Background HD is an inherited autosomal dominant neurodegenerative disease. While there is biological certainty that individuals with a pathogenic expansion in the huntingtin gene (HTT) will develop the signs and symptoms of HD within a normal lifespan, this is not reflected in present terminology. Current staging methods do not address disease progression before an overt clinical phenotype, despite well-accepted biomarkers of neurodegeneration predating clinical diagnosis.

Aims To propose a new HD framework, referred to as the HD-ISS, that comprises an HD biological research definition and evidence-based staging centered on prognostic biological, clinical, and functional landmarks.

Methods This framework is the result of a formal consensus process by the HD-RSC’s Regulatory Science Forum (RSF), a working group of expert representatives from industry and academia. Observational data was employed to calculate ‘cut-offs’ using the extreme values in models of the control population to define the HD-ISS Stages and to evaluate the framework.

Results The HD-ISS defines HD biologically as the presence of the expanded HTT gene. The HD-ISS landmarks demonstrate robust prognostic value to classify individuals into each Stage and data-driven landmark thresholds to define Stage boundaries that are not CAG-dependent. Individual study visits, participant Stage progression, and longitudinal models of Stage progression align with the natural history of HD and with increased CAG predicting accelerated transitions.

Conclusions The RSF has developed a biological definition of HD and an evidence-based staging system that encompass the full course of the disease and are unconstrained by concepts such as ‘manifest’ or ‘pre-manifest.’ The HD-ISS is intended for research settings to allow clinical trials earlier in the disease course, and provides a new structure to anchor and harmonize clinical study populations. The immediate use of the HD-ISS will allow for further validation.