Objective: To evaluate the effects of cinpanemab on biomarkers in participants with Parkinson’s disease (PD).

Background: SPARK (NCT03318523) was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of cinpanemab, a monoclonal antibody against a-synuclein (α-syn). Participants were randomized across 4 arms (250mg, 1250mg, 3500mg, placebo) and dosed monthly up to Wk96 – with placebo group randomized to an active arm after Wk52. SPARK was terminated due to a lack of efficacy based on primary and secondary endpoints.

Method: Participants underwent imaging at screening, Wk24, Wk52, and Wk96. Image acquisition/processing was standardized across sites. DaT-SPECT and neuromelanin (NM)-sensitive MRI were used to quantify nigral-striatal dopaminergic integrity. T1-MRI was used to assess regional atrophy. A CSF substudy was conducted, with lumbar puncture at screening, Wk24, and Wk52. CSF proteins were evaluated using multiple assays including protein misfolding cyclic amplification (PMCA) of α-syn seeds, neurofilament light chain (NfL), and total α-syn.

Results: 3.8% of screened participants lacked abnormal striatal DaT uptake and were not randomized. The striatal binding ratio change in the ipsilateral putamen of the placebo group was -7.2±12.0% at Wk52, relative to baseline. There was statistically significant improvement of some striatum divisions SBR in the high/mid dose arms relative to placebo/low dose at Wk24, yet no statistically significant treatment effect was evident at Wk52. Small magnitude, non-significant differences in NM-MRI intensity and volume of the substantia nigra were observed at Wk24 and Wk52 across dose arms relative to placebo. In the CSF substudy, PMCA binary classification indicated the majority of substudy participants (108/119) were PMCA+, confirming the presence of α-syn seeds. Most PMCA+ subjects with follow-up remained PMCA+ through Wk52 (83/84). There was no statistically significant difference in NfL or total α-syn levels between active and placebo arms. In plasma samples, there was a dose-dependent increase in total α-syn.

Conclusion: Biomarkers suggest the targeted patient population – those with abnormal striatal update and evidence of α-syn seeds – was enrolled in SPARK. No clear evidence of cinpanemab treatment effect was observed despite favorable numerical trends on some exploratory endpoints.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cinpanemab-in-parkinsons-disease-imaging-and-fluid-biomarker-results-from-the-phase-2-spark-study/