Comment from Annika Roll

I strongly support the FDA's proposed Plausible Mechanism Framework. I come from a large family affected by MAPT-associated frontotemporal dementia (FTD), a rare, autosomal dominant genetic disease. For our mutation (V337M), the average age of onset is 48.2 years and average disease duration is 14.2 years. At 27, I tested positive for the same mutation my mother carries; she has been living with FTD since age 49. The New York Times wrote about my family in 2023: https://www.nytimes.com/2023/07/20/magazine/family-genetics-frontotemporal-dementia.html. Through Cure MAPT FTD (curemaptftd.org), I am part of a community of 55+ families ready to participate in research. Our genetic data has informed Alzheimer's research for decades, but our distinct disease biology has kept us out of those trials. We need a framework built for rare, monogenic, rapidly progressive diseases, and this guidance delivers it. I especially support these provisions: - A single adequate and well-controlled trial with confirmatory evidence, in place of multiple RCTs that are not feasible in small populations. - Natural history data as an external control, removing the unethical requirement of a placebo arm in a uniformly progressive, fatal disease. - "All-in-one" hybrid preclinical POC / safety / biodistribution studies. - Master/umbrella protocols and data leveraging across product variants targeting different mutations within the same gene. - Biomarkers as surrogate endpoints supporting accelerated approval — essential when waiting for clinical decline means waiting for irreversible harm. Two requests: 1. Please explicitly include pre-symptomatic carriers. For autosomal dominant neurodegenerative diseases, intervening before symptoms is likely the only path to preserving cognition. I would like to request the guidance to make clear that genetically confirmed, pre-symptomatic carriers may appropriately be enrolled in natural history studies, observational lead-in periods, and pivotal trials. 2. Please make patient and family community input an expected element of protocol design, including endpoint selection and biomarker prioritization. The draft guidance in this Plausible Mechanism Framework aligns with the requests made in a FDA Patient Listening session held by our community last year. Read more here about our requests to FDA: https://curemaptftd.org/en/fda-patient-listening-session Thank you for your consideration