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).
