We are getting closer to a world where the debilitating pain and complications of sickle cell disease are a thing of the past. For the 17,500 people in the UK living with this genetic condition, this is becoming a reality, thanks to groundbreaking advancements in gene therapy and, now, the approval by NICE for the use of exagamglogene autotemcel (exa-cel) for sickle cell in the NHS. The innovative treatment exa-cel had previously been approved for treating beta-thalassemia in the UK in September 2024.
Characterized by abnormal haemoglobin that distorts red blood cells into a sickle shape, the condition has long been challenging to manage. For many years, treatment options have been limited, focusing mainly on managing symptoms and preventing complications. Exa-cel provides a new hope for people with sickle cell disease to have a cure.
Understanding sickle cell disease
Sickle cell disease is caused by a mutation in the HBB gene, which encodes the beta-globin subunit of hemoglobin. This mutation results in the production of hemoglobin S, which can clump to together under low oxygen conditions, causing red blood cells to become rigid and sickle-shaped. These sickle cells can obstruct blood flow, leading to painful vaso-occlusive crises, increased risk of infection, and chronic organ damage. This can be debilitating and affects peoples lives significantly.
Traditional treatments include pain management, blood transfusions, and hydroxyurea, a medication that can reduce the frequency of crises. While these treatments can improve quality of life, they do not address the underlying genetic cause of the disease. Bone marrow transplants offer a potential cure, but finding a suitable donor and the risk of rejection are significant challenges.
The role of gene therapy
Gene therapy represents a revolutionary approach to treating genetic disorders like sickle cell disease. By directly addressing the genetic mutation responsible for the disease, gene therapy has the potential to provide a long-term cure. One of the most promising gene therapies for sickle cell disease is exa-cel, which uses the CRISPR-Cas9 gene-editing technology to modify the patient’s own hematopoietic stem cells.
Exa-cel works by harvesting the patient’s hematopoietic stem cells from their bone marrow. These cells are then genetically modified using CRISPR-Cas9 to correct the mutation in the HBB gene. The edited cells are expanded in the laboratory and then re-infused into the patient. Before this can happen, the patient needs to undergo a conditioning regimen, which involves a combination of chemotherapy and/or radiation therapy to eliminate the existing bone marrow cells. This process prepares the bone marrow to receive the new cells, similar to a traditional bone marrow transplant from a donor.
Once in the body, these gene-edited cells can produce healthy red blood cells, significantly reducing and even eliminating the symptoms. By addressing the genetic root of the disease, exa-cel has the potential to provide a long-term cure and significantly improve the quality of life for those affected.
The benefits of exa-cel are significant. By using the patient’s own cells, the risk of rejection is minimized – a major advantage over traditional bone marrow transplants. Additionally, the potential to reduce or eliminate crises, improve overall quality of life, and decrease the need for ongoing treatments like blood transfusions and pain management.
Clinical trials for exa-cel have shown promising results that it has been authorised by the FDA and MHRA for use in beta thalassemia and sickle cell disease. These successes make CRISPR technology, as used by exa-cel, a viable treatment option for many patients.
Side effects and considerations
While exa-cel offers great promise, it is important to consider the potential side effects and challenges associated with this therapy. The conditioning regimen required before the infusion of gene-edited cells can cause side effects similar to those experienced with bone marrow transplants, such as infections, nausea, and fatigue. Additionally, long-term monitoring is necessary to ensure the safety and efficacy of the treatment. Participants who took part of the initial trials are going to be monitored for 15 years to monitor efficacy over time.
NICE has chosen managed access for exa-cel due to remaining uncertainties in the clinical evidence, such as the long-term effects of the treatment. It is for treating severe SCD in people 12 years and over with recurrent crises who have a βS/βS, βS/β+ or βS/β0 genotype. Managed access is a framework used to provide patients with early access to promising new treatments, while collecting additional data on their long-term effectiveness and safety. By using managed access, NICE aims to resolve these uncertainties through ongoing data collection, ensuring that patients benefit from the treatment while robust evidence is gathered to support its broader use.
Value for money?
The list price for exa-cel is £1,651,000 per course of treatment. However, there is a commercial arrangement with the manufacturer, Vertex, that makes exa-cel available to the NHS at a discounted rate. NICE’s decision that the cost of exa-cel is valuable for the NHS has been carefully calculated, taking into consideration the long-term treatments required throughout a sickle cell disease patient’s lifetime. This included the use of a severity modifier—a numerical value that adjusts the perceived severity of a medical condition for healthcare planning and resource allocation.
For sickle cell disease, a 1.2 severity modifier was used to reflect the chronic nature of the disease, frequent painful crises, organ damage, and the significant impact on patients’ quality of life. This modifier helps ensure that healthcare systems allocate appropriate resources and provide the necessary care to meet the complex needs of individuals with sickle cell disease.
The future of gene therapy for sickle cell disease
There is still much to learn about sickle cell disease and how it affects patients. NHSE estimates that around 50 patients per year will benefit from exa-cell, leaving many others still requiring treatment and care.
To gain a better understanding, the James Lind Alliance (JLA) Sickle Cell Genomics Priority Setting Partnership (PSP) has been established with Genomics England and the Sickle Cell Society. They are engaging with patients, carers, carriers, and healthcare professionals to identify uncertainties about the relationship between sickle cell disease and genomics. We encourage everyone to participate in the survey to ensure their voices are heard on these important topics and look forward to hearing the results.
Research and clinical trials will continue to refine the therapy, seek alternatives and address remaining concerns. The ongoing research and development of exa-cel and other gene therapies represents a significant step forward in the treatment of genetic disorders.