Genetics & Molecular · 2023
Exagamglogene Autotemcel (Casgevy): First Approved CRISPR-Based Therapy
When Jennifer Doudna and Emmanuelle Charpentier published their 2012 paper describing programmable CRISPR-Cas9 DNA cutting, clinicians working in hemoglobinopathies recognized almost immediately what it might mean for sickle cell disease and beta-thalassemia. Both conditions result from well-defined mutations in a single gene, and both had a known molecular rescue: fetal hemoglobin, which the body normally silences after birth through a transcriptional repressor called BCL11A. If BCL11A could be disrupted in hematopoietic stem cells, HbF would re-emerge and compensate for the defective adult hemoglobin. The question was whether CRISPR editing could accomplish that in patient-derived stem cells precisely enough to be safe, and durably enough to be therapeutic.
Vertex Pharmaceuticals and CRISPR Therapeutics developed exagamglogene autotemcel (exa-cel), marketed as Casgevy. The approach requires collecting the patient's own hematopoietic stem and progenitor cells, editing the BCL11A enhancer ex vivo using CRISPR-Cas9, and reinfusing the cells after myeloablative conditioning. In the registration trial, 28 of 29 sickle cell patients were free of severe vaso-occlusive crises for at least 12 months after infusion; 39 of 42 transfusion-dependent thalassemia patients required no red cell transfusions. Haydar Frangoul at Children's Hospital at TriStar Centennial in Nashville was the lead clinical investigator on the published data.
The UK's Medicines and Healthcare products Regulatory Agency cleared Casgevy on November 16, 2023, the first regulatory body in the world to approve a CRISPR-based therapy. The FDA followed on December 8 for sickle cell disease and December 9 for thalassemia. Eleven years separated the Doudna-Charpentier 2012 paper from those approvals, a comparatively short arc from fundamental biochemistry to licensed medicine. A second gene therapy, lovotibeglogene autotemcel (Lyfgenia, using a lentiviral vector rather than CRISPR), received simultaneous FDA approval for sickle cell disease.
The single-course treatment listed at $2.2 million in the United States, a price that reflected the complexity of individualized manufacturing but generated immediate tension around equity. Sickle cell disease disproportionately affects patients from sub-Saharan Africa, South Asia, and the African-American community, populations with historically inconsistent access to even standard-of-care hydroxyurea. Vertex and CRISPR Therapeutics began negotiating outcomes-based agreements with payers as a model for cost amortization. Access in lower-income countries, where the burden of hemoglobinopathies is greatest, remained almost entirely unresolved at the time of approval.
Key People
- Haydar Frangoul — Lead clinical investigator, Children's Hospital at TriStar Centennial
- Jennifer Doudna — Co-developer of CRISPR-Cas9 gene editing, 2020 Nobel laureate
- Emmanuelle Charpentier — Co-developer of CRISPR-Cas9 gene editing, 2020 Nobel laureate
- Samarth Bhatt — Vertex Pharmaceuticals clinical development, exa-cel program
Frangoul H, et al. N Engl J Med. 2021;384(3):252-260 (pivotal trial data); UK MHRA and US FDA approvals 2023.
Related landmarks
- 2017 · Voretigene Neparvovec (Luxturna): First FDA-Approved In Vivo Gene Therapy for an Inherited Disease (Genetics & Molecular)
- 2012 · CRISPR-Cas9 Programmable Genome Editing (Genetics & Molecular)
- 2003 · Human Genome Project Completion (Genetics & Molecular)
- 2001 · Human Genome Project: First Draft Human Genome Sequence (Genetics & Molecular)