Exagamglogene Autotemcel (Monograph)

Brand name: Casgevy
Drug class: Gene Therapy

Introduction

Exagamglogene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy.

Uses for Exagamglogene Autotemcel

Exagamglogene autotemcel has the following uses:

Sickle Cell Disease

Exagamglogene autotemcel is indicated for the treatment of sickle cell disease (SCD) in patients 12 years of age and older with recurrent vaso-occlusive crises (VOCs). Exagamglogene autotemcel has been designated an orphan drug by FDA for the treatment of SCD.

Exagamglogene autotemcel is an autologous hematopoietic stem cell-based gene therapy prepared from the patient's own hematopoietic stem and progenitor cells (HSPCs), which are genetically edited using clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) and the SPY101 single guide RNA to disrupt expression of the B-cell lymphoma/leukemia 11A (BCL11A) gene in erythroid cells and increase production of fetal hemoglobin. Patients undergo initial RBC transfusion to dilute sickle hemoglobin, followed by hematopoietic stem cell mobilization and apheresis. The collected cells are shipped to the manufacturing site where CD34+ cells are selected and then edited with the Cas9/SPY101 ribonucleoprotein complex.

Efficacy and safety of exagamglogene autotemcel for the treatment of SCD were evaluated in an ongoing, single-arm, multicenter trial (Trial 1 [NCT03745287]) in adult and adolescent patients with SCD and severe episodes of VOC during the 2 years prior to screening. Patients underwent mobilization and apheresis, followed by myeloablative conditioning and IV infusion of exagamglogene autotemcel. An interim analysis was conducted based on data from 31 evaluable patients; the primary efficacy outcome was the proportion of VF12 responders (defined as patients who did not experience any protocol-defined VOCs for at least 12 consecutive months within the first 24 months after exagamglogene autotemcel infusion). The VF12 response rate was 93.5% at the time of interim analysis (median duration of 22.2 months). One patient who initially responded experienced a severe VOC at 22.8 months requiring hospitalization.

Transfusion-dependent β-Thalassemia

Exagamglogene autotemcel is indicated for the treatment of transfusion-dependent β-thalassemia (TDT) in patients 12 years of age and older.

Exagamglogene autotemcel is an autologous hematopoietic stem cell-based gene therapy prepared from the patient's own HSPCs, which are genetically edited using CRISPR/Cas9 and the SPY101 single guide RNA to disrupt expression of the B-cell lymphoma/leukemia 11A (BCL11A) gene in erythroid cells and increase production of fetal hemoglobin. Patients undergo initial RBC transfusion, followed by hematopoietic stem cell mobilization and apheresis. The collected cells are shipped to the manufacturing site where CD34+ cells are selected and then edited with the Cas9/SPY101 ribonucleoprotein complex.

Efficacy and safety of exagamglogene autotemcel for the treatment of TDT were evaluated in an ongoing, open-label, multicenter, single-arm trial (Trial 2 [NCT03655678]) in adult and adolescent patients Patients underwent mobilization and apheresis, followed by myeloablative conditioning and IV infusion of exagamglogene autotemcel. An interim analysis was conducted with 35 patients eligible for the primary efficacy analysis. The primary outcome was the proportion of patients achieving transfusion independence for 12 consecutive months (defined as maintaining weighted average hemoglobin ≥9 g/dL without RBC transfusions for at least 12 consecutive months any time within the first 24 months after exagamglogene autotemcel infusion). Transfusion independence was achieved in 91.4% of patients, and all patients who responded to therapy remained transfusion-independent for a median duration of 20.8 months and had normal mean weighted average total hemoglobin levels (mean 13.1 g/dL).

Exagamglogene Autotemcel Dosage and Administration

General

Exagamglogene autotemcel is available in the following dosage form(s) and strength(s):

Exagamglogene autotemcel is a cell suspension for IV infusion.
Supplied in 1 or more vials, each vial containing 4 to 13 x 10⁶ CD34⁺ cells/mL suspended in 1.5 to 20 mL of cryopreservative medium containing 5% DMSO and dextran 40.
A patient's dose may consist of multiple vials; all vials must be administered.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

For autologous use only. IV use only.

