OBJECTIVES: CRISPR/Cas9 gene editing is a Nobel Prize-winning technology heralded for its promise in treating cancer and genetic diseases. Following regulatory approvals of the first CRISPR-based product, exagamglogene autotemcel (exa-cel), this study aimed to identify likely challenges for this technology in health technology assessment (HTA).

METHODS: The FDA, EMA, MHRC, ICER, and NICE websites were searched for regulatory and HTA documents on exa-cel, which were reviewed and compared with documents for selected other cell and gene therapies for hematological conditions: etranacogene dezaparvovec-drlb, valoctocogene roxaparvovec-rvox, betibeglogene autotemcel (beti-cel), tisagenlecleucel (tisa-cel), and axicabtagene ciloleucel (axi-cel).

RESULTS: A number of documents relating to exa-cel were identified: FDA advisory committee documents, US prescribing information (PI), an ICER assessment, a CHMP summary of positive opinion, a UK summary of product characteristics, and two final scope documents from NICE.

The US PIs for other cell and gene therapies all included a warning regarding malignancies, carcinogenicity, or oncogenesis; while the exa-cel PI did not, it did include a warning regarding “off-target genome editing risk”.

Common issues between exa-cel and other gene therapies included reliance on single-arm trials with limited numbers of patients (and consequent challenges in establishing comparative efficacy), uncertainty regarding duration of treatment effect, limited follow-up, and whether a claim of cure was justified.

For tisa-cel, axi-cel and beti-cel (all autologous products) regulators and HTAs highlighted adverse events associated with conditioning treatment, this was also seen for exa-cel. While manufacturing failure was discussed for tisa-cel and axi-cel there was little mention of it for exa-cel.

CONCLUSIONS: Exa-cel and subsequent CRISPR-based technologies are expected to face similar challenges to other cell and gene therapies, with the risk of off-target gene editing likely to be scrutinized for many years to come. HTA agencies may be more willing to accept uncertainty around clinical benefit for products demonstrating cost savings for healthcare systems.