The Scottish Medicines Consortium (SMC) has accepted exagamglogene autotemcel (Casgevy, Vertex Pharmaceuticals) for use within NHS Scotland to treat sickle cell disease (SCD) in patients aged 12 years or older who experience recurrent vaso-occlusive crises (VOCs).

The recommendation applies to patients with βS/βS, βS/β+ or βS/β0 genotypes who are eligible for haematopoietic stem cell transplantation (HSCT) but lack a suitable human leukocyte antigen-matched related donor.

This decision follows a full submission assessed through the SMC orphan medicine process and applies only in the context of an approved NHS Scotland Patient Access Scheme, which allows confidential pricing arrangements for high-cost therapies.

Disease Context

SCD is a chronic, inherited blood disorder caused by mutations in the beta-globin gene, leading to the production of sickle haemoglobin. Recurrent VOCs lead to severe pain, frequent hospitalisations, progressive organ damage, and reduced life expectancy, typically estimated at 40-50 years with current standard care. The condition disproportionately affects people of Mediterranean, Middle Eastern, African, and Asian ancestry.

The SMC concluded that exagamglogene autotemcel addresses a significant unmet need for patients with severe SCD who lack curative treatment options. Clinical experts highlighted its potential to deliver durable disease modification after a single intervention, reducing dependence on hydroxycarbamide, blood transfusions, and recurrent hospital care.

How the Gene Therapy Works

Exagamglogene autotemcel is a personalised, autologous, cell-based gene therapy that uses CRISPR/Cas9 gene-editing technology to modify a patient’s own stem cells. Autologous haematopoietic stem and progenitor cells are collected and edited ex vivo to increase the production of foetal haemoglobin (HbF). Elevated HbF levels inhibit red blood cell sickling and prevent the cascade of complications that characterise SCD.

The treatment is administered as a single intravenous infusion following standard autologous HSCT procedures, including mobilisation, apheresis, and myeloablative conditioning. The minimum recommended dose is 3 × 10⁶ CD34+ cells per kilogram of body weight.

Clinical Evidence

The SMC’s decision was based on evidence from the CLIMB SCD-121 study and its ongoing long-term follow-up study, CLIMB-131. CLIMB SCD-121 was a single-arm phase 1/2/3 study, and CLIMB-131 provides up to 13 years of post-treatment follow-up. 

The trials included patients aged 12-35 years with severe SCD and recurrent VOCs who lacked a matched related donor and received a single infusion of exagamglogene autotemcel.

In the primary efficacy analysis, 97% of treated patients remained free from severe VOCs for at least 12 consecutive months after infusion. At the most recent August 2024 data cutoff, 88% of patients continued to meet this endpoint, with additional patients achieving sustained VOC-free periods during extended follow-up.

Treatment also produced sustained improvements in haemoglobin levels, increasing from a baseline mean of 9.1 g/dL to more than 12 g/dL. Foetal haemoglobin increased from 5.2% to more than 40% of total haemoglobin.

Safety Profile 

All patients experienced treatment-related adverse events, which were primarily attributable to busulfan conditioning treatment rather than to the gene therapy itself. 

Common events included febrile neutropenia, infections, and cytopenias, typically occurring within the first 6 months after infusion.

No cases of graft failure or graft-vs-host disease were reported. Long-term safety monitoring is ongoing due to the novel nature of CRISPR-based gene editing.

Implementation Considerations

The therapy requires significant healthcare infrastructure, including multidisciplinary teams for patient selection, pretransplant preparation, and posttreatment monitoring. Healthcare services must establish protocols for managing complications and providing long-term follow-up care. 

The treatment carries an upfront cost of £1,651,000 per patient, although it is a one-time intervention that may eliminate the need for regular blood transfusions and reduce hospitalisations for pain episodes.

Patient and clinician representatives described the approval as a major advance, noting the potential for meaningful improvements in pain control, quality of life, and long-term outcomes for eligible patients in Scotland.