Abstracts

Rationale: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy affecting children and their families. While there are no disease-modifying therapies (DMTs) currently approved for DS, ETX101, a potential one-time gene regulation therapy targeting the underlying cause of DS, has shown promising results in animals. DMTs may produce the most benefit in children < 5 years who have not yet experienced the full neurodevelopmental stagnation associated with DS. As part of the design of the first-in-human trial (FIHT) of ETX101(ENDEAVOR), we initiated Dravet ENGAGE to obtain meaningful input from the patient community. This aimed to understand and identify, from the caregiver perspective, hopes, fears, and considerations informing decisions to enroll in ENDEAVOR.

Methods: We used qualitative narrative inquiry within a patient-oriented framework. We conducted three discussion groups (n=10) and optional follow-up in-depth individual interviews (n=6) with parents of DS children. We conducted a narrative thematic analysis and results were triangulated with an advisory group.

Results: Participants described how DS manifestations negatively impact quality of life for the whole family. To them, DS is much more than a disease affecting children’s health. As children grow, the effects of DS expand to altering family dynamics, increasing family social isolation, affecting caregivers’ career development and financial constraints, and changing siblings’ physical and social wellbeing. Because caregivers perceive these effects differently based on the child’s age, each effect influences the decision of enrolling their child in a FIHT differently. Caregivers of older children highly value stability and the ability to balance caring for a DS child and having a healthy family routine. This is related to the conceptualization of DS as a disability and the acceptance of the disease progression. In contrast, caregivers of younger children conceptualize DS as an acute disease that may not progress and expressed hope that their child may not experience all manifestations of DS. This reveals their low acceptance of DS as a catastrophic disease, which may produce resistance to participation in FIHTs for investigational therapies and to seeking support for their own mental health.

Conclusions: Families at different stages of DS have different views and therefore needs, which must be considered when designing FIHT. Importantly, what and how information about DS is communicated has important ethical implications. Additionally, caregivers and siblings of DS children need tailored resources to help manage the negative impacts of DS on mental health and social wellbeing. A patient-oriented research framework is needed, one that integrates the needs and experiences of caregivers, siblings, and DS children with the goals of clinicians and scientists. We recommend a patient engagement framework to clinical trials design to strengthen trial feasibility, increase result impacts, and create meaningful knowledge that benefits all.

Funding: Please list any funding that was received in support of this abstract.: This abstract was supported by Encoded Therapeutics.