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CSTI-500: A Phase 2-Ready, Tunable Triple Monoamine Reuptake Inhibitor

An innovative therapy aiming to comprehensively address hyperphagia and other neurobehavioral challenges in Prader-Willi Syndrome.

Overview

CSTI-500 is an innovative, orally administered New Chemical Entity (NCE) designed to restore key neurotransmitter balance in Prader-Willi Syndrome (PWS). This Phase 2–ready therapy aims to comprehensively address hyperphagia and other neurobehavioral challenges, offering a promising approach to improve patient outcomes.

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Mechanism of Action

CSTI-500 is a triple monoamine reuptake inhibitor (TRI) that modulates serotonin, dopamine, and norepinephrine by inhibiting their respective transporters (SERT, DAT, and NET). These neurotransmitters are key regulators of behavior, feeding, and mood control.

Research in both human and animal models indicates that Prader-Willi Syndrome (PWS) is associated with deficiencies in serotonin, dopamine, and norepinephrine, contributing to feeding and behavioral dysregulation. By simultaneously modulating these three neurotransmitters, CSTI-500 has the potential to help address hyperphagia, anxiety, irritability, temper outbursts, and other neuropsychiatric challenges associated with PWS. Clinical efficacy and safety of CSTI-500 in this context are still being investigated.

CSTI-500 modulates three monoamines involved in appetite, mood, and behaviors.

Tunable & Personalized Dosing

CSTI-500 is the first and only triple monoamine reuptake inhibitor (TRI) with a “tunable” profile, supported by human brain target engagement data from PET imaging. As the drug concentration increases, SERT occupancy saturates early at SSRI-like levels - potentially providing behavioral control for irritability and anxiety - while DAT and NET occupancy increases more gradually, offering a path to curb hyperphagia and reinforce behavioral benefits.

Relationship between CSTI-500 blood drug concentrations and transporter blockade

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Why It Matters?

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  • Offers a potential single-agent approach for PWS’s complex neuropsychiatric profile.

  • Enables personalized balance between efficacy & tolerability

  • Uses PK-Guided, individualized dosing to keep each patient in the optimal therapeutic window

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In short, CSTI-500’s tunable mechanism and individualized dosing strategy potentially offers a novel way to address the full spectrum of PWS symptoms safely and effectively.

Note: The clinical benefit of CSTI-500 has yet to be confirmed in trials, and further research is underway.

Clinical Development Status

  • Generally safe and well-tolerated in Phase I studies in healthy volunteers (n = 87)

  • Demonstrated CNS target engagement via Positron Emission Tomography (PET) imaging

  • Phase I in PWS patients completed (n = 10), confirming PK and tolerability in the target population

  • Phase II study initiating in 2025

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