In our last post, we introduced the team leading the MT1988 proof-of-principle clinical trial – a major collaboration under the AMP® SCZ programme focused on accelerating early intervention in individuals at clinical high risk (CHR) for psychosis.
This week, we explore the science behind MT1988 – its mechanism of action as a nicotinic agonist, how it builds on decades of insight from nicotinic receptor research, and how it represents a targeted, safe and more effective treatment for cognitive dysfunction in psychiatric illness.
Learning From The Field’s History
The nicotinic self-medication hypothesis of schizophrenia first drew attention to the cholinergic system after researchers observed that people with schizophrenia smoke at much higher rates than the general population. Nicotine’s ability to transiently enhance attention, working memory, and attenional gating suggested that stimulating nicotinic acetylcholine receptors (nAChRs) might help improve cognitive impairments associated with the the disorder. These receptors are expressed in brain regions critical for cognition—including the prefrontal cortex, hippocampus, and thalamus—where they modulate glutamatergic, dopaminergic, and GABAergic signalling essential for information processing and executive control.
Multiple compounds targeting the α7 nicotinic acetylcholine receptor (α7 nAChR) have been evaluated for cognitive impairment associated schizophrenia, and other psychiatric conditions. Many trials have demonstrated promise in preclinical and early phase clinical studies but failed at either Phase II or Phase III testing.
Challenges that have been proposed to contribute to these setbacks, include:
- Biological Heterogeneity: Diverse patient populations diluting true treatment effects.
- Offtarget Activity: Many α7 agonists have off-target activity at the 5HT3 receptor in the gastrointestinal (GI) tract where activation of these receptors causes gut motility and tolerability issues.
- Receptor Desensitization: A phenomenon where sustained stimulation reduces receptor responsiveness, limiting cognitive benefit.
- Suboptimal Dosing: The cognitive effects of nicotinic stimulation follow an inverted U-shaped dose–response curve, where both insufficient and excessive receptor activation can impair rather than enhance performance.
Together these factors have underscored the need for more mechanistically balanced and better-tolerated approaches to nicotinic stimulation.
The Rationale For MT1988
MT1988 was designed to address historical issues with α7 compounds. The compound combines tropisetron (nAChR partial agonist and 5-HT₃ antagonist), and varenicline (full agonist at α7, partial agonist at α4β2 nicotinic receptors, and 5HT₃ agonist) into a single fixed dose combination, optimised for efficacy, safety and chronic administration.
The complimentary activity across receptor subtypes is central to MT1988’s pro-cognitive potential. Research suggests that α7 as well as α4β2 receptors play an important role in regulating cognitive functions. Both tropisetron and varenicline have independently demonstrated cognitive benefits in individuals with schizophrenia, and preclinical data from Monument’s programme shows synergistic effects on cognitive performance when the two are administered together.
The opposing 5-HT₃ receptor actions of MT1988 are designed to counterbalance GI side effects, improving tolerability without compromising central efficacy. This strategy to off-set peripheral side effexts in a fixed-dose combination is similar to the successful approach undertaken with KarXT (Cobenfy®) for the treatment of psychosis.
Notably, varenicline, best known as a smoking cessation therapy, has shown measurable cognitive benefits in individuals with schizophrenia who smoke, demonstrating that the nicotinic pathway remains responsive even in the nicotinic-adapted brain. Observations such as this calls into questions whether previous α7 trials may have failed due to methodological limitations rather than pharmacologic utility associated with receptor desensitization. Specifically, the lack of biomarker-based stratification to identify biologically responsive subgroups.
Looking Ahead
By combining mechanistic insight with biomarker integration in the AMP SCZ trial, MT1988 represents a promising and exciting opportunity to examine nicotinic-based therapy through the lens of precision psychiatry. Using stratification tools to link treatment effects to biological mechanisms is designed to increase the likelihood of clinical success—a key step toward delivering on the promise of precision psychiatry in mental health.
Our next post will explore how our science is being transformed into action as MT1988 moves toward its first clinical evaluation in patients within the AMP SCZ trial. 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
