Objective: To investigate the progression over time and the effect of minzasolmin on digital outcomes collected in ORCHESTRA (NCT04658186).

Background: Minzasolmin is an oral small molecule that targets α-syn misfolding—the initial step in the pathological cascade of Parkinson’s disease (PD)—to prevent future α-syn aggregation, Lewy body formation, and neuron loss. ORCHESTRA was a multicenter, double-blind, Phase II study that failed to show effects on any clinical endpoint. Patients with early-stage PD were randomized (1:1:1) to receive low- or high-dose, or placebo. Virtual Motor Exams (VMEs) were optionally implemented using the Verily study watch.

Method: VMEs were performed during in-clinic (IC) visits (every 2 months) and at-home (AT, once a week) for 18 months. Four composites (V-gait, V-bradykinesia, V-tremor and V-overall motor) were derived from the VMEs. To investigate the composite changes from baseline in the arms, linear random coefficients mixed-effects models were used, in which time (weeks), treatment × time, and baseline characteristics (age, sex, disease duration and baseline value of the composite) were entered as fixed effects, with subject as random intercept. Data used for modelling was censored when patients started symptomatic treatment.

Results: A total of 93 participants wore the watch, approximately equally distributed in the 3 arms. Both IC and AT adherence decreased over time, with no differences observed across the groups. Wearable-based data could quantify disease progression in all arms for 3 out of 4 digital measures (V-overall motor, V-bradykinesia, V-tremor). Two of the measures (V-overall motor, V-bradykinesia) detected subtle delayed progression in Minzasolmin arms in IC and AT settings. V-tremor results showed a minor treatment effect only in the AT setting (Table 1: Number of patients per arm and model-estimated weekly rate of change from baseline with 95% confidence intervals (CI).

Conclusion: In the context of a Phase II where no meaningful effects were shown on clinical scales, digital outcomes captured subtle changes in motor symptoms in early-stage PD, particularly in V-bradykinesia and V-overall motor composites. These results could pave the way towards future progression biomarkers in early PD. However, the study’s small sample size and declining adherence over time must be considered when interpreting the results.

Table 1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-minzasolmin-effect-on-digital-measures-captured-by-the-verily-study-watch-in-a-subset-of-the-orchestra-trial-participants/