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.

Source:

Figure 2. Hemoglobin fractionation, F-cell levels, and transfusion events in the study patients (early results).

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.

Table 1. Demographics and Baseline Characteristics of Patients Treated with Exagamglogene Autotemcel (Casgevy) at the Interim Analysis in CLIMB THAL-111

Source: Casgevy (exagamglogene autotemcel) [prescribing information]. Vertex Pharmaceuticals, December 2023.

Table 2. Demographics and Baseline Characteristics of Patients Treated with Exagamglogene Autotemcel (Casgevy) at the Interim Analysis in CLIMB SCD-121

Source: Casgevy (exagamglogene autotemcel) [prescribing information]. Vertex Pharmaceuticals, December 2023.

PREPARATION AND DOSING

Exagamglogene autotemcel is prepared as a single-dose cell suspension for intravenous infusion.^8,10 This product consists of one or more vials containing 4–13 × 10⁶ CD34⁺ cells/mL in 1.5–20 mL of cryopreservative solution with 5% dimethyl sulfoxide (DMSO) and dextran 40.

The recommended minimum dose of exagamglogene autotemcel is 3 × 10⁶ CD34⁺ cells/kg of body weight. In the clinical trial for SCD, the median (min, max) dose of exagamglogene autotemcel was 4.0 (2.9, 14.4) × 10⁶ CD34⁺ cells/kg. In the clinical trial for TDT, the median (min, max) dose of exagamglogene autotemcel was 7.5 (3.0, 19.7) × 10⁶ CD34⁺ cells/kg.

Storage and Handling

Exagamglogene autotemcel should be stored in liquid nitrogen at -135°C or lower (-211°F or lower) for a maximum of 18 months from the manufacturing date. Before use, each vial must be thawed and administered within 20 minutes.^7-10 Once thawed, this product may appear slightly cloudy or have small particulate matter because of the presence of cells and cell derivatives.

ADVERSE EFFECTS

The most common adverse events with exagamglogene autotemcel use in SCD and TDT include mucositis (86% and 71%), febrile neutropenia (48% and 54%), neutropenia (100%), thrombocytopenia (100%), leukopenia (98%), lymphopenia (50% and 79%), anemia (84% and 92%), and loss of appetite (41% and 23%).⁸

Precautions/Warnings⁸

• Neutrophil engraftment failure

• Delayed platelet engraftment

• Hypersensitivity reactions (i.e., anaphylaxis)

o Because of the DMSO and dextran 40 contents in the cryopreservative solution

• Risk of off-target genome editing

• Risk of bleeding

Contraindications

According to the manufacturer’s labeling, there are no contraindications for exagamglogene autotemcel.⁸

MONITORING

Mobilization and Apheresis

Before treatment with exagamglogene autotemcel, patients should complete a plerixafor-only mobilization and apheresis of their CD34⁺ cells for 2 consecutive days per manufacturing cycle.⁸ If tolerated, at least 20 × 10⁶ CD34⁺ cells/kg is recommended for HSC collection. Any collected cells should still be sent to the manufacturer, even if this goal is not met. In addition, 2 × 10⁶ CD34⁺ cells/kg should be collected for unmodified back-up rescue cells. If needed, a third consecutive day of collection may be completed for the back-up rescue cells. If additional mobilization and apheresis cycles are necessary to achieve the minimum dose (3 × 10⁶ CD34⁺ cells/kg), each cycle must be separated by at least 14 days.

Myeloablative Conditioning

After HSC collection, patients should receive myeloablative therapy.⁸ In the clinical trials for SCD and TDT, busulfan was used as myeloablative therapy, and seizure prophylaxis (excluding phenytoin) was administered to the study participants.

Administration

Administration of exagamglogene autotemcel may occur after a washout period of 48 hours to 7 days after the last dose of myeloablative therapy.^8,10 In the clinical trials for SCD and TDT, all the study participants were premedicated with an antihistamine and antipyretic before the infusion.

Exagamglogene autotemcel should be administered through a central intravenous line and should not exceed a total volume administered within 1 hour of 2.6 mL/kg. After administration, the intravenous tubing used should be flushed with 0.9% sodium chloride solution. If more than one vial is needed, each vial should be thawed and administered completely before proceeding to an additional vial.

DRUG INTERACTIONS

Formal drug interaction studies were not conducted for exagamglogene autotemcel; however, this product is not expected to have any hepatic CYP drug interactions.⁸

Patients are advised to discontinue the use of granulocyte colony-stimulating factor, hydroxyurea, voxelotor, and crizanlizumab at least 8 weeks before therapy. Iron chelators should be discontinued at least 7 days before treatment, and subsequent use should be avoided for at least 6 months (or 3 months for nonmyelosuppressive iron chelators).

