NAV

Exagamglogene autotemcel

Identification

Summary

Exagamglogene autotemcel is an autologous CRISPR-Cas9 modified hematopoietic stem cell therapy for the treatment of patients with sickle cell disease and recurrent vaso-occlusive crises.

Brand Names
Casgevy
Generic Name
Exagamglogene autotemcel
DrugBank Accession Number
DB15572
Background

Sickle cell disease (SCD) is a genetic disorder characterized by the production of abnormal sickle-shaped red blood cells (called hemoglobin S, HbS) that initiate a pathophysiology resulting in severe pain, progressive multi-organ damage, and premature death.1 Treatment options for SCD are largely focused on preventing the production and circulation of HbS and inducing the production of normal fetal hemoglobin (HbF),2,3 including hydroxyurea - a mainstay of treatment since the 1990s - as well as newer agents like crizanlizumab and voxelotor.

Exagamglogene autotemcel is an autologous CRISPR-Cas9 modified CD34+ human hematopoietic stem and progenitor cells which has been investigated in clinical trials for the treatment of severe SCD and severe beta-thalassemia.4 Following engraftment, it causes an increase in the production of HbF and a subsequent decrease in HbS. It was approved by the FDA in December 2023 for the treatment of patients with SCD with recurrent vaso-occlusive crises.5 It is the first CRISPR-based gene editing therapy to be approved in the United States.6 In January 2024, exagamglogene autotemcel received an additional FDA approval for the treatment of transfusion-dependent β-thalassemia.7

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Other gene therapies
Synonyms
  • Autologous CD34+ cells isolated from mobilised peripheral blood by positive selection, modified by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) mediated gene editing consisting of a guide RNA (gRNA)
  • Exa-cel
External IDs
  • CTX 001
  • CTX-001
  • CTX001
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Pharmacology

Indication

Exagamglogene autotemcel (Casgevy) is a gene therapy indicated for the treatment of sickle cell disease in patients ≥12 years of age with recurrent vaso-occlusive crises (VOCs).5 It is also indicated for the treatment of patients ≥12 years of age with transfusion-dependent β-thalassemia.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofSickle cell disease (scd)••••••••••••••••••••• •••••••••••••• •••••••••••••••• ••••••••••
Treatment ofTransfusion dependent beta-thalassaemia•••••••••••••••••••••• ••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Exagamglogene autotemcel exerts its therapeutic effects by increasing the production of normal fetal hemoglobin and decreasing the production of sickle hemoglobin.5 As an autologous therapy, patients must undergo stem cell mobilization and myeloablative conditioning prior to infusion with exagamglogene autotemcel. Plerixafor is preferable for stem cell mobilization, as filgrastim should not be used for mobilization in patients with sickle cell disease.5 Disease-modifying therapies for sickle cell disease - such as hydroxyurea, crizanlizumab, and voxelotor - should be discontinued at the initiation of blood transfusions prior to myeloablative conditioning, and any iron chelating therapies should be discontinued at least 7 days prior.5

Mechanism of action

Exagamglogene autotemcel is an autologous gene therapy in which patient CD34+ hematopoietic stem cells are edited using CRISPR/Cas9 technology. A precise DNA double-strand break is made at a critical transcription factor binding site (GATA1) in the erythroid-specific enhancer region of the BCL11A gene, which disrupts GATA1 binding and reduces BCL11A protein expression. Following infusion and engraftment, the reduction in BCL11A expression results in an increase in γ-globin expression and downstream fetal hemoglobin production. Fetal hemoglobin expression reduces intracellular sickle hemoglobin concentration, preventing red blood cells from sickling and addressing the underlying cause of the disease.5

Absorption

As an autologous cell therapy, conventional studies on pharmacokinetics are not applicable to exagamglogene autotemcel.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
CefiderocolThe risk or severity of myelosuppression can be increased when Exagamglogene autotemcel is combined with Cefiderocol.
Chromium picolinateThe risk or severity of myelosuppression can be increased when Exagamglogene autotemcel is combined with Chromium picolinate.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CasgevyInjection, suspension13000000 1/1mLIntravenousVertex Pharmaceuticals Incorporated2023-12-08Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans

Chemical Identifiers

UNII
S53L777GM8
CAS number
Not Available

References

General References
  1. Doerfler PA, Sharma A, Porter JS, Zheng Y, Tisdale JF, Weiss MJ: Genetic therapies for the first molecular disease. J Clin Invest. 2021 Apr 15;131(8):e146394. doi: 10.1172/JCI146394. [Article]
  2. Meier ER: Treatment Options for Sickle Cell Disease. Pediatr Clin North Am. 2018 Jun;65(3):427-443. doi: 10.1016/j.pcl.2018.01.005. [Article]
  3. Brandow AM, Liem RI: Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol. 2022 Mar 3;15(1):20. doi: 10.1186/s13045-022-01237-z. [Article]
  4. BioPharma Dive: First look at CRISPR, Vertex gene-editing therapy hints at treatment potential [Link]
  5. FDA Approved Drug Products: Casgevy (exagamglogene autotemcel) suspension for intravenous infusion (January 2024) [Link]
  6. FDA Press Announcements: FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease [Link]
  7. Vertex Pharmaceuticals News Release: Vertex Announces US FDA Approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia [Link]
RxNav
2671667
Wikipedia
Exagamglogene_autotemcel

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Enrolling by InvitationOtherBeta-Thalassemia / Genetic Diseases, Inborn / Haemoglobinopathies congenital / Hematologic Disease and Disorders / Sickle Cell Anemia / Sickle Cell Disease (SCD) / Thalassemia1
3Not Yet RecruitingTreatmentSickle Cell Disease (SCD)1
3RecruitingTreatmentBeta-Thalassemia / Genetic Diseases, Inborn / Haemoglobinopathies congenital / Hematologic Disease and Disorders / Sickle Cell Anemia / Sickle Cell Disease (SCD) / Thalassemia1
3RecruitingTreatmentBeta-Thalassemia / Genetic Diseases, Inborn / Haemoglobinopathies congenital / Hematologic Disease and Disorders / Thalassemia1
3RecruitingTreatmentHaemoglobinopathies congenital / Hematologic Disease and Disorders / Hydroxyurea Failure / Hydroxyurea Intolerance / Sickle Cell Disease (SCD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, suspensionIntravenous13000000 1/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Drug created at November 19, 2019 16:39 / Updated at January 20, 2024 14:03