A Trial to Evaluate the Efficacy and Safety of PQ912 in Patients With Early AD

A Phase 2A Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Varoglutamstat (PQ912) in Patients With Early Alzheimer's Disease With a Stage-Gate to Phase 2B (VIVA-MIND)

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.

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).

The study is a Phase 2A multi-center, randomized, double-blind, parallel group trial, with a stage gate to Phase 2B.

This study is conducted to further evaluate whether varoglutamstat's mechanism of action can result in a measurable therapeutic effect on cognition, function and relevant pharmacodynamic (PD) and biological markers in early AD.

Phase 2A is designed to determine the highest dose that is both safe and well tolerated using a predefined Pocock safety stopping boundary based on the rate of adverse events of special interest (AESIs).

During this phase there is an adaptive dosing evaluation with exposure to varoglutamstat or placebo for a minimum of 24 weeks (Phase 2A). Participants are randomized 1:1 to varoglutamstat or placebo, and randomization is stratified between mild AD and MCI, as well as by site.

During Phase 2A participants are to be enrolled sequentially into one of three dose cohorts (labelled Cohort A, B and C, with 60 participants per cohort (n=30 active, n=30 placebo)) and treated at the originally assigned full dose until the Data Safety Monitoring Board (DSMB) provides a protocol-specified dose decision:

Cohort A (600 mg): First 4 weeks 150 mg BID, week 5-8 300 mg BID, week 9-up to 72 600 mg BID;

Cohort B (300 mg): First 4 weeks 150 mg BID, week 5-up to 72 300 mg BID;

Cohort C (150 mg): up to 72 weeks on 150 mg BID.

In addition, at the end of Phase 2A (after 24 weeks) an interim analysis for futility will be conducted evaluating both cognitive function (ADNI Battery Composite score) and pharmacodynamics changes on electroencephalogram (EEG) spectral analysis (EEG theta power) to inform a stage-gate decision on whether to proceed with Phase 2B (72 weeks). If the Phase 2A study meets the predefined criteria to proceed to Phase 2B, then Phase 2B will assess the longer-term efficacy and safety of varoglutamstat in a larger study group, using the dose level determined during 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.

According to the protocol, during Phase 2A the DSMB performs a continuous review of the safety data using a predefined Pocock safety stopping boundary to provide a dose decision.

If Cohort A does not meet the safety stopping boundary until the last participant of the Cohort A reaches 8 weeks on full dose (600 mg BID) the DSMB will provide a dose decision as per protocol for the dose of Cohort A to be carried forward for all participants in the active arm for the remainder of the study. In case Cohort A meets the stopping boundary, all participants will be down-titrated to the next lower planned dose level (Cohort B) and the same review process by the DSMB will continue until either dose-selection, down-titration to the lowest dose level (Cohort C) or stage-gate decision. As pre-specified, the Pocock safety stopping boundary applies only until dose selection. If the first cohort (Cohort A) with the highest dose of PQ912 (600 mg BID) is selected to be carried forward, evaluation of other dose levels is no longer applicable and all data will be collected as one single active Arm/Group.

All participants randomized to PQ912 will start at 150 mg BID and will be titrated to the dose level selected per protocol; all participants in the placebo group will receive matching placebo. Participants enrolled in Phase 2A remain in the study for seamless inclusion in the Phase 2B evaluation (up to 72 weeks).

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 cerebrospinal fluid (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
• Monoclonal antibody treatment with anti-amyloid or anti-tau agents intended to address the pathophysiologic processes associated with AD within the previous 180 days prior to baseline (BL)
• Participants who are planning to receive treatment with aducanumab or any Amyloid Beta Antibody during the course of the study
• 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.