Previously, we introduced our nicotinic drug MT1988’s journey from concept to clinic as our Proof-of-Principle (PoP) trial in clinical high risk (CHR) for psychosis gets underway (NCT07226895). Here, we take a deeper dive into how biomarkers are central to the trial, why they matter, and how Monument’s proprietary digital biomarker is being evaluated as a stratification tool to predict MT1988’s effect on cognitive performance.
Why Biomarkers Are Central to This Study
As highlighted earlier in this series, individuals at clinical high risk (CHR) for psychosis show substantial biological and cognitive variability, even when they present with similar symptoms. This variability has historically made the interpretation of clinical outcomes in schizophrenia studies difficult by making it harder to detect true drug effects, thereby contributing to the high failure rate of otherwise promising new treatments.
In the MT1988 PoP trial multiple biological, cognitive and functional measures have been included to understand how these change in response to treatment. Establishing reliable pharmacodynamic biomarkers as endpoints in the study is essential to assess whether and how MT1988 is influencing the specific symptoms and functional impairments seen in the CHR population.
Within this framework, Monument’s proprietary digital biomarker, latent inhibition, provides a biologically relevant measure of cognitive function that is closely aligned with MT1988’s nicotinic mechanism of action. Assessing latent inhibition performance at baseline will evaluate whether task performance is a predictor of pro-cognitive change following MT1988 administration.
Primary and Secondary Measures
The measures included in the PoP trial are designed to provide insight into pharmacodynamic responses to MT1988 – that is, how the drug engages multiple biological and functional domains relevant to CHR.
Change in cognition is a primary measure, reflecting the central role of cognitive dysfunction in psychosis risk states and its association with long-term functional outcomes. Cognitive performance is assessed using established, standardised batteries, with the Penn Computerized Neurocognitive Battery (PennCNB) serving as the primary cognitive assessment, complemented by additional measures from the Cambridge Neuropsychological Test Automated Battery (CANTAB).
In addition, the study includes a range of secondary measures, including:
- Neurophysiological measures, including EEG-based mismatch negativity and auditory oddball paradigms (neural responses linked to attention and information processing).
- Biological measures, including inflammatory and stress-related markers derived from blood and saliva.
- Clinical and functional assessments, including measures of attenuated positive symptoms (subthreshold psychotic experiences), negative symptoms (e.g., reduced motivation and social engagement), mood and sleep, alongside momentary digital measures of real-world behaviour (e.g., rest-activity and roaming patterns).
Together, this biomarker framework is intended to help identify meaningful changes relevant to early intervention, support stratification of CHR populations in clinical trials, and inform biomarker-driven development strategies.
Full details of the MT1988 PoP trial design are now available on the AMP Schizophrenia website: MT1988 Proof of Principle Clinical Trial Design | AMP SCZ.
Latent Inhibition as Mechanism-Linked Stratification Biomarker
At the centre of Monument’s biomarker strategy is the stratification of patients based on latent inhibition performance, measured using a proprietary digital cognitive task. This is a test that reflects attentional gating which is the brain’s ability to prioritise relevant information while filtering out distractions, and importantly, the ability to learn and adapt when the relevance of information changes.
The task involves learning rules about which cues are relevant and then flexibly updating that learning when the relevance of cues changes. In this way, latent inhibition captures a core aspect of cognitive flexibility. In schizophrenia-related disorders, this process of cognitive flexibility is often impaired, making it difficult to adjust to changes in relevance as circumstances shift.
These challenges in cognitive flexibility are closely linked to downstream difficulties in attention, working memory, and executive function, which are central to everyday cognitive performance.
Across genetic, neurophysiological, imaging, and behavioural studies, abnormalities in attentional gating have been repeatedly associated with reduced α7 nicotinic receptor function, a pathway consistently implicated in cognitive impairment associated with schizophrenia. This supports latent inhibition as a biologically grounded biomarker of nicotinic system dysfunction relevant to cognition.
In the MT1988 PoP trial, latent inhibition is assessed at baseline and used as a stratification measure to examine whether abnormal baseline performance is associated with subsequent pro-cognitive changes following MT1988 administration. In this context, latent inhibition functions as a biomarker linked to MT1988’s mechanism of action and the cognition-related pathways it targets, to identify participants most likely to show cognitive benefit from the drug, rather than serving as an endpoint in its own right.
Looking Ahead
Biomarkers are reshaping how we design and interpret CNS clinical trials and hold promise to significantly improve clinical trial success rates—but their impact extends beyond study design alone. In our next post, we’ll turn to the regulatory landscape, exploring how agencies are adapting to biomarker-driven approaches and what this evolution means for the future of CNS drug development. Stay tuned!
Visit our website to read our blog series to date: www.monumenttx.com
To learn more about the FNIH, please visit fnih.org
To learn more about AMP SCZ, please visit fnih.org/AMP and www.ampscz.org
#FromSymptomstoSignals #PrecisionPsychiatry #Biomarkers #DrugDevelopment
