• Abstract 701 – Results from REACT-PD – a randomised, placebo-controlled, multi-centre phase IIb study evaluating the efficacy of pirepemat on falls frequency in patients with Parkinson’s disease will be presented by Fredrik Hansson, Director of Clinical Science and Biometrics & Susanna Waters, Director of Systems Pharmacology. Theme C, Poster Shift 02, March 19-21, Board 088.
• Abstract 2455 – Searching for novel CNS therapies in Parkinson’s and Alzheimer’s disease using Integrative Screening process (ISP): An AI/ML driven phenotypic drug discovery platform will be presented by Sebastian Oleszko, Research Scientist AI/Data Science. Theme C, Poster Shift 02, March 19-21, Board 157.
• Abstracts 2995 – Amantadine for levodopa induced dyskinesias in PD: Prevalence, clinical correlates, and treatment outcomes in the PPMI study cohort will be presented by Sebastian Oleszko, Research Scientist AI/Data Science and Susanna Waters, Director of Systems Pharmacology. Theme C, Poster Shift 02, March 19-21, Board 086.

Abstract 701
Results from REACT-PD – a randomised, placebo-controlled, multi-centre phase IIb study evaluating the efficacy of pirepemat on falls frequency in patients with Parkinson’s disease
Recurrent falls are among the most problematic symptoms in PD, with no satisfactory treatment. Pirepemat enhances neurotransmission in the prefrontal cortex (PFC) by increasing synaptic availability of dopamine (DA) and norepinephrine (NA). This addresses impairment in mesocortical DA and NA, which is associated with executive dysfunction and falls in PD.
REACT-PD, a Phase IIb study, evaluated the effect of 13 weeks of treatment with pirepemat on falls frequency in patients with PD. While topline results showed a markedly reduced fall rate across all treatment groups, but no statistically significant difference was found vs. placebo. Here we show results focusing on the effect of pirepemat in different plasma concentration intervals. A significant, U-shaped plasma concentration response pattern was observed, indicating that pirepemat, in an optimal plasma concentration range, could significantly and clinically meaningfully reduce falls in PD. The relative fall rate was reduced by 31% vs. placebo in the optimal plasma concentration range.
The findings align with previous research of dopaminergic compounds acting in the PFC, suggesting that dosing of pirepemat should be individualized, based on plasma concentrations. In terms of the absolute number of falls, the effect at optimal concentrations corresponds to a reduction of 7 falls monthly vs. placebo. The reduction in falls observed in the optimal plasma concentration range was not associated with any change in motor symptoms. Collectively, the study results support further development of pirepemat.
Authors: Joakim Tedroff, Fredrik Hansson, Erik Werner, Olivia Vu Van, Johanna Landström, Nicholas Waters, Clas Sonesson, Susanna Waters
Theme C: α-SYNUCLEINOPATHIES / DRUG DEVELOPMENT, CLINICAL TRIALS / NEUROTRANSMITTER-BASED AGONISTS AND MODULATORS, GLP-1 RECEPTOR AGONISTS

Abstract 2455
Searching for novel CNS therapies in Parkinson’s and Alzheimer’s disease using Integrative Screening process (ISP): An AI/ML driven phenotypic drug discovery platform
Traditional, target-based drug discovery (DD) relies on a reductionist approach focused on optimizing an isolated target in in vitro systems, a strategy with known shortcomings such as uncertain translational capacity and inherent druggability issues. In contrast, ISP is a DD platform based on comparative in vivo phenotypic profiling, targeting neurotransmitter dysregulations in neurodegenerative and psychiatric disorders. ISP allows clustering of compounds in a multivariate space by their system response profile (response profiles on biomarkers including neurochemistry, gene expression, behavioural patterns).
Here we present a significant advancement in the behavioural assessment tools, based on AI-driven identification of behavioural features captured by video recordings. This novel technology enhances overall phenotyping applied in ISP, further improves predictive accuracy, and reinforces the capability of ISP to identify druggable, safe, and innovative first-in-class candidate drugs.
Authors: Susanna Waters, Peder. Svensson, Nicholas Waters, Erik. Werner, Daniel. Andersson, Fredrik. Wallner, Joakim Tedroff, Clas Sonesson, Sebastian Oleszko
Theme C: α-SYNUCLEINOPATHIES / THERAPEUTIC TARGETS, MECHANISMS FOR TREATMENT / DOPAMINE, ACETYLCHOLINE, NEUROTRANSMITTERS, GLP-1 RECEPTOR

Abstract 2995
Amantadine for levodopa induced dyskinesias in PD: Prevalence, clinical correlates, and treatment outcomes in the PPMI study cohort
Levodopa induced dyskinesias (LIDs) represent a common, disabling complication of Parkinson’s disease (PD), typically emerging after 5-10 years of levodopa-treatment. An extended-release (ER) formulation of amantadine, an NMDA-receptor antagonist with anti-cholinergic/ and dopamine-releasing properties, was approved for LIDs treatment in 2017. Here, we examined use patterns of amantadine in a large observational PD-cohort. Clinimetric, demographic, genotype and imaging data on 1340 subjects with PD were accessed November- 2025. Data were analysed with respect to overall correlation structure, factors discriminating subjects with/without amantadine, and factors discriminating subjects who discontinued amantadine.
Amantadine was used by about 30% of subjects with dyskinesia, with roughly one-third eventually discontinuing as their disease progressed. Most patients received daily doses below 300 mg. Dyskinetic subjects on amantadine tended to have more severe PD symptoms across modalities, including overall severity, ADL-function, cognitive impairment, and motor symptoms including dyskinesias. In contrast, tremor was unrelated to amantadine use. Additionally, MDS-UPDRS part 3 scores, an objective motor assessment performed by clinicians, were generally lower among those receiving amantadine. Subjects on amantadine were more likely to have the “genetic” subtype, especially LRRK, while sporadic PD was linked to less amantadine use. Subjects who discontinued amantadine generally experienced more severe symptoms, although differences compared to those who continued were modest.
Authors: Sebastian Oleszko, Joakim Tedroff, Susanna Waters, and Nicholas Waters
Theme C: α-SYNUCLEINOPATHIES / DRUG DEVELOPMENT, CLINICAL TRIALS / NEUROTRANSMITTER-BASED AGONISTS AND MODULATORS, GLP-1 RECEPTOR AGONISTS

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