A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 2 Study to Evaluate the Safety and Efficacy of CT1812 in Subjects with Dementia with Lewy Bodies

点击翻译按钮获取中文摘要

ABSTRACT: Cognition Therapeutics, Inc. (CogRx) is developing CT1812 for neurodegenerative conditions, including Dementia with Lewy Bodies (DLB). This first-in-class small molecule drug candidate selectively displaces Aβ oligomers bound to neuronal receptors at synapses and protects synapses from toxic oligomer effects, clearing them from the brain into the cerebrospinal fluid (CSF). CT1812 also displaces α-synuclein oligomer binding to neurons in vitro. CT1812 is currently in a Phase 2 trial in patients with mild to moderate Alzheimer's disease (AD), where it has been found to be safe and generally well-tolerated. When administered once daily for 28 days to AD patients, CT1812 significantly reduced concentrations of synaptic degeneration markers in CSF. Similar to Aβ oligomers, α-synuclein oligomers bind to neurons and cause synaptic dysfunction and loss, spreading throughout the brain as disease progression is observed in DLB. Eighty percent of patients with DLB reflect both Aβ and α-synuclein pathology at autopsy. Patients with DLB likely have both types of oligomers and should benefit from treatment with CT1812. This clinical trial project proposes to conduct a Phase 2 randomized, double-blind, placebo-controlled, six-month study to evaluate the safety, tolerability, and exploratory efficacy of CT1812 at 100 mg and 300 mg daily doses in mild to moderate DLB patients (N=40/group). Trial endpoints will include safety as well as exploratory efficacy measures (Montreal Cognitive Assessment [MoCA], Cognitive Drug Research Battery [CDR], Clinician Assessment of Fluctuation [CAF], Epworth Sleepiness Scale [ESS], Movement Disorder Society – Unified Parkinson's Disease Rating Scale – Part III [MDS-UPDRS3], The Alzheimer's Disease Cooperative Study – Clinical Global Impression of Change [ADCS-CGIC], ADCS-Activities of Daily Living [ADL], and Neuropsychiatric Inventory [NPI]) at baseline, 3 months, and 6 months. Additional measurements of plasma and CSF concentrations of drug, target engagement biomarkers (including Aβ and α-synuclein oligomers), disease progression protein markers (Aβ and α-synuclein monomer, total and phosphorylated tau protein) and synaptic damage/neurodegeneration biomarkers (neurogranin, synaptotagmin, synaptosomal-associated protein 25 [SNAP-25], and neurofilament light [NFL]) at baseline and at 6 months will allow correlation of drug concentrations with measures of synaptic damage and cognitive performance. Conducting a study with this patient population will leverage the ongoing CT1812 development efforts for AD and will provide a near-term opportunity to investigate a clinical candidate therapeutic in DLB, an indication for which no disease-modifying treatments exist. Completion of this study will provide an initial assessment of CT1812 efficacy in DLB patients that will inform design of subsequent pivotal trials necessary for further clinical development of CT1812.