Exploring changes in cognitive, clinical, biological and digital measures after 8 weeks dosing MT1988 in participants at clinical-high-risk for psychosis

Background

The clinical high risk syndrome for psychosis (CHR-P) constitutes a major unmet medical need, affecting approximately 1.7% of the youth population and is associated with considerable functional impairment, stigma, and morbidity. Whilst there are advances in understanding early risk states, there are currently no approved pharmacological treatments that modify illness trajectories or prevent transition to psychosis. In current practice, treatment often relies on medications developed for other disorders, most commonly antidepressants and antipsychotics which show limited efficacy in available data and carry burdensome side effect profiles. With around 20-30% of CHR-P individuals developing a full psychotic disorder within two to three years, the CHR stage represents a critical window for intervention and prevention. Advances in neurobiological, cognitive, and molecular research are helping to identify mechanistic targets for new treatments in this population. The Accelerating Medicines Partnership® in Schizophrenia (AMP® SCZ)—a public–private collaboration between academic, industry, government, and advocacy partners—was established to address this gap by developing measures that further define at-risk states, predict the likelihood of progression to psychosis and define targets for treatment development. Detection and intervention before psychosis develops could attenuate, slow down, or even prevent the conversion to psychosis and improve individuals’ clinical and functional outcomes.

Methods

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

The Investigational New Drug (IND) application for MT1988 has been approved and is active. At the time of submission, this study is currently in the recruitment phase, with data collection on-going. Participants will be recruited from approximately 15 CHR and clinical treatment sites in the US, over 12-18 months. The expected study close is Q1 2027.

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.

References

No references.