Back in November 2023, the UK’s Medicines and Healthcare product Regulatory Agency (MHRA) granted the world’s first regulatory approval of a CRISPR-based therapy1.
Now it has been announced that this groundbreaking therapy, known as exagamglogene autotemcel, or exa-cel for short (brand name Casgevy®), has been approved for use on the National Health Service (NHS) in England, offering patients the prospect of a cure for severe sickle cell disease (SCD)2.
What does this mean for patients?
The role of National Institute for Heath and Care Excellence (NICE) is to provide an independent evaluation of how treatments affect health outcomes and whether they are cost-effective for the public healthcare system. In practice, this NICE approval means that exa-cel will be routinely publicly funded and accessible to patients with certain types of severe SCD, regardless of their income or employment status, via the NHS.
Before exa-cel, the only curative treatment for SCD was a stem cell transplant, but this relies on finding a matched donor. This new therapy no longer relies on finding a matched donor because it uses the patient’s own stem cells (as discussed in more detail below).
What is exa-cel?
Exa-cel is a non-viral, autologous ex vivo CRISPR/Cas9 gene-edited therapy developed by CRISPR Therapeutics and Vertex. A first-of-its-kind treatment, this approval comes just over a decade after Nobel Prize winning technology was reported in the landmark Science paper3.
How does it work?
Exa-cel is targeted at patients’ own CD34+ hematopoietic stem cells (HSCs), and works by editing these HSCs and progenitor cells at the erythroid specific enhancer region of the BCL11A gene through a precise double strand break4. BCL11A represses transcription of the gene encoding γ-globin, which along with α-globin forms the tetrameric protein fetal hemoglobin (HbF). This edit disrupts expression of BCL11A resulting in production of high levels of HbF, the form of oxygen-carrying hemoglobin naturally present during fetal development. Production of HbF compensates for the loss of adult hemoglobin and is associated with reduced symptoms and improved outcomes in patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT).
How is it administered5?
CD34+ hematopoietic stem cells are isolated from the patient’s own bone marrow and electroporation is used to introduce the CRISPR editing components, a ribonucleoprotein complex comprising a synthetic guide RNA and Cas9 endonuclease. The CRISPR edited CD34+ cells are then reinfused into the patient. The entire process can take several months as a result of the preconditioning regimen required prior to administration of exa-cel. Sickle cell anaemia patients must undergo blood transfusions for two months, followed by two rounds of cell mobilisation and apheresis (a process of separating blood into its individual elements in order to collect or remove the required elements). All of which is to obtain the CD34+ cells to be edited by the CRISPR components. Before reinfusion of these edited cells, patients are required to undergo a highly toxic chemotherapy-based myeloablative preconditioning regimen with dose-adjusted busulfan to clear out space in the bone marrow for the edited cells. This makes for a costly and complex therapy but it could represent a potential cure for certain patients with severe sickle cell disease.
Clinical trials
Despite the intensive regimen for administration, impressive results were published in the New England Journal of Medicine6,7, detailing the clinical trials: CLIMB SCD-121 for severe sickle cell disease (NCT03745287) and CLIMB THAL-111 for transfusion-dependent β-thalassemia (NCT03655678).
CLIMB SCD-121 (severe sickle cell disease) demonstrated elimination of severe vaso-occlusive crises (a blockage resulting in lack of oxygen and extremely painful inflammatory attacks) for at least 12 consecutive months in 29 out of 30 participants who had sufficient follow-up data for evaluation. All 30 participants were free from hospitalisation for vaso-occlusive crises for at least 12 consecutive months6. CLIMB THAL-111 (transfusion-dependent β-thalassemia) demonstrated transfusion independence in 32 out of 35 participants who had sufficient follow-up data for evaluation7. It is therefore no surprise that the UK endorsed exa-cel with MHRA approval, followed in quick succession by US FDA approval for treatment of sickle cell anemia.
What next?
The clinical trials demonstrated safety profiles consistent with myeloablative busulfan conditioning (the required myeloablative preconditioning regimen) and autologous hematopoietic stem and progenitor cell transplantation. Nevertheless, an overarching concern associated with CRISPR therapies is the potential introduction of off-target double strand breaks in a patient’s DNA. As of yet, exa-cel’s long-term safety profile has not been determined. However, patients have enrolled in CLIMB-1318, an ongoing long-term, open-label trial evaluating the safety and efficacy of exa-cel for up to 15 years in patients who received exa-cel in earlier trials, such as CLIMB SCD-121 and CLIMB THALL-111 described above.
Exa-cel approval is a major scientific milestone that highlights the enormous potential CRISPR therapies hold in revolutionizing treatment of genetic diseases and disorders. Following decades of development, CRISPR is not just a tool used for cleaving DNA strands, it has given rise to technologies such as single-base gene editing approaches, RNA cleaving, and transcriptional regulation, all of which hold promise in clinical applications going forward.
Our team has considerable experience advising clients on patent matters in relation to CRISPR technologies and gene therapies, as well as assisting clients throughout all stages of clinical trial candidate development. Please get in touch with Beth Ormrod, Jamie Atkins, or your usual Kilburn & Strode advisor if you have any related queries.
1: https://crisprtx.com/therapies
2: https://www.nice.org.uk/news/articles/nice-approves-groundbreaking-one-off-gene-therapy-for-severe-sickle-cell-disease
3: Jinek, M. et al., A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science, 337(6096): 816-821 (2012)
4: https://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-announces-us-food-and-drug-administration
5: Sheridan, Cormac. The world’s first CRISPR therapy is approved: who will receive it?. Nature Biotechnology (2023)
6: Frangoul, H. et al., Exagamglogene Autotemcel for Severe Sickle Cell Disease. New England Journal of Medicine, 390: 1649-1662 (2024)
7: Locatelli, F. et al., Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia. New England Journal of Medicine, 390: 1663-1676 (2024)
8: https://crisprtx.com/about-us/press-releases-and-presentations/crispr-therapeutics-and-vertex-complete-submission-of-rolling-biologics-license-applications-blas-to-the-us-fda-for-exa-cel-for-the-treatment-of-sickle-cell-disease-and-transfusion-dependent-