Pharmacokinetics

There are no pertinent pharmacokinetic parameters for exagamglogene autotemcel.

PLACE IN THERAPY

Exagamglogene autotemcel serves as the first-in-class CRISPR/Cas9 genome editing, one-time use, curative treatment for SCD with recurrent VOC events and TDT.^6-8,11 Given the scarcity of finding a perfectly matched donor for allogeneic HSC transplantation and the risks associated (i.e., graft-vs.-host disease), exagamglogene autotemcel offers a more simplified means of achieving a potential cure for SCD and TDT. Competitor therapeutic options are available; however, given the limited choices for achieving a cure, the unique targeting of exagamglogene autotemcel and ability to use this product in patients 12 years and older seem to highlight its distinct place in therapy.

SPECIAL POPULATIONS

Use in Pregnancy and Lactation

Exagamglogene autotemcel was not studied in pregnant or lactating populations.⁸ Similarly, reproductive or lactation toxicology studies were not conducted. Given the potential toxicity from myeloablative conditioning, this product is not recommended for pregnant or breastfeeding patients.

Use in Children

The safety and efficacy of exagamglogene autotemcel have only been studied in patients 12 years and older.⁸ Overall, the effects with this product in patients 12 years and older were congruent with those in adult patients.

Use in Older Adults

Exagamglogene autotemcel was not studied in adult patients older than 65; thus, patient screening should be used to ensure that HSC transplantation is appropriate.⁸

Use in Renal Impairment

Exagamglogene autotemcel was not studied in patients with renal impairment (glomerular filtration rate less than 60 mL/minute); thus, patient screening should be used to ensure that HSC transplantation is appropriate.⁸

Use in Hepatic Impairment

Exagamglogene autotemcel was not studied in patients with hepatic impairment; thus, patient screening should be used to ensure that HSC transplantation is appropriate.⁸ Moreover, this product was not studied in patients with HIV (HIV-1, HIV-1), hepatitis B virus, or hepatitis C virus infection; therefore, this product should not be used in these populations.

PATIENT EDUCATION

Exagamglogene autotemcel is a one-time use, curative treatment option for those 12 years and older who have SCD with recurrent vaso-occlusive crises (VOCs) or β-thalassemia needing regular blood transfusions (transfusion-dependent β-thalassemia [TDT]).⁸ This product uses genome editing technology called CRISPR/Cas9 to cure SCD and TDT through editing the DNA of the body’s stem cells to increase the production of fetal hemoglobin. Before initiating exagamglogene autotemcel, a health care provider will administer a medicine to allow for mobilization of your stem cells from the bone marrow to the bloodstream to prepare for collection, and your stem cells will be sent to a manufacturing site used to make exagamglogene autotemcel. Afterward, you will be given a preconditioning treatment to clear your remaining stem cells and prepare for the exagamglogene autotemcel infusion. Finally, exagamglogene autotemcel will be infused intravenously, and you will be monitored. Common adverse effects of exagamglogene autotemcel include low platelet and low white blood cell counts, which could increase the risk of bleeding and infection. Similarly, please tell your health care provider if you experience any infection, fever, chills, severe bleeding, severe headache, abnormal bruising, or spontaneous or prolonged bleeding. Of importance, patients receiving exagamglogene autotemcel should not donate blood, organs, tissues, or cells at any point after treatment, in the future.

References

1. Centers for Disease Control and Prevention (CDC). Data & Statistics on Sickle Cell Disease [last reviewed Jul 6, 2023]. Available at https://www.cdc.gov/ncbddd/sicklecell/data.html.

2. National Heart, Lung, and Blood Institute (NHLBI). What Is Sickle Cell Disease? Available at https://www.nhlbi.nih.gov/health/sickle-cell-disease.

3. Centers for Disease Control and Prevention (CDC). Complications of Sickle Cell Disease [last reviewed Nov 8, 2023]. Available at https://www.cdc.gov/sickle-cell/complications/index.html.

4. Abboud MR. Standard management of sickle cell disease complications. Hematol Oncol Stem Cell Ther 2020;13:85-90.

5. Johnson KM, Jiao B, Ramsey SD, et al. Lifetime medical costs attributable to sickle cell disease among nonelderly individuals with commercial insurance. Blood Adv 2023;7:365-74.

6. GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021 [published correction appears in Lancet Haematol 2023;10:e574]. Lancet Haematol 2023;10:e585-e599.

7. Brandow AM, Liem RI. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol 2022;15:20.

8. Casgevy (exagamglogene autotemcel) [prescribing information]. Vertex Pharmaceuticals, December 2023.

9. 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.

10. Exagamglogene autotemcel. Lexi-Drugs [online database]. Lexicomp, December 20, 2023.

11. Kuriri FA. Hope on the horizon: new and future therapies for sickle cell disease. J Clin Med 2023;12:5692.