Objective: ORCHESTRA XT (PD0055; NCT05543252) was a Phase II, dose-blinded extension of the ORCHESTRA Phase II, proof-of-concept study (NCT04658186). ORCHESTRA XT assessed the pharmacodynamic effects of minzasolmin on biomarkers and symptomatic treatment (ST) intake in early-start or delayed-start participants diagnosed with early-stage Parkinson’s disease (PD) when entering ORCHESTRA; the safety of minzasolmin was also assessed.

Background: Minzasolmin is an oral small molecule that acts on alpha-synuclein (ASYN) misfolding, the initial step of the PD pathological cascade, to prevent future ASYN aggregation, Lewy body formation and neuron loss. In ORCHESTRA, minzasolmin did not demonstrate an effect on the clinical outcome measures assessed; however, some differences versus placebo were observed in dopamine transporter imaging with single photon emission computed tomography (DaT-SPECT) at 12 months.

Method: Following completion of 18 months of treatment in ORCHESTRA, participants were eligible to enter ORCHESTRA XT and receive oral minzasolmin for a further 18 months, continuing on the same regimen (180 mg twice daily [BID] or 90 mg BID; early start) or 180 mg BID if they received placebo in ORCHESTRA (delayed start). Participants eligible for ORCHESTRA were 40–75 years old, diagnosed with PD for ≤2 years (based on 2015 Movement Disorder criteria), with a modified H&Y stage ≤2.5. In ORCHESTRA XT, co-administration of ST was permitted, and participants were excluded if they met ORCHESTRA withdrawal criteria. ORCHESTRA XT endpoints included baseline-adjusted DaT-SPECT whole striatum specific binding ratio signal and cumulative levodopa equivalent daily dose (LEDD) at Months 18 or early termination, incidence of treatment-emergent adverse events (TEAEs), serious adverse events and TEAEs leading to study withdrawal. As ORCHESTRA did not meet its clinical endpoints, ORCHESTRA XT was terminated.

Results: Overall, 428 participants were enrolled in ORCHESTRA XT. Study results are expected in Quarter 3 2025; we will present DaT-SPECT, LEDD and safety data.

Conclusion: ORCHESTRA XT was an extension study of ORCHESTRA to provide understanding of the longer-term efficacy, safety and tolerability of minzasolmin in participants with PD. Although ORCHESTRA XT was terminated early, the data obtained will provide valuable contributions to the field.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/results-from-a-dose-blinded-phase-ii-extension-study-evaluating-long-term-efficacy-safety-and-tolerability-of-minzasolmin-in-participants-with-parkinsons-disease/