Re-evaluating acceptable risk of death from gene therapy

Abstract

Patient and caregiver treatment preferences should be incorporated into the drug development process. We updated a 2018 survey to reflect current knowledge about gene therapy for Duchenne muscular dystrophy (DMD) and obtained new data in the U.S., U.K., and other countries. At data collection in 2023, there were no approved gene therapies for DMD. Using the threshold technique, we assessed the maximum acceptable risk of death (MAR) from non-curative gene therapy with time-limited benefit at different stages of DMD progression. Among 263 participants, mean MAR ranged from 2.4% (treatment in newborns) to 5.4% (last year able to lift hands to mouth); risk tolerance increased with advancing disease stages. Significant proportions (22.4% to 32.8%) were willing to accept MAR >10%. Reasons for higher MAR included the progressive and severe disease, limited treatment alternatives, and participant-reported expected therapy benefits. Those who demonstrated less risk tolerance described uncertainty, maintaining quality of life, optimism regarding future therapies, and the currently uncertain duration of benefit. There were no significant differences in MAR between caregivers and adults with DMD and between respondents in the U.S. and U.K except in the newborn period, though our small sample size is a limitation. MARs remained relatively stable from 2018 to 2023.