Comment from Canary Cure Therapeutics

Canary Cure Therapeutics urges FDA to clarify that the Plausible Mechanism Framework ("PMF") is a principles-based evidentiary framework that may be relevant not only to individualized therapies, but also to therapies for rare genetically defined diseases with a known causal mechanism. In these settings, meaningful benefit may need to be demonstrated through an integrated package of mechanistic, pharmacodynamic, intermediate clinical, and functional evidence rather than through a single conventional endpoint. Some rare diseases also have multisystem and developmentally staged phenotypes, making narrower, mechanism-relevant subpopulations and age-appropriate endpoints the most scientifically interpretable approach. Prader-Willi syndrome is one example: it is genetically defined, the SNORD116 defect is a key mechanistic feature, and infants with PWS represent a distinct developmental stage from older children. Recommendations •Clarify that PMF may apply to rare genetically defined diseases beyond bespoke or highly individualized products. •Recognize that, in rare genetic diseases, FDA may need to evaluate an integrated evidentiary package spanning causal biology, pharmacologic effect, biomarker or intermediate clinical change, and functional evidence, rather than relying on a single conventional endpoint. •Permit use of mechanism-relevant subpopulations and age-appropriate endpoints where scientifically justified. •Confirm that FDA may rely on a multidomain totality-of-evidence package rather than a single endpoint alone. We would welcome clarification in the final guidance that the PMF evidentiary framework encompasses these development contexts.