First participant dosed in Phase 2a trial of CSTI-500 for Prader-Willi syndrome

The first participant has been dosed in a proof-of-concept, open-label Phase 2a clinical trial testing Consynance Therapeutics’ experimental oral therapy CSTI-500 in adolescents and adults with Prader-Willi syndrome (PWS).

Supported in part by a venture philanthropy investment from the Foundation for Prader-Willi Research (FPWR), the Phase 2a study (NCT07348601) is expected to enroll approximately 12 people, ages 13 to 50, with genetically confirmed PWS, at Vanderbilt University Medical Center, in Nashville, Tennessee.

The study will primarily evaluate the safety and tolerability of CSTI-500 while also exploring early signs of its effects on hyperphagia, or excessive hunger, and related neurobehavioral symptoms.

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“Dosing the first patient in our Phase 2a trial is an important milestone for ConSynance and for the PWS community,” Shuang Liu, PhD, founder and CEO of Consynance, said in a company press release. “This study will allow us to further evaluate the safety and tolerability of CSTI-500 in individuals with PWS and to gather early data on its potential to improve hyperphagia, and more notably, the related neurobehavioral symptoms commonly experienced by this population.”

PWS is caused by the loss of function of certain genes on chromosome 15. The disorder can cause a wide range of symptoms, including hyperphagia, learning difficulties, sleep disturbances, and behavioral problems such as emotional outbursts and compulsive behaviors.

According to Theresa Strong, PhD, FPWR’s director of research programs, “data from the Global PWS Registry consistently show that behavioral outbursts and hyperphagia are among the most challenging aspects of PWS for families.”

Research suggests PWS is associated with reduced or altered signaling involving serotonin, dopamine, and norepinephrine — chemical messengers, or neurotransmitters, that help regulate appetite, mood, behavior, and sleep.

To communicate with one another, nerve cells release neurotransmitters into the space between cells. Afterward, cells normally take those neurotransmitters back up, a process called reuptake, which helps control the strength and duration of the signal.

Oral therapy aims to target brain signaling

CSTI-500 is an investigational oral triple monoamine reuptake inhibitor designed to block that reuptake, thereby increasing the availability of serotonin, dopamine, and norepinephrine in the brain. By boosting their levels, the therapy is being developed to help address hyperphagia and behavioral symptoms associated with PWS.

The therapy received rare pediatric disease designation from the U.S. Food and Drug Administration for PWS. That status is intended to encourage the development of treatments for rare pediatric diseases, defined as serious or life-threatening conditions primarily affecting patients younger than age 18 and affecting fewer than 200,000 people in the U.S.

Earlier Phase 1 studies evaluating single and multiple ascending doses of CSTI-500 in healthy volunteers showed the therapy was generally safe and well tolerated, and demonstrated a favorable pharmacokinetic profile, or how the body processes the therapy. Brain imaging scans also confirmed that CSTI-500 engaged its intended targets in the brain.

The company later completed a Phase 1 trial (NCT05504395) involving 10 adolescents and adults with PWS enrolled at Vanderbilt University Medical Center. Participants received a single 10 mg oral dose of a newly developed capsule formulation.

The therapy was generally safe and well tolerated in that study, with no severe side effects reported. The capsule formulation also showed a pharmacokinetic profile similar to that seen with the older formulation in healthy volunteers.

Phase 1 findings supported Phase 2a testing

These findings supported advancing CSTI-500 into Phase 2a clinical testing.

In the ongoing Phase 2a study, participants will receive individualized doses of CSTI-500 for about 84 days, or nearly three months, guided by a pharmacokinetic model, which estimates how each person’s body processes the therapy.

The study’s main goals are to evaluate CSTI-500’s safety and determine whether individualized dosing can be used to achieve low, medium, or high target exposure levels.

Researchers will also explore CSTI-500’s effects on hyperphagia, behavioral symptoms, and overall disease severity using standardized clinician- and caregiver-reported assessments. According to Consynance, the results will help guide the future clinical development of CSTI-500.

Strong noted that treatments addressing hyperphagia and behavioral symptoms remain major unmet needs for people with PWS. Dosing the first participant, she said, “represents an important step in FPWR’s effort to accelerate the development of therapies that directly address these unmet needs.”