In our last post, we explored the scientific rationale behind MT1988 and how the history of nicotinic receptor research has shaped its design. In this post we shift gears from why MT1988 matters, to how it has progressed from concept to clinical reality as it enters evaluation in a clinical high risk (CHR) for psychosis patient trial. We also reflect on how MT1988 is an example of how lessons learned, strategic development planning, and precision-focused thinking can reshape the path forward for neuropsychiatric treatments.

Starting From A Strong Scientific Foundation

A major advantage while developing MT1988 has been the extensive knowledge already available for its two components: tropisetron and varenicline.  Both compounds have well-established safety profiles from many years of use as individual products, and each have individually demonstrated measurable improvements in cognition in people with schizophrenia. This wealth of data behind the two compounds provided an opportunity to create a therapy which already reduced early-stage uncertainty, provided confidence in mechanistic feasibility, and offered an accelerated route to market.

Building A Combination With Mechanistic Balance

As described previously, MT1988 brings together tropisetron’s α7 partial agonism and 5-HT₃ antagonism with varenicline’s α7 and α4β2 agonism and 5-HT₃ agonism. As a fixed-dose combination MT1988 is designed to promote pro-cognitive efficacy via the α7 and α4β2 routes (e.g., improving attention and memory problems) while counteracting peripheral 5-HT₃ side effects (gut-related intolerance) that hampered earlier efforts with α7 treatments. Turning this mechanistic concept into a viable therapeutic required coordinated scientific, regulatory, and manufacturing work:

1. Early-stage work: A package of studies demonstrated synergistic effects (i.e. the sum of the two products is greater than adding the two individual effects together) on cognitive performance when tropisetron and varenicline were administered together.
2. Early engagement with regulators: A successful pre-IND meeting with the FDA allowed us to align our development approach with regulatory expectations from the outset. Correspondence with the MHRA clarified expectations relating to the MT1988 formulation.
3. A Phase I study: Before producing a novel combination formulation, we evaluated the safety and tolerability of tropisetron and varenicline taken at the same time. This demonstrated a favourable safety and tolerability profile, supporting the feasibility of chronic administration in a patient population.
4. Formulation innovation: Supported through an Innovate UK (IUK) Investor Partnership grant, we developed the first fixed dose capsule containing both actives. This was a substantial development milestone, requiring careful manufacturing to achieve a consistent, homogenous blend of the actives.
5. New intellectual property: The formulation and dosing insights gained during development enabled us to build upon our existing patent portfolio and secure additional IP with new composition-of-matter claims. This is a significant achievement for a therapy built from two known compounds, strengthening the long-term value of MT1988.

What Our Journey Has Revealed

We believe the lessons from the development of MT1988 offer broader insights into how innovation in neuroscience can be accelerated:

1. Repurposed molecules are underutilised assets: Repurposed compounds bring established safety and mechanistic insight, allowing teams to shift focus toward improving efficacy and clinical trial design, rather than navigating early-stage uncertainty – accelerating development while still supporting strong IP and therapeutic innovation.
2. Repurposed products can be protected by strong and new IP: New combinations, doses and formulations can result in IP as strong as new chemical entities, such as the composition-of-matter claims now filed for MT1988.
3. Small, experienced teams can deliver big advances: While laboratory, clinic and formulation work has been outsourced, all strategy, programme leadership, scientific direction and operations have been done by Monument’s very small team.

We hope MT1988’s development journey that we’ve shared so far illustrates a broader point: innovation in mental health can be accelerated when we combine known pharmacology with thoughtful scientific design, biomarker integration, and strategic regulatory pathways.

Stay tuned as we get ready to launch our Proof of Principle (PoP) clinical trial in patients at clinical high risk for psychosis! Our next post will take a deeper dive into the use of digital biomarkers for patient stratification as our PoP trial gets underway as the first trial in our precision medicine pipeline…. More to come soon!

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