# Efficacy of Novel Melanocortin and Gut-peptide Dual Agonists for Childhood Obesity Treatment

> **NIH NIH R21** · SEATTLE CHILDREN'S HOSPITAL · 2024 · $531,174

## Abstract

SUMMARY
The high prevalence of pediatric obesity requires new anti-obesity agents with increased efficacy, safety, and
tolerance. Recent treatments based on endogenous gut peptides such as glucagon-like peptide-1 receptor
agonists (GLP-1RAs) are effective at inducing weight loss through a suppression of food intake, but they are
often associated with nausea/malaise and gastrointestinal ailments, leading to poor compliance with, or
discontinuation of, treatment, particularly in children and adolescents. The melanocortin (MC) pathway, in
particular central MC4-receptor (MC4R) signaling, has been implicated in the regulation of energy homeostasis.
Previous evidence, including our own, has shown that treatment with MCR agonists is effective at inducing weight
loss in obese patients caused by deficient hypothalamic MC signaling, including patients with genetic obesity
and forms of hypothalamic injury-related obesity, in part, by increasing energy expenditure. While treatment with
the MC4R agonist setmelanotide (SETMEL) is effective, as a monotherapy it is limited, and there may also be
unwanted off-target effects such as non-selective MC1R-mediated melanocyte stimulation and
hyperpigmentation. Our group has therefore focused on the development of a new generation of therapeutics
that target multiple receptors of complementary neurocircuits regulating energy balance to induce greater weight
loss, with minimal side effects. In support of this, our recently published findings show that our first tri-agonist
GEP44, which targets the GLP-1R and the neuropeptide receptors Y1R and anorexigenic Y2-R, reduces feeding
and body weight in diet-induced obese (DIO) rodents and shrews more potently than GLP-1RAs exendin-4 and
liraglutide, but without nausea and emesis. Based on these findings, we recently developed a novel GLP-
1R/MC4R dual agonist (KCEM1) and our Preliminary Data show that treatment of DIO rats with KCEM1 reduced
food intake and body weight, and improved glycemic control compared to controls, and these effects were
stronger vs. equimolar injections of the GLP-1RA liraglutide, and semaglutide, respectively. The goal of this
research is to: 1) fully characterize and develop our GLP-1R/MC4R monomeric peptide dual agonists with
improved efficacy by optimizing specific MC4R binding (over MC1/2/3/5Rs), and 2), create two novel
neuropeptide Y receptor Y2R/MC4R agonists, which act independently of the GLP-1R pathway entirely thus
avoiding associated side-effects. Specific Aim 1 will test the hypothesis that KCEM1 both prevents and reverses
DIO and improves glucoregulation relative to vehicle and FDA-approved single agonists. Comprehensive
measures of energy homeostasis will be supported by the Nutrition Obesity Research Center Energy Balance
Core at the University of Washington. Specific Aim 2 (exploratory) will develop novel GLP-1R/MC4R and
Y2R/MC4R dual agonists including long-acting lipidated multiagonists, and elucidate their penetration into the
brain...

## Key facts

- **NIH application ID:** 11056615
- **Project number:** 1R21HD115119-01A1
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Robert P Doyle
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $531,174
- **Award type:** 1
- **Project period:** 2024-09-19 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11056615

## Citation

> US National Institutes of Health, RePORTER application 11056615, Efficacy of Novel Melanocortin and Gut-peptide Dual Agonists for Childhood Obesity Treatment (1R21HD115119-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11056615. Licensed CC0.

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