Overview
This is a phase 2A multi-center, randomized, double blind, placebo-controlled, parallel group study of varoglutamstat, with a stage gate to phase 2B.
In phase 2A there will be adaptive dosing evaluation of three dose levels with exposure to varoglutamstat or placebo for a minimum of 24 weeks, with preliminary evaluation of both cognitive function and pharmacodynamic changes on EEG spectral analysis in approximately 180 participants.
In the event that the stage gate for phase 2B is reached, then phase 2B will assesses efficacy and longer-term safety in a larger study group, i.e., 414.
Description
The goal of this study is to advance a first-in-class, new small molecule treatment for early Alzheimer's disease (AD). Varoglutamstat (PQ912) is an oral, twice daily medication that addresses a novel and significantly differentiated amyloid target: N-terminal post-translationally modified Ab (pGlu-Ab), a particularly toxic subspecies of amyloid beta (Ab). This study will further evaluate whether varoglutamstat's mechanism of action can result in a measurable therapeutic effect on cognition, function and relevant pharmacodynamic and biological markers in early AD.
The study is a phase 2A multi-center, randomized, double-blind, parallel group trial, with a stage gate to phase 2B. Phase 2A will determine the highest dose that is both safe and well tolerated. During this phase, there is an adaptive dosing evaluation, using a well-defined safety stopping boundary, of three dose levels with exposure to varoglutamstat or placebo for a minimum of 24 weeks to help determine which dose will be carried forward in phase 2B. A sequential dose design will be employed in phase 2A where each of three dose cohorts are randomized equally to placebo or varoglutamstat and treated for at least 8 weeks at the originally assigned full dose. Participants will be randomized 1:1 to varoglutamstat or placebo, and stratified between mild AD and MCI, as well as by site.
Phase 2A also includes preliminary evaluation of both cognitive function and pharmacodynamics changes on electroencephalogram (EEG) spectral analysis.
In the event that the stage gate for phase 2B is reached from data in this phase 2A study, then phase 2B will assess the longer-term efficacy and safety of varoglutamstat in a larger study group, using the highest dose selected in phase 2A. In phase 2B, a composite cognitive and functional measure as well as PD biomarkers will be used to evaluate efficacy during the extended treatment period.
Eligibility
Key Inclusion Criteria:
- Age 50-89 (inclusive) at screening
- Diagnosed as having Mild Cognitive Impairment (MCI) due to Alzheimer's disease (AD) or Mild probable AD according to workgroups of the Diagnostic Guidelines of the National Institute on Aging and Alzheimer's Association (NIA-AA)
- Mini-Mental State Examination (MMSE) score 20-30 inclusive at screening
- Montreal Cognitive Assessment score (MoCA) < 26 at screening
- Clinical Dementia Rating global score 0.5 or 1 with memory score of > 0.5 at screening
- Positive CSF AD biomarker signature
- A brain MRI scan within 6 months of screening consistent with a diagnosis of Alzheimer's disease
- Participants must have a study partner who has frequent interaction with them (approximately >3-4 times per week), will be present for all clinic visits, and can assist in compliance with study procedures.
Key Exclusion Criteria:
- • Significant neurodegenerative diseases and causes of dementia, other than AD, including Parkinson's disease and Huntington's disease, vascular dementia, CJD (Creutzfeldt-Jakob disease), LBD (Lewy Body dementia), PSP (Progressive Supranuclear Palsy), AIDS (Acquired Immunodeficiency Syndrome), or NPH (normal pressure hydrocephalus)
- Meeting Diagnostic Criteria for Possible AD according to workgroups of the Diagnostic Guidelines of the NIA-AA
- Hepatic impairment defined as Child-Pugh class A or more severe liver impairment
- History of moderate or severe skin reactions to medications or current moderate or severe disease of the skin and subcutaneous tissues
- History of a major depressive episode within the past 6 months of screening
- History of diagnosis of schizophrenia
- History of uncontrolled bipolar disorder within past five years of screening
- History of seizures within past two years of screening
- Contraindication to lumbar puncture and MRI
- Participation in another clinical trial for an investigational agent and having taken at least one dose of study drug, unless confirmed as having been on placebo, within 90 days prior to the baseline visit. The end of a previous investigational trial is defined as the date of the last dose of an investigational agent.