World’s First CRISPR Gene-Editing Therapy Casgevy™ Receives Conditional Approval in the UK

On November 16, Vertex Pharmaceuticals and CRISPR Therapeutics announced that they had received conditional marketing authorization from the UK Medicines and Healthcare products Regulatory Agency (MHRA) for the CRISPR/Cas9 gene-editing therapy Casgevy™ (exa-cel), marking the world’s first approved CRISPR gene-editing therapy.

Casgevy™ has been approved in the UK for two indications: one is for the treatment of patients aged 12 years and older with sickle cell disease (SCD) who suffer from recurrent vaso-occlusive crises; the other is for the treatment of patients aged 12 years and older with transfusion-dependent β-thalassemia (TDT). Both patient populations are eligible for hematopoietic stem cell transplantation but lack a human leukocyte antigen-matched related hematopoietic stem cell donor.

Currently, Vertex and CRISPR Therapeutics have not yet determined the pricing of Casgevy™ in the UK. In the United States, the Biologics License Application (BLA) for Casgevy™ has been accepted; the FDA has granted Priority Review for the treatment of sickle cell disease (SCD) and Standard Review for transfusion-dependent beta-thalassemia (TDT). The Prescription Drug User Fee Act (PDUFA) target date for SCD is December 8, 2023, and for TDT is March 30, 2024.

Casgevy™ is an autologous, ex vivo CRISPR/Cas9 gene-editing therapy. It modifies patients’ hematopoietic stem cells ex vivo to induce high levels of fetal hemoglobin (HbF) in red blood cells. HbF is an oxygen-carrying hemoglobin present during fetal development that transitions to adult forms after birth. Treatment with Casgevy™ increases HbF levels, alleviates transfusion dependence in patients with transfusion-dependent β-thalassemia (TDT), and reduces or eliminates pain and vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD).

CASGEVY™ was developed based on the innovative gene-editing tool, the CRISPR/Cas9 system. The inventors of this tool, French scientist Emmanuelle Charpentier and American scientist Jennifer A. Doudna, were awarded the 2020 Nobel Prize in Chemistry for their groundbreaking work.

Previously, Vertex announced data from two global clinical trials of CASGEVY™ for SCD and TDT—CLIMB-111 and CLIMB-121.

In clinical trials for SCD, 45 patients have received treatment with Casgevy™. Among the 30 subjects evaluable for efficacy, 29 (96.7%) have met the criteria for the interim primary efficacy assessment, with 28 of these patients (97%) remaining free from severe pain crises for at least 12 months post-treatment. All 30 (100%) evaluable subjects achieved HF12 (within 12 months following Casgevy™ infusion).

In the clinical trials for TDT, 54 patients have received treatment with Casgevy™. Among them, 42 patients have participated in the trial for a sufficient duration to qualify for the interim analysis of primary efficacy. Of these, 39 patients (93%) did not require red blood cell transfusions for at least 12 months post-treatment. The remaining three patients experienced a reduction in red blood cell transfusion requirements of more than 70%. Furthermore, the side effects associated with the treatment were similar to those related to autologous stem cell transplantation, including nausea, fatigue, and fever.

To date, no major safety concerns have been identified in these ongoing clinical trials. The safety profile of CASGEVY™ in patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) is generally consistent with that associated with myeloablative conditioning using busulfan and hematopoietic stem cell transplantation.

Furthermore, Vertex and CRISPR Therapeutics are conducting the open-label Phase III trials CLIMB-141 and CLIMB-151, designed to evaluate the efficacy and safety of CASGEVY™ treatment in patients aged 2–11 years with transfusion-dependent beta-thalassemia (TDT) or sickle cell disease (SCD), respectively.

SCD is one of the most common genetic diseases in the world.

According to World Health Organization estimates, there are currently more than 5 million patients with sickle cell disease (SCD) worldwide. Each year, at least 500,000 newborns are affected by the most severe form of this condition—homozygous SS—and the majority of these cases occur in low- and middle-income countries, with approximately 80% of all SCD cases concentrated in sub-Saharan Africa. In the absence of adequate medical care and community support, 50%–80% of affected children die before the age of five, succumbing to common infections such as colds and bronchitis or to tissue hypoxia caused by anemia.

Currently, the standard treatments for sickle cell disease (SCD) and thalassemia major (TDT) include hydroxyurea therapy, red blood cell transfusions, or iron chelation therapy. However, these approaches are associated with risks of toxicity and do not provide a curative solution. The only potential cure is hematopoietic stem cell transplantation (HSCT), but this option is limited by the scarcity of matched donors and the ever-present risks of graft rejection and post-transplant complications.

In June 2023, The Lancet Haematology published the Global Burden of Disease Study 2017 (GBD), which quantified the global incidence, prevalence, specific etiologies, and overall mortality burden of sickle cell disease (SCD).

Research data indicate that the number of deaths caused by sickle cell disease (SCD) is 11 times higher than that shown by mortality data sources alone, and SCD is a leading cause of death among children under 5 years of age, youths aged 5–14 years, and adults aged 15–49 years. In epidemiological modeling, integrating prevalence and birth rate data from other sources with mortality data revealed that the “total mortality burden” of SCD in 2021 amounted to 373,000 deaths, whereas deaths attributed solely to SCD, or “cause-specific deaths,” totaled 34,600.

The approval of Casgevy™ will provide these patients with a brand-new treatment option.

Julian Beach, Executive Director of Healthcare Quality and Interim Access at the MHRA, stated that there are currently approximately 15,000 patients with sickle cell disease (SCD) in the UK, and around 2,000 of them meet the eligibility criteria for treatment with Casgevy™ under the conditions approved by UK regulators. Previously, bone marrow transplantation was the only curative treatment option for patients with SCD and transfusion-dependent beta-thalassemia (TDT). The approval and launch of Casgevy™ will enable these patients to produce healthy hemoglobin, thereby alleviating disease symptoms.