Neva Coello1, Brigitte Lacroix2, Thomas Faller1, Himanshu Naik3, Tomás Sou1, Akash Khandelwal4
1Novartis Pharmaceuticals, 2UCB Biopharma SRL, 3UCB BioSciences Inc, 4UCB Biosciences GmbH
Introduction: Minzasolmin is an orally available inhibitor of alpha-synuclein (ASYN) misfolding and subsequent aggregation. Aggregated forms of ASYN are the hallmark fibrillar protein deposits in Parkinson’s disease, and evidence suggests that the misfolded forms of ASYN propagate through the central nervous system during disease progression [1]. A phase 2 proof-of-concept (PoC, ‘ORCHESTRA’, NCT04658186) study was initiated, aiming at demonstrating the superiority of minzasolmin at low (90 mg bid) and high (180 mg bid) doses over placebo in terms of clinical symptoms of disease progression over 12 and 18 months (primary efficacy objectives), as well as effect on neurodegeneration of dopaminergic neurons and the intake of symptomatic treatments (secondary efficacy objectives). Population pharmacokinetic and exposure-response analyses were performed on unblinded data from the PoC study, with quick delivery of the results needed for internal decision-making and to support the dosing rationale for potential phase 3 studies. Objectives: The objective of this analysis was to understand the relationship between minzasolmin exposure and various efficacy endpoints, mainly MDS-UPDRS total score (clinical score for evaluating Parkinson’s disease) and MDS-UPDRS part III (assessment of motor symptoms) sub-scale, time to worsening of the MDS-UPDRS score, time to initiation of symptomatic therapy, and changes in the DaT-SPECT mean striatum specific binding ratio (imaging technique to evaluate the function of dopaminergic neurons in the brain) using a fit for purpose approach to inform dose selection for potential phase 3 studies. Methods: Classical cross-sectional and longitudinal statistical linear mixed effect models were developed, incorporating treatment effect, drug exposure, and the initiation of symptomatic therapy where relevant. Results: For the MDS-UPDRS total score and MDS-UPDRS part III subscale no exposure-response relationship was identified whether in the presence or absence of symptomatic therapy. Minzasolmin was not associated with a decrease in the clinical score, neither with a change in the slope of the total or the part III MDS-UPDRS scores. The time since the start of the treatment, age of the subjects, and initiation of symptomatic therapy, but not the gender, were found to statistically significantly affect the total and motor scores. No differences were identified between treatment arms or drug exposure categories. Minzasolmin was not either associated with the time to worsening in the clinical MDS-UPDRS scores or with a meaningful clinical delay in the initiation of symptomatic rescue treatment. A statistically significant association between minzasolmin exposure and changes in DAT-SPECT was identified, but this association decreased at month 18 compared to month 12. Conclusions: This analysis enabled the early identification of the lack of exposure-response relationships and the drug’s superiority over placebo. The use of linear statistical models allowed for rapid delivery of results. Given the endpoints and short timeframe, it would likely not have been possible to achieve these results using more complex models.
1. Chen SW, Drakulic S, Deas E, Ouberai M, Aprile FA, Arranz R, et al. Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation. Proc Natl Acad Sci. 2015;112:E1994-E2003.
Reference: PAGE 33 (2025) Abstr 11519 [www.page-meeting.org/?abstract=11519]
Poster: Drug/Disease Modelling - CNS