¹Monument Therapeutics, Science, Manchester, United Kingdom, ²Yale University, Medicine, Connecticut, United States, ³Harvard Medical School, Psychiatry and Radiology, Massachusetts, United States, ⁴UCLA, Psychology, California, United States, ⁵École de Technologie Supérieure, Software Engineering and Information Technology, Montreal, Canada, ⁶Northwell, Northwell Health, New York, United States, ⁷Mount Sinai, Icahn School of Medicine, New York, United States, ⁸Harvard Medical School, Psychiatry, Massachusetts, United States, ⁹Foundation for the National Institutes of Health, FNIH, North Bethesda, United States

Background: The Accelerating Medicines Partnership® in Schizophrenia (AMP® SCZ) programme aims to develop measures that further define the early stages of risk for schizophrenia, predict likelihood of progression to psychosis and other clinical outcomes in individuals at clinical high risk (CHR), and define targets for treatment development. The CHR phase represents a critical window for intervention and importantly, for studying early disruptions in cognition, clinical symptomatology, neurophysiology, and molecular pathology, as these alterations may serve as early markers of disease progression and potential pharmacodynamic targets.

Aims & Objectives: The aim of this study is to investigate how a range of cognitive, clinical, biological, and digital biomarkers respond to 8 weeks of treatment with MT1988 in individuals at clinical high risk for psychosis, and to evaluate the safety and tolerability of MT1988 in this population.

Method: This exploratory, 8-week, randomized, double-blind, placebo-controlled, parallel group, multi-site, proof-of-principle study in a CHR population is designed to investigate how a range of cognitive, clinical, biological and digital biomarkers respond to MT1988. MT1988, in development by Monument Therapeutics, is a novel fixed-dose combination of tropisetron and varenicline. Approximately 150 participants aged 17-30 years, meeting diagnostic criteria for CHR will be randomized 1:1:1 to receive low-dose MT1988, high-dose MT1988, or placebo twice-daily for 8 weeks. The primary endpoints are change from baseline to week 8 in a cognitive test of verbal memory (PennCNB test battery), attenuated positive symptoms (PSYCHS total score), and negative symptoms (Negative Symptom Inventory-Psychosis Risk). Secondary endpoints include a range of cognitive, clinical, biological and digital biomarkers, and an evaluation of the safety and tolerability of MT1988 during the 8-week treatment period.

Results: At the time of submission, this study is currently in the pre-recruitment phase, with data collection pending initiation. The Investigational New Drug (IND) application for MT1988 has been approved and is active. Recruitment is scheduled to begin Q1 2026, and participants will be recruited from approximately 15 CHR and clinical treatment sites in the US, over 12-18 months. The expected study close is Q2 2027. Data on sample characteristics available at time of presentation will be included.

Discussion & Conclusions: This study will provide insights into the responsiveness of cognitive, clinical, biological, and digital biomarkers to MT1988 in individuals at clinical high risk for psychosis. Findings will help to inform the validity of these biomarkers as pharmacodynamic indicators and contribute to the broader AMP SCZ initiative to refine risk stratification, understand early disease mechanisms, and accelerate treatment development for schizophrenia. In addition to assessing therapeutic effects, the approach is designed to explore whether these biomarkers support prediction and monitoring of treatment response over time.