Comparing Ex-Vivo and In-Vivo Administration in CRISPR-Based Gene Therapies for Beta-Thalassemia: A Cost-Effectiveness Analysis

OBJECTIVES: CRISPR-based gene therapies offer transformative potential for previously untreatable diseases. The ex-vivo CRISPR therapy exagamglogene autotemcel (exa-cel) was recently approved by the National Institute for Health and Care Excellence (NICE) under a managed access agreement. Exa-cel requires autologous hematopoietic stem cell transplantation (HSCT), associated with significant costs and risks. In-vivo CRISPR delivery, still in development, could simplify administration and address these limitations. This analysis compares the economic and clinical implications of ex-vivo and in-vivo CRISPR approaches for beta-thalassemia.
METHODS: A semi-Markov cost-effectiveness model (CEM) was developed, based on the exa-cel CEM submitted to NICE. Whilst the NICE model compared exa-cel with standard of care (SoC), this analysis compares ex-vivo CRISPR (exa-cel, involving HSCT after myeloablative conditioning) and hypothetical in-vivo CRISPR (using lipid nanoparticles for delivery). Health states included transfusion-dependence, transfusion-independence, transfusion-reduction and death. Complications were modeled for each intervention and health state. Inputs for ex-vivo therapy were derived from the CLIMB THAL-111 trial, while in-vivo assumptions were based on hypothetical efficacy, durability, and safety profiles. Scenario analyses explored the sensitivity of in-vivo outcomes to these assumptions. Outcomes included costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs).
RESULTS: Ex-vivo therapy demonstrated high efficacy, but incurred lifetime transplant- related costs of £60,633 including screening, fertility preservation, mobilization, hospitalization, transplantation and monitoring. In contrast, hypothetical in-vivo CRISPR had administration and monitoring related costs of £1,275, resulting in cost-savings of £59,358. In-vivo therapy provided 0.11 additional QALYs during the transplant year and 0.71 additional QALYs over a lifetime, assuming equal efficacy. Scenario analyses showed in-vivo cost-effectiveness sensitivity to efficacy and durability assumptions.
CONCLUSIONS: In-vivo CRISPR offers cost savings, reduced patient burden, and improved cost-effectiveness compared to ex-vivo therapy. However, these results depend on assumptions regarding in-vivo efficacy and safety. Future research should address uncertainties as in-vivo CRISPR trial data emerge.