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T12

MAZINDOL IR/SR: A 50-YEAR LEGACY REPOSITIONED AS A FIRST-IN-CLASS OREXIN–MONOAMINE MODULATOR FOR ADHD AND AROUSAL-RELATED DISORDERS

Eric Konofal — Jean-Charles Bizot2, Bruce Corser3, Michael J. Thorpy4, Christelle Peyron5, Jeffrey H. Newcorn6, Michel Lecendreux7, Sharon Wigal8, Tim Wigal8, Clete A. Kushida9, Bruno Figadere10, Isabelle Arnulf11 1University of Paris, Robert-Debré Hospital, 2Key-Obs SAS, 3Sleep Management Institute, 4Montefiore Medical Center, Sleep-Wake Disorders Center, 5Centre de Recherche en Neurosciences de Lyon (CRNL), Equipe SLEEP, UMR5292 CNRS / Université Claude Bernard Lyon1, 6SUNY Upstate Medical University, 7Pediatric Sleep Disorders Center, National Reference Centre for Orphan Diseases, Narcolepsy–Rare Hypersomnias, Robert Debré Hospital, 8AVIDA Inc., 9Stanford University, 10University Paris-Sud, CNRS, Châtenay-Malabry, 11National Reference Centre for Orphan Diseases, Narcolepsy– Rare Hypersomnias, Sleep Disorders Clinic, Pitié-Salpêtrière Hospital

2026 ASCP Annual Meeting

Mazindol, originally introduced in the 1970s, is being repositioned in modern immediate-release (IR) and sustained-release (SR) formulations as a multimodal neuromodulator targeting the intersection of monoaminergic, orexinergic, and opioid signaling systems. Mazindol IR/SR exhibits a unique pharmacological profile combining dopamine and norepinephrine transporter inhibition, serotonergic engagement, partial orexin2 receptor (OX2R) modulation, and interaction with opioid-related pathways. This integrated mechanism supports a unifying hypothesis: disorders such as adult ADHD, Central Disorders of Hypersomnolence (including narcolepsy), and opioid use disorder (OUD) share a common pathophysiology of alertness instability, reward dysregulation, and impaired motivational control. In a previous randomized, placebo-controlled Phase 2b study in adults with ADHD, mazindol IR/SR demonstrated rapid onset of efficacy (Week 1), robust symptom improvement, and favorable tolerability without stimulant-like dopaminergic release. In narcolepsy and other central hypersomnolence disorders, the POLARIS study demonstrated clinically meaningful reductions in excessive daytime sleepiness and improvements in wake stability. Preclinical models further showed restoration of wakefulness in orexin-deficient paradigms and attenuation of opioid-conditioned place preference and withdrawal behaviors, supporting exploration in fentanyl-related OUD and stimulant–opioid co-use. The therapeutic implications of mazindol IR/SR extend beyond single-indication targeting. Through simultaneous modulation of arousal (orexin), executive function (dopamine/norepinephrine), and reward circuitry (opioid–monoamine interaction), mazindol IR/SR may represent a platform approach for arousal deficit syndromes. This broad-spectrum activity differentiates mazindol IR/SR from classical stimulants and selective OX2R agonists by addressing both wake stabilization and reward regulation within a single pharmacological framework. With a 50-year safety legacy, modern formulation refinement, Phase 2 validation in ADHD, clinical data in narcolepsy (POLARIS), and translational evidence in opioid-related models, mazindol IR/SR is positioned as a scalable neurotherapeutic candidate across disorders characterized by alertness dysregulation and motivational instability.