Preparing for Disease‐Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose?

Abstract

Building on decades of observational and preclinical studies, the field of degenerative ataxias is currently preparing or-in the case of multiple system atrophy of cerebellar type (MSA-C) and, very recently, spinocerebellar ataxia type 3 (SCA3)-already actively conducting trials with possible disease-modifying therapies. [1][2][3] Despite potentially exciting developments, a number of fundamental questions need to be answered in the upcoming years. These not only involve practical matters, such as identifying the optimal dose and administration schedule in phase I studies, but also importantly relate to the selection of clinically meaningful and responsive outcome measures and stratification of patients. Additional key issues for MSA-C will be to accurately diagnose and include patients at the earliest disease stages and distinguish them with reasonable certainty from other disorders, in particular immunemediated ataxias, hereditary ataxias, and sporadic adult-onset ataxia with unknown etiology (SAOA). 4 Delineating and predicting natural disease evolution with clinical rating scales, patient-reported outcomes, observerindependent metrics, (infratentorial) MRI measures, and biofluid markers constitutes an essential prerequisite for conducting meaningful disease-modification trials. This issue of Movement Disorders features a series of articles on dominantly inherited SCAs, MSA-C, SAOA, and Friedreich ataxia (FRDA) that share this important outcome theme. [5][6][7][8]