues become deprived of oxygen, which causes an inflammatory response — for patients with sickle cell and transfusion requirements for patients with beta thalassemia. Patients receiving this therapy have their own cells edited using the CRISPR/Cas9 technology. The edited cells, exa-cel, will then be infused back into the patient as part of an autologous hematopoietic stem cell transplant.

Results from two pivotal trials of exa-cel will be presented at the Annual European Hematology Association Congress on June 11, 2023. Both the CLIMB-111 and CLIMB-121 trials met their primary endpoint and key secondary endpoint.

Franco Locatelli, M.D., Ph.D.

“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, M.D., Ph.D., professor of pediatrics at the Sapienza University of Rome, director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital, said in a press release. “This therapy offers the potential of a functional cure for patients with transfusion-dependent beta thalassemia or severe sickle cell disease along with a favorable safety profile.”

In the trial assessing 48 patients with transfusion-dependent beta thalassemia, more than half (58.3%) have genotypes associated with severe disease. At the time of the data cut, 27 of the patients were evaluable. Of these 88.9% achieved the primary endpoint of transfusion-independence for at least 12 months and the secondary endpoint of transfusion-independence for at least six months.

In the trial assessing the 35 patients with sickle cell, 17 patients were evaluable; 16 achieved the primary endpoint of freedom from vaso-occlusive crises for at least 12 months. All patients achieved the key secondary endpoint of being free from hospitalizations related to vaso-occlusive crises for at least 12 months.

In both groups of patients, the gene-edited alleles were stable in the bone marrow and peripheral blood, indicating successful permanent editing in the long-term hematopoietic stem cells.

Two patients with beta thalassemia had serious adverse events considered related to exa-cel, which occurred the context of the peri-engraftment period and have resolved. Among the 35 patients with sickle cell, there were no serious adverse events considered related to exa-cel.

The ongoing open-label trial, CLIMB-131, will follow partients for up to 15 years after exa-cel infusion. Additionally, the ongoing phase 3 open-label trials, CLIMB-141 and CLIMB-151, are enrolling patients ages 2 to 11 years with beta thalassemia or with sickle cell.

The gene editing technique, CRISPR/Cas9, was developed by CRISPR Therapeutics. Vertex has collaborated with CRISPR Therapeutics for the development of exa-cel, formerly known as CTX001. Emmanuelle Charpentier, Ph.D., one of CRISPR Therapeutics’ scientific founders, co-invented CRISPR/Cas9 gene editing. Charpentier and Jennifer A. Doudna, Ph.D., won a Nobel Prize in Chemistry in 2020. CRISPR/Cas9 acts like a “genetic scissors” precisely cutting DNA and then allowing natural DNA repair processes to take over.