1. Academic Validation
  2. SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET/fMRI assessment of target engagement

SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET/fMRI assessment of target engagement

  • Front Pharmacol. 2023 Jan 17:13:1066447. doi: 10.3389/fphar.2022.1066447.
Wouter Botermans 1 Michel Koole 2 Koen Van Laere 2 Jonathan R Savidge 3 John A Kemp 3 Stefan Sunaert 3 Maeve M Duffy 3 Steven Ramael 3 Andrea M Cesura 3 Kevin D'Ostilio 4 Denis Gossen 4 Torsten M Madsen 3 Thomas Lodeweyckx 1 Jan de Hoon 1
Affiliations

Affiliations

  • 1 Center for Clinical Pharmacology, University Hospital Leuven, Leuven, Belgium.
  • 2 Nuclear Medicine and Molecular Imaging, Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium.
  • 3 Translational MRI, Department of Imaging and Pathology, KU Leuven, Leuven Brain Institute, KU Leuven, Radiology, University Hospital Leuven, Leuven, Belgium.
  • 4 Aepodia SA, Louvain-LaNeuve, Belgium.
Abstract

Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit. Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80 mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [11C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives. Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy. Conclusion: Single oral doses of SDI-118 up to 80 mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05486195.

Keywords

SDI-118; SV2A; cognitive impairment (CI); positron emission tomography; randomized controlled trial; resting state functional MRI (rsfMRI); synaptic vesicle glycoprotein; target occupancy.

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