Patients are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34⁺ cells for exagamglogene autotemcel manufacturing.
Exagamglogene autotemcel must be administered between 48 hours and 7 days after the last dose of the myeloablative conditioning.
Prophylaxis for seizures should be considered prior to initiating myeloablative conditioning.
Verify that the patient's identity matches the unique patient identification information on the product labels and lot information sheet prior to thaw and infusion.
Do not sample, alter, or irradiate exagamglogene autotemcel.
Do not use an in-line blood filter or infusion pump when infusing exagamglogene autotemcel.
Administer each vial of exagamglogene autotemcel via IV infusion within 20 minutes of thaw. A patient's dose may consist of multiple vials; all vials must be administered and the entire volume of each vial provided should be infused.

Pediatric Patients

Dosage for SCD and TDT

Dosing of exagamglogene autotemcel is based on body weight. The minimum recommended dose in adolescents ≥12 years of age is 3 × 10⁶ CD34⁺ cells/kg.

Adults

Dosage for SCD and TDT

Dosing of exagamglogene autotemcel is based on body weight. The minimum recommended dose in adults is 3 × 10⁶ CD34⁺ cells/kg.

Cautions for Exagamglogene Autotemcel

Contraindications

None.

Warnings/Precautions

Potential Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with exagamglogene autotemcel. In the clinical trials, all treated patients achieved neutrophil engraftment and no patients received rescue CD34⁺ cells.

Monitor absolute neutrophil counts (ANC) and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, patients should be infused with rescue CD34⁺cells.

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with exagamglogene autotemcel treatment. There is an increased risk of bleeding until platelet engraftment is achieved. In the clinical trials, there was no association observed between incidence of bleeding events and time to platelet engraftment.

Monitor patients for bleeding according to standard guidelines and medical judgement. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis can occur due to dimethyl sulfoxide (DMSO) or dextran 40 in the cryopreservative solution. Monitor patients for hypersensitivity reactions during and after infusion.

Off-target Genome Editing Risk

Although off-target genome editing was not observed in the edited CD34⁺ cells evaluated from healthy donors and patients, the risk of unintended, off-target editing in an individual's CD34⁺ cells cannot be ruled out due to genetic variants. The clinical significance of potential off-target editing is unknown.

Specific Populations

Pregnancy

There are no clinical data from the use of exagamglogene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman. Exagamglogene autotemcel must not be administered during pregnancy because of the risks associated with myeloablative conditioning. Pregnancy after exagamglogene autotemcel infusion should be discussed with the treating physician.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Lactation

There are no data on the presence of exagamglogene autotemcel in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential risks associated with myeloablative conditioning, breastfeeding should be discontinued during conditioning. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for exagamglogene autotemcel and any potential adverse effects on the breastfed child from exagamglogene autotemcel or from the underlying maternal condition. Breastfeeding after exagamglogene autotemcel infusion should be discussed with the treating physician.

Females and Males of Reproductive Potential

A negative serum pregnancy test must be confirmed prior to the start of each mobilization cycle and re-confirmed prior to myeloablative conditioning.

There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with exagamglogene autotemcel. Women of childbearing potential and men capable of fathering a child must use effective method of contraception from start of mobilization through at least 6 months after administration of exagamglogene autotemcel. Advise patients of the risks associated with conditioning agents.

There are no data on the effects of exagamglogene autotemcel on human fertility. Effects on male and female fertility have not been evaluated in animal studies. Infertility has been observed with myeloablative conditioning; therefore, advise patients of fertility preservation options before treatment, if appropriate.

Pediatric Use

The safety and efficacy of exagamglogene autotemcel have been established in pediatric patients with SCD and TDT who are 12 years of age and older. Use of exagamglogene autotemcel in patients 12 to less than 18 years of age is supported by data in 12 patients with SCD in Trial 1 (6 patients evaluable for the primary efficacy analysis), and 18 patients with TDT in Trial 2 (11 patients evaluable for the primary efficacy analysis). The efficacy and safety profile of exagamglogene autotemcel in pediatric patients 12 years of age and older were consistent with the efficacy and safety in adult patients.

Patients with SCD: The median (min, max) time to platelet engraftment was 45 (23, 81) days in pediatric patients 12 years of age and older and 32 (23, 126) days in adult patients. The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in pediatric patients 12 years of age and older and 26 (15, 38) days in adult patients.

Patients with TDT: The median (min, max) time to platelet engraftment was 45 (20, 199) days in pediatric patients aged 12 years and older and 41.5 (24, 200) days in adult patients. The median (min, max) time to neutrophil engraftment was 30 (19, 56) days in pediatric patients aged 12 years and older and 28.5 (12, 40) days in adult patients.

The safety and efficacy of exagamglogene autotemcel in pediatric patients younger than 12 years of age have not been established.

