FDA Set to Review Exagamglogene Autotemcel for Sickle Cell Disease, Transfusion-Dependent Beta Thalassemia

Carmen Bozic, MD

The FDA has granted priority and standard review designations to the biologics license applications for exagamglogene autotemcel (exa-cel; formerly CTX001) for the treatment of patients with sickle cell disease and transfusion-dependent beta thalassemia, respectively, marking the first CRISPR gene editing filings to be accepted for review by the FDA.^1,2

The FDA has set action dates of December 8, 2023, for the sickle cell indication, and March 30, 2024, for the transfusion-dependent beta thalassemia indication.

Both applications are supported by findings from two, phase 3 trials––CLIMB-111 (NCT03655678) and CLIMB-121 (NCT03745287)––results of which were recently presented at the 2023 EHA Congress.

“The updated results from both the transfusion-dependent beta thalassemia and sickle cell disease trials are remarkable and bring the promise of an autologous CRISPR/Cas9 gene-edited cell therapy one-step closer to patients who are waiting,” Carmen Bozic, MD, executive vice president of Global Medicines Development and Medical Affairs, and chief medical officer at Vertex, stated in a press release.²

Previously, the FDA granted exa-cel Regenerative Medicine Advanced Therapy, fast track, orphan drug, and Rare Pediatric Disease designations from the FDA for both transfusion-dependent beta thalassemia and sickle cell disease.²

Additionally, in January 2023, the European Medicines Agency (EMA) and the Medicines and Healthcare Products Regulatory Agency validated the marketing authorization applications for approval of exa-cel, an autologous cell therapy that harnesses CRISPR-Cas9 to edit hematopoietic stem cells, thereby increasing fetal hemoglobin levels, rendering patients free from transfusions and vaso-occlusive events after a single administration. Exa-cel also received PRIME designation from the EMA, allowing for priority review of the application.^2,4

The ongoing phase 2/3 open-label CLIMB-111 and CLIMB-121 trials are evaluating the safety and efficacy of exa-cel in patients ages 12 to 35 years with transfusion-dependent beta thalassemia and sickle cell disease, respectively.²

Results showed that of the 27 evaluable patients enrolled in the CLIMB-111 trial, 24 (88.9%) achieved the primary end point of transfusion independence for at least 12 consecutive months.³ Mean duration of transfusion-independence was 20.5 months, reaching up to 40.7 months.Additionally mean hemoglobin among all 48 patients who received exa-cel to date was reduced by at least 11 g/dL after 3 months and at least 12 g/dL from 6 months.

Furthermore, interim findings from the CLIMB-121 trial demonstrated that 16 patients (94.1%) achieved the primary end point of freedom from vaso-occlusive crises (VOC) for at least 12 consecutive months (95% CI, 71.3%-99.9%; P = .0001). Mean duration of being VOC-free was 18.7 months, reaching up to 36.5 months. Among the 35 patients who had received treatment with exa-cel, mean fetal hemoglobin was more than 30% of the total hemoglobin by the third month, stabilizing at approximately 40% to follow-up.

The safety profile of exa-cel was similar to that of standard therapy with myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant in patients with sickle cell disease.

No treatment-related adverse effects (TRAEs) occurred with exa-cel in patients with sickle cell disease. However, 2 patients with transfusion-dependent beta thalassemia experienced serious TRAEs, including one patient who experienced hemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, and headache, as well as another who reported idiopathic pneumonia syndrome.

“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, professor of pediatrics at the Sapienza University of Rome, and director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital. “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.”³

References

1. Landmark approval for Vertex's CRISPR drug 2 steps closer after trial wins, PDUFA date granted. News release. Fierce Biotech. June 9, 2023. Accessed June 12, 2023. https://www.fiercebiotech.com/biotech/landmark-approval-vertexs-crispr-drug-two-steps-closer-after-trial-wins-pdufa-date-granted
2. FDA accepts biologics license applications for exagamglogene autotemcel (exa-cel) for severe sickle cell disease and transfusion-dependent beta thalassemia. News release. Vertex Pharmaceuticals. June 8, 2023. Accessed June 12, 2023. https://investors.vrtx.com/news-releases/news-release-details/fda-accepts-biologics-license-applications-exagamglogene
3. Positive results from pivotal trials of exa-cel for transfusion-dependent beta thalassemia and severe sickle cell disease presented at the 2023 Annual European Hematology Association (EHA) Congress. News release. Vertex Pharmaceuticals. June 9, 2023. Accessed June 12, 2023. https://www.businesswire.com/news/home/20230609005104/en/
4. EMA validates Vertex’s CRISPR application, clearing barrier on road to landmark approval. News release. Fierce Biotech. January 25, 2023. Accessed June 12, 2023. https://www.fiercebiotech.com/biotech/ema-validates-vertexs-crispr-application-clearing-barrier-road-landmark-approval