MHRA Approves First CRISPR-Based Therapy Exa-cel for Sickle Cell and Transfusion-Dependent β-Thalassemia

The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) has approved Vertex Pharmaceuticals and CRISPR Therapeutics’ autologous gene-edited cell therapy exagamglogene autotemcel (exa-cel), which is to be marketed under the name Casgevy, for the treatment of both sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) in patients aged 12 years and older.¹

Exa-cel remains an investigational treatment in the United States, though the FDA has granted Priority Review for SCD with a Prescription Drug User Fee Act (PDUFA) target action date of December 8, 2023, and Standard Review for TDT with a PDUFA target action date of March 30, 2024.² It is the first CRISPR-based gene therapy to be approved in the UK.^1,2 The MHRA’s decision was based on results from the phase 1/2/3 CLIMB-121 clinical trial (NCT03745287), which was conducted exclusively in patients with SCD, the phase 1/2/3 CLIMB-111 clinical trial (NCT03655678) in TDT, and the phase 3 long-term follow-up study CLIMB-131 (NCT04208529), which includes both patients with SCD and patients with TDT.

“Both SCD and TDT are painful, life-long conditions that in some cases can be fatal,” Julian Beach, MBA, BSc, FRSC, the interim executive director of healthcare quality and access at the MHRA , said in a statement.¹ “To date, a bone marrow transplant—which must come from a closely matched donor and carries a risk of rejection—has been the only permanent treatment option. I am pleased to announce that we have authorized an innovative and first-of-its-kind gene-editing treatment called Casgevy, which in trials has been found to restore healthy hemoglobin production in the majority of participants with SCD and TDT, relieving the symptoms of disease. The MHRA will continue to closely monitor the safety and effectiveness of Casgevy, through real-world safety data and post-authorization safety studies being carried out by the manufacturer. I would like to thank the patients with lived experiences who engaged with us as part of the assessment process and gave us valuable insight into their lives and the challenges of managing their condition.”

Thus far, 45 patients with SCD have been treated with exa-cel in CLIMB-121. The MHRA reported that among 29 of these patients who were evaluable for efficacy at the data cutoff, 28 (97%) have not had severe pain crises for at least 12 months posttreatment. In CLIMB-111, 42 of 54 patients with TDT were evaluable for the primary efficacy interim end point at the time of the data cutoff; it was reported that 39 (93%) of these patients were free of the need for a red blood cell (RBC) transfusion for 12 months or more posttreatment. Furthermore, the 3 patients who did not achieve this end point demonstrated a greater than 70% decrease in necessitation of RBC transfusions. In terms of safety, the MHRA stated that no significant safety concerns came up during these trials and that the adverse event (AE) profile of exa-cel displayed similarity to that of autologous stem cell transplant. AEs such as nausea, fatigue, fever, and increased risk of infection were specifically noted by the MHRA.

“SCD is an incredibly debilitating condition, causing significant pain for the people who live with it and potentially leading to early mortality,” John James, OBE, the chief executive of the Sickle Cell Society added to the statement.¹ “There are limited medicines currently available to patients, so I welcome today’s news that a new treatment has been judged safe and effective, which has the potential to significantly improve the quality of life for so many.”

Exa-cel consists of patients’ own bone marrow stem cells that have been genetically modified ex-vivo to produce normal hemoglobin. Conditioning therapy is necessary before patients can receive the modified cells. 

In the United States, the FDA is currently reviewing a biologics license application (BLA) for exa-cel submitted in June 2023 by Vertex and CRISPR for both SCD and TDT.³ A recent FDA Cellular, Tissue, and Gene Therapies Advisory Committee (AdComm) discussion held on October 31, 2023, specifically focused on the potential SCD indication, was generally favorable towards the therapy.² The committee spoke on the question: “Please discuss the Applicant's off-target analysis (eg, in silico and cellular methods) and provide recommendations for additional studies, if needed, to assess the risk of off-target editing for exa-cel?” During the discussion, the members of the AdComm were generally of the opinion that the off-target analyses conducted by Vertex were reasonably robust, and that in light of the positive efficacy data demonstrating transformative potential for a patient population with very great unmet need, further risk analyses prior to approval are unlikely to be necessary.

REFERENCES
1. MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia. News release. MHRA. November 16, 2023. Accessed November 16, 2023. https://www.gov.uk/government/news/mhra-authorises-world-first-gene-therapy-that-aims-to-cure-sickle-cell-disease-and-transfusion-dependent-thalassemia
2. 76th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. October 31, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-october-31-2023-meeting-announcement-10312023
3. 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 November 16, 2023. https://investors.vrtx.com/news-releases/news-release-details/fda-accepts-biologics-license-applications-exagamglogene