Geriatric Use

Exagamglogene autotemcel has not been studied in patients >65 years of age. HSC transplantation must be appropriate for a patient to be treated with exagamglogene autotemcel.

Renal Impairment

Exagamglogene autotemcel has not been studied in patients with renal impairment, defined as estimated glomerular filtration rate <60 mL/min/1.73 m². Patients should be assessed for renal impairment to ensure HSC transplantation is appropriate.

Hepatic Impairment

Exagamglogene autotemcel has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate.

Patients Seropositive for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV)

Exagamglogene autotemcel has not been studied in patients with HIV-1, HIV-2, HBV or HCV. Perform screening for HIV-1, HIV-2, HBV and HCV and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. Exagamglogene autotemcel should not be used in patients with active HIV-1, HIV-2, HBV or HCV.

Patients with Prior HSC Transplant

Exagamglogene autotemcel has not been studied in patients who have received a prior allogeneic or autologous HSC transplant. Treatment with exagamglogene autotemcel is not recommended in these patients.

Common Adverse Effects

The most common Grade 3 or 4 non-laboratory adverse reactions (incidence ≥25%) were mucositis and febrile neutropenia in patients with SCD and TDT, and decreased appetite in patients with SCD.

The most common Grade 3 or 4 laboratory abnormalities (≥50%) were neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Granulocyte Colony Stimulating Factor: Granulocyte-Colony Stimulating Factor (G-CSF) must not be used for CD34⁺ HSC mobilization of patients with sickle cell disease.
Hydroxyurea: Discontinue hydroxyurea at least 8 weeks prior to start of mobilization and conditioning.
Voxelotor and Crizanlizumab: Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilization and conditioning.
Iron Chelators: Discontinue iron chelators at least 7 days prior to initiation of myeloablative conditioning. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after exagamglogene autotemcel infusion.

Actions

Mechanism of Action

After exagamglogene autotemcel infusion, the edited CD34⁺ cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and fetal hemoglobin (HbF) protein production in erythroid cells. In patients with severe sickle cell disease, HbF expression reduces intracellular hemoglobin S (HbS) concentration, preventing the red blood cells from sickling and addressing the underlying cause of disease, thereby eliminating vaso-occlusive crises (VOCs).

In patients with transfusion-dependent β-thalassemia, γ-globin production improves the α-globin to non-α-globin imbalance thereby reducing ineffective erythropoiesis and hemolysis and increasing total hemoglobin levels, addressing the underlying cause of disease, and eliminating the dependence on regular RBC transfusions.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).
Prior to treatment, advise patients of the risks associated with mobilization and myeloablative conditioning agents and to read the FDA approved patient labeling (Patient Information) for these agents.
Advise patients of the potential need for additional cell collection. Ensure patients understand that if the minimum dose of exagamglogene autotemcel is not met after initial product manufacturing, additional cycles of mobilization and apheresis will be needed to collect additional cells for product manufacture.
Advise patients that disease modifying therapies (e.g., hydroxyurea, crizanlizumab, voxelotor) should be discontinued 8 weeks before the planned start of mobilization and conditioning.
Advise patients that iron chelation should be stopped at least 7 days prior to myeloablative conditioning. If iron chelation is required, the use of non-myelosuppressive iron chelators should be avoided for at least 3 months after exagamglogene autotemcel administration and use of myelosuppressive iron chelators should be avoided for at least 6 months after exagamglogene autotemcel administration. Phlebotomy can be used in lieu of iron chelation, when appropriate.
Advise patients of the risk of neutrophil engraftment failure after treatment. Advise patients they will need to receive rescue treatment with their collection of unmodified CD34⁺ cells if they do not achieve neutrophil engraftment after exagamglogene autotemcel administration.
Advise patients that there is an increased risk of bleeding from initiation of myeloablative conditioning until platelet engraftment is achieved. Advise patients to monitor for signs and symptoms of new or worsening bleeding or bruising and have frequent blood draws for platelet counts, until platelet recovery has been achieved.
Advise patients that they should not donate blood, organs, tissues, or cells at any time in the future.

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Exagamglogene Autotemcel
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Suspension, for IV infusion	4 to 13 × 10⁶ CD34+ cells/mL	Casgevy (supplied in 1 or more vials containing a frozen suspension of genome-edited autologous CD34+ cells in a cryopreservative medium containing 5% DMSO and dextran 40)	Vertex Pharmaceuticals