Objective: This analysis characterized the exposure-response (E-R) relationship of glovadalen (UCB0022) in the ATLANTIS Phase-IIa proof-of-concept study, to understand the apparent lack of dose-response for OFF time reduction [1].

Background: Glovadalen is a selective positive allosteric modulator of the D1 receptor (D1 PAM). While ATLANTIS demonstrated significant efficacy of glovadalen in OFF time reduction versus placebo, a numerically larger effect was observed in the low- versus high-dose arms. Understanding response drivers is essential for informing dose optimization and interpreting outcomes from this study.

Method: Univariate E-R models assessed associations between exposure and changes from Baseline in OFF time and ON time; area under the concentration-time curve for 24 hours (AUC₂₄), derived from the population pharmacokinetic (PK) model, was the primary exposure variable. Univariate analysis was followed by multivariate modeling for OFF Time. The final model was used to perform clinical study simulations (N=100), using ATLANTIS covariate distributions across treatment arms to determine the impact of covariates.

Results: Despite the large overlap in exposure between dose arms, a linear E-R relationship was observed for OFF time reduction in univariate analysis, with higher glovadalen exposure associated with greater improvement (slope −0.017 h/µmol·h; p=0.03). A positive E-R trend was observed for good ON time (slope +0.012 h/µmol·h; p=0.16). Multivariate modelling demonstrated that Baseline OFF time and daily levodopa dose significantly influenced response, and were imbalanced between dose groups in ATLANTIS. Clinical study simulations performed with the multivariate model demonstrated a 39% probability of observing a higher effect in the low-dose arm when covariates were sampled from the full study population, and a 51% probability using observed covariate distributions across treatment arms, consistent with the findings in ATLANTIS.

Conclusion: Glovadalen demonstrated a robust E-R relationship for OFF time reduction. The apparent absence of a dose-response in ATLANTIS is explained by high overlap in exposure between the low- and high-dose arms, and covariate imbalance between arms. These results confirm the mechanistic validity of glovadalen, support continued dose refinement and provide critical guidance for future study design.

References: [1] Biagioni MC, Nicholl R, Bornemann T, et al. Glovadalen, a D1 receptor positive allosteric modulator for people with Parkinson’s who experience significant daily motor fluctuations: a Phase II, double-blind, randomized trial. Oral presentation LBA 20 at the International Congress of Parkinson’s Disease and Movement Disorders, Honolulu, Hawaii, USA, October 8, 2025.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/exposure-response-analysis-of-glovadalen-in-the-atlantis-phase-ii-study-trial-simulation-explains-dose-response-for-off-time-in-parkinsons/