Multiple system atrophy as emerging template for accelerated drug discovery in α-synucleinopathies

Abstract

There is evidence that the α-synucleinopathies Parkinson's disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P) overlap at multiple levels. Both disorders are characterized by deposition of abnormally phosphorylated fibrillar α-synuclein within the central nervous system suggesting shared pathophysiological mechanisms. Despite the considerable clinical overlap in the early disease stages, MSA-P, in contrast to PD, is fatal and rapidly progressive. Moreover recent clinical studies have shown that surrogate markers of disease progression can be quantified easily and may reliably depict the rapid course of MSA. We therefore posit that, MSA-P may be exploited as a filter barrier in the development of disease-modifying therapeutic strategies targeting common pathophysiological mechanisms of α-synucleinopathies. This approach might reduce the number of negative phase III clinical trials, and, in turn, shift the available resources to earlier development stages, thereby increasing the number of candidate compounds validated.

Keywords: Drug development; Multiple system atrophy; Parkinson's disease; Synucleinopathies.

Fig. 1

Overlapping and discriminating features of MSA and idiopathic PD. The figure shows distinguishing and overlapping features of MSA-P and Parkinson's disease at the pathogenic, pathologic and clinical level. Unique MSA-P features are emphasized by a red highlight, PD features are shaded in blue and overlapping features are presented on a purple background.

Fig. 2

Modified quick win, fast fail drug development approach The figure illustrates possible time- and cost-savings of a modified quick-win, fast fail proof of concept (PoC) approach (B) in comparison to the current drug development and validation strategy (A). We posit that introduction of a MSA interventional trial as PoC filter barrier would be useful to pre-select the most promising candidate compounds and thereby substantially reduce the number of negative phase III trials being carried out.