CSTI-500
Overview
CSTI-500 is First-in-Class, orally administered New Chemical Entity (NCE), Triple Monoamine Reuptake Inhibitor (TRI). By simultaneously inhibiting the reuptake of serotonin, dopamine, and norepinephrine, CSTI-500 can address the often-reduced levels of these neurotransmitters in PWS patients. It is an optimally balanced TRI with unique pharmacological features that allow for predictable and safe titration to an efficacious dose tailored to the individual patient.
CSTI-500 was generally safe and well-tolerated and has a half-life of 50 hours in Phase I clinical trials. Also importantly, it demonstrated CNS target engagement via positron emission tomography (PET) that predicts efficacy in patients. CSTI-500 is now posed for Phase 2 development.
Mechanism of Action
CSTI-500 has the potential to provide a transformative therapy, not just for addressing hyperphagia in PWS, but also for tackling many of the associated psychiatric co-morbidities.
Tunable & Personalized Dosing
ConSynance holds the exclusive global rights to CSTI-500.
Illustrative representation of CSTI-500 brain occupancy vs plasma concentration at steady state in healthy humans
What does "tunable" mean?
SERT engagement predominates at lower exposures, while DAT and predicted NET engagement increase as exposure rises.
What is the supporting evidence?
Human PK/PET studies established exposure–occupancy relationships for SERT and DAT.
Why does the profile matter?
At lower exposures, CSTI-500 pharmacology is dominated by SERT engagement, modulating serotonin pathways associated with emotional regulation, behavioral flexibility, and compulsivity. As exposure rises, DAT and predicted NET engagement increase, adding modulation of dopamine pathways associated with food-related reward and motivation and norepinephrine pathways associated with arousal and attention.
This concentration-dependent profile provides the rationale for PK-guided dose titration across behavioral and feeding-related symptom domains in PWS. Whether this mechanistic rationale translates into clinical benefit remains to be established in clinical trials.
How is this applied clinically?
In the ongoing U.S. Phase 2 study in PWS, measured plasma concentrations guide dose titration toward predefined target-exposure ranges. Brain occupancy is not directly measured in study participants.
This quantitative approach supports individualized dose selection while safety, tolerability, pharmacokinetics, and preliminary clinical activity are evaluated.
Clinical Development Status
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Generally safe and well-tolerated in Phase 1 studies in healthy volunteers (n = 87)
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Demonstrated CNS target engagement via Positron Emission Tomography (PET) imaging
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Phase 1 in PWS patients completed (n = 10), confirming PK and tolerability in the target population
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Phase 2 clinical trial currently recruiting (NCT07348601)