INTRODUCTION

Epidemiology

Sickle cell disease (SCD) is a chronic multisystem, genetic disease affecting around 100,000 patients in the United States and 20 million patients worldwide.^1,2 Sickle cell disease appears to be most prevalent among African American/Black patients, with this condition occurring in 1 of 365 births, and with an estimated 1 in 13 infants born with the sickle cell trait. Similarly, other ethnicities also highly affected by SCD include those with Middle Eastern, Indian, Asian, Mediterranean, and Spanish ancestry (including Central and South America).¹ Complications of SCD include anemia, acute and chronic pain, acute chest syndrome, stroke, serious infections, venous thromboembolism, priapism, dactylitis, retinopathy, renal disease, and heart failure.^3,4 Sickle cell disease is also very costly, with an estimated SCD-related lifetime medical cost of $1.2 million.⁵

With the growing impact of SCD, there has been an increase in mortality associated with the disease. Globally, in 2021, there were an estimated 34,400 cause-specific deaths and 376,000 total deaths in patients with SCD. Furthermore, SCD is associated with the highest overall and cause-specific mortality rates in children younger than 5 years. In 2021, there were 81,000 reported deaths in children younger than 5 years from SCD, making it the 12th global leading cause of death in this age demographic.⁶

Pathophysiology

Sickle cell disease is an autosomal recessive genetic mutation of the hemoglobin β gene, leading to the malformation of RBCs into crescent-shaped cells.^3,4 These sickled RBCs tend to aggregate, leading to vaso-occlusion, inflammation, endothelial damage, pain, and hypercoagulability.

Although different genetic variants exist, the most common form of SCD is the hemoglobin S (Hb S) mutation resulting from an incorrect substitution of valine in place of glutamic acid. Other variants include Hb C, Hb D, and Hb O.⁷ Similarly, the presence of quantitative variants resulting from multiple substitutions and various deletions may be present in certain individuals with β⁰ or β⁺ forms of β-thalassemia. This leads to the reduction in β-globin, α-hemoglobin buildup, and hemolysis seen with β-thalassemia.⁷ Typically, the coinheritance of Hb S and β⁰-thalassemia causes a more severe form of SCD because of the reduced solubility of the mutated hemoglobin.

MECHANISM OF ACTION

On December 8, 2023, the FDA approved Vertex and CRISPR Therapeutic’s first-in-class CRISPR/Cas9 genome-edited cell therapy, exagamglogene autotemcel (Casgevy), for the treatment of severe SCD in patients 12 years and older on the basis of the CLIMB SCD-121 trial. Shortly afterward, on January 16, 2024, exagamglogene autotemcel received FDA approval for the treatment of transfusion-dependent β-thalassemia (TDT) in patients 12 years and older on the basis of the CLIMB THAL-111 trial.⁸ This curative treatment consists of DNA editing of autologous CD34⁺ hematopoietic stem cells (HSCs) using CRISPR/Cas9 technology. Specifically, this technology targets the B-cell lymphoma/leukemia 11A (BCL11A) gene, leading to its downregulation, thus increasing the production of γ-globin and fetal hemoglobin.^7,8

CLINICAL TRIALS: CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287)

The safety and efficacy of exagamglogene autotemcel were evaluated in the single-arm, open-label, multicenter, phase I/II/III trials CLIMB THAL-111 and CLIMB SCD-121, which have been ongoing since November 2018 in the United States, Belgium, Canada, France, Germany, Italy, and the United Kingdom.^8,9 The CLIMB THAL-111 study includes participants 12–35 years of age with diagnosed severe TDT (βS/βS or βS/β₀ genotypes) and a documented history of receiving 100 mL/kg/year of RBC transfusions within the 2 years before enrollment. The CLIMB SCD-121 study includes participants 12–35 years of age with diagnosed severe SCD with a significant history of vaso-occlusive crisis (VOC) events within the 2 years before enrollment. The primary end points for CLIMB THAL-111 include the proportion of patients achieving transfusion independence for a consecutive 12-month period (TI12), the proportion of patients with engraftment, time to neutrophil and platelet engraftment, frequency and severity of adverse events, incidence of transplant-related mortality, and all-cause mortality.⁹ The primary end points for CLIMB SCD-121 include the proportion of patients without any VOC events for a consecutive 12-month period (VF12 responders), the proportion of patients without any VOC events requiring hospitalization for a consecutive 12-month period (HF12), the proportion of patients with engraftment, time to neutrophil and platelet engraftment, frequency and severity of adverse events, incidence of transplant-related mortality, and all-cause mortality. Patients enrolled in the study underwent RBC transfusions at least 8 weeks before mobilization to maintain Hb S levels less than 30% and Hgb of 11 g/dL or less in SCD and 11 g/dL or greater in TDT. Moreover, patients were given myeloablative therapy with busulfan after mobilization and subsequently received an intravenous infusion of exagamglogene autotemcel.

Interim CLIMB THAL-111 and CLIMB SCD-121 Study Results

At the time of the interim analysis for CLIMB THAL-111, a total of 59 patients were enrolled and participated in mobilization, 52 patients received exagamglogene autotemcel, and 35 patients were eligible for the primary efficacy analysis.⁸ Of the patients with TDT, 91.4% (98.3% one-sided CI, 75.7%, 100%) achieved TI12 response.

At the time of the interim analysis for CLIMB SCD-121, a total of 63 patients were enrolled, 58 participated in mobilization, 44 received exagamglogene autotemcel, and 31 were eligible for the primary efficacy analysis. Of the patients with SCD, 93.5% (98% one-sided CI, 77.9%, 100.0%) achieved VF12 response. Similarly, 100% (98% one-sided CI, 77.9%, 100.0%) of these responders also achieved HF12.

Figure 1. CTX001 molecular approach and preclinical studies.

Source: Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med 2021;384:252-60.