A novel strategy to improve inclusion criteria, assess target engagement and determine efficacy in alpha-synucleinopathy treatment trials (5464)

Objective: To report a novel study design for a disease modifying clinical trial in patients with suspected Parkinson’s Disease (PD) and other alpha-synucleinopathies. Background: Typical studies of PD use clinical assessments as inclusion criteria although diagnostic challenges exist, particularly in early disease. Furthermore, no biomarkers exist to measure target engagement nor are there surrogate biomarkers to determine intervention efficacy. Recently, studies show that cutaneous phosphorylated alpha-synuclein (P-SYN) has high diagnostic sensitivity and specificity in PD and other alpha-synucleinopathies; correlates with disease severity; and may predict disease progression. Design/Methods: A comparative power analysis of two study designs for a disease modifying trial in PD. One study uses traditional MDS-PD ‘probable PD inclusion criteria. The second study use cutaneous P-SYN deposition combined with non-motor findings for study inclusion. The MDS-UPDRS is the primary outcome for both study designs. Results: Assumptions: a 30% change in disease progression vs. placebo represents a 2.4 point change in the MDS-UPDRS over a baseline change of 8 points in12 months. In study 1 (traditional) with 80% diagnostic accuracy 280 subjects per study arm are required, 560 subjects total with ~1100 subjects screened. In study 2, with P-SYN, and 95% diagnostic accuracy only 194 subjects per arm, 392 total with ~784 subjects screened. Study 2 could enroll subjects several years earlier in the disease course. Conclusions: These data support the role of cutaneous P-SYN testing to effectively reduce study size in disease modification trials of PD by hundreds of subjects. The benefits of earlier disease intervention on the potential amplification of disease modification effects is an additional consideration. Furthermore, trial efficiency could be enhanced by early information of target engagement and the development of pathological surrogate endpoints. An urgent need exists, for sensitive, specific and reproducible tissue markers of disease in synucleinopathy trials. Disclosure: Dr. Levine has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Griffons, Alexion, Nufactor, Diplomat, Shire, Corinthian Reference Labs. Dr. Levine holds stock and/or stock options in Corinthian Reference Labs, Cutaneous Neurodiagnostics. Dr. Levine has received research support from PTC Therapeutics, Sun Pharmaceuticals, Actinogen. Dr. Bellaire has nothing to disclose. Dr. Gibbons has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Lundbeck Inc.. Dr. Gibbons has received personal compensation in an editorial capacity for Associate Editor for Autonomic Neuroscience: Basic and Clinical. Dr. Gibbons has received compensation for serving on the Board of Directors of Cutaneous NeuroDiagnostics. Dr. Gibbons holds stock and/or stock options in Cutaneous NeuroDiagnostics. Dr. Gibbons has received research support from Grifols Inc.. Dr. Freeman has nothing to disclose.