Therapies for Treatment-Resistant Childhood Common Obesity, Hypothalamic Obesity and Type 2 Diabetes

Developing and clinically testing multireceptor agonists for weight and blood glucose control

Technology Overview

Current therapeutic options for treating obesity and type 2 diabetes (T2D), including glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide, mainly target single receptors. Side effects of these drugs (e.g., nausea, vomiting, diarrhea) are associated with high rates of treatment discontinuation, particularly in children and adolescents. In addition, single-target medications often have limited effects because obesity and T2D are influenced by multiple pathways that regulate appetite, blood glucose and energy balance.

Dr. Christian Roth

To address the unmet clinical need for metabolic disorders such as obesity and T2D, pediatric endocrinologist Christian Roth, MD, is identifying and testing single-molecule peptide drugs that bind multiple receptors. Using in vitro assays, animal models, and human and animal ex vivo tissues, Dr. Roth and colleagues showed that some chimeric peptides are more potent than are the drugs currently in use for controlling appetite, losing weight and regulating blood glucose. In animal models, these peptides cause fewer side effects than the well-described GLP-1 receptor agonists exendin-4 and liraglutide.

Hypothalamic obesity can result from a hypothalamic injury, often due to surgery or radiation treatment for brain tumors in the hypothalamic area. Dr. Roth’s Lab found that the monomeric peptide KCEM1 shows promise for treating this type of obesity. KCEM1 combines agonists for both the GLP-1 receptor and the melanocortin-4 (MC4) receptor. In hypothalamic obesity, MC4 receptor signaling often is disrupted, and the unique KCEM1 peptide is designed to overcome this deficiency.

In addition, in obesity induced by a calorie-rich diet, Dr. Roth’s team found that KCEM1 yielded similar reductions in calorie intake and body weight after daily subcutaneous injections when compared with the widely used GLP-1 agonists semaglutide and tirzepatide. More surprisingly, KCEM1 was associated with marked differences in glucose metabolism and offered superior glycemic control during glucose tolerance testing — meaning the differences were not solely due to weight loss.

If these early results are replicated in further preclinical tests, KCEM1 could advance to human clinical trials as a weight loss drug candidate that also improves glucose metabolism more than current medications do. Another well-known phenomenon, disturbed lipid metabolism due to obesity, has been linked to cardiovascular and liver disease. In studies in animal models, the Roth Lab found that KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Additional research findings from the Roth Lab suggest that KCEM1 holds promise for treating MASH before it progresses to fibrosis, cirrhosis and hepatic cancer.

In a phase 2 randomized clinical trial, Dr. Roth and colleagues found that another MC4 receptor agonist called setmelanotide, a first-in-class drug already approved by the U.S. FDA to treat obesity caused by rare genetic disorders, is also effective for hypothalamic obesity. The trial showed that setmelanotide significantly reduces BMI and self-reported hunger in patients. Dr. Roth is now collaborating with Rhythm Pharmaceuticals on a phase 3 international trial testing the efficacy of setmelanotide on 120 patients with hypothalamic obesity, for which FDA approval is expected soon.

Another drug, GEP-44, is a triple-agonist peptide that binds the GLP-1 receptor and the neuropeptide Y1 and Y2 receptors. The combined multiagonist effects of GEP-44 include stimulation of the rate of insulin secretion in pancreatic islets and Y1-receptor agonism that results in insulin-independent glucose uptake into muscle — importantly, only at elevated glucose levels. The resulting reductions in blood glucose and appetite and increases in glucose uptake by muscle lead to significant weight loss and improved blood glucose regulation. Tests in animal models suggest that GEP-44 also carries fewer side effects such as nausea and vomiting than do leading alternatives.

In other studies, Dr. Roth’s lab is testing analogs of the peptide hormone oxytocin, modified for in vivo stability, for effectiveness in reducing body weight. In animal models, oxytocin reduces food intake and increases energy expenditure. In an animal model of obesity, Dr. Roth and team showed that administration of the oxytocin analog ASK2131 led to significant weight loss, whereas control animals maintained or gained weight. Moreover, a promising feature of oxytocin analogs, especially for use in children, is effective intranasal delivery that avoids the need for injections.

Drugs designed to treat obesity often yield good initial results before plateauing, due in part to compensatory mechanisms that dampen the drugs’ effects. Functional imaging studies from the Roth Lab, in fact, have shown that weight loss in children can lead to an exaggerated regulation of appetite-associated centers in the brain, priming the children to regain weight due to increased hunger.

Recent research findings from the Roth Lab could drive the use of multireceptor polypharmacy to treat metabolic syndrome, especially in pediatric patients. By addressing different pathways simultaneously, the strategy could dampen the compensatory mechanisms that work against sustained reductions in calorie intake and weight loss.

Dr. Roth is interested in industry partnerships to pursue mechanistic and behavioral model testing and drug screening, and to extend his preclinical and clinical-stage programs. Potential collaborations include using functional MRI (fMRI) to monitor the satiety response to candidate medications in humans, with the ultimate goal of advancing peptide drugs for the treatment of common obesity, hypothalamic obesity and T2D.

Stage of Development

• Preclinical in vivo
• Preclinical in vitro
• Preclinical ex vivo
• Clinical trials

Partnering Opportunities

• Collaborative research and development
• Sponsored research agreement
• Consultation agreement
• Clinical trials
• Data access
• Tissue sample access
• Animal model access

Learn More

• Christian L. Roth, MD
• Rhythm Pharmaceuticals

Publications

1. Ashlaw EF, Elfers CT, Chichura KS … Roth CL. A melanocortin 4-and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity. Metabolism. 2026;174:56414.
2. Argente J, Clément K, Duis J … Roth CL, et al. Hyperphagia in rare melanocortin-4 receptor pathway diseases: therapeutic options and assessing treatment response. Rev Endocr Metab Disord. 2025;26(6):917-935.
3. Heymsfield SB, Clément K, Dubern B … Roth CL, et al. Defining hyperphagia for improved diagnosis and management of MC4R pathway-associated disease: A roundtable summary. Curr Obes Rep. 2025;14(1):13.
4. Elfers CT, Chichura KS, Ashlaw EF … Roth CL. Reductions of food intake and body weight in diet-induced obese rats following chronic treatment with a monomeric peptide multiagonist. Clin Nutr. 2024;43:1782-1790.
5. Roth CL, Scimia C, Shoemaker AH, et al. Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial. Lancet Diabetes Endocrinol. 2024;12(6):380-389.
6. Chichura KS, Elfers CT, Salameh T… Roth CL, et al. A peptide triple agonist of GLP-1, neuropeptide Y1, and neuropeptide Y2 receptors promotes glycemic control and weight loss. Sci Rep. 2023;13:9554.
7. Roth CL, Melhorn SJ, De Leon MRB, et al. Impaired brain satiety responses after weight loss in children with obesity. J Clin Endocrinol Metab. 2022;107(8):2254-2266.
8. Sewaybricker LE, Melhorn SJ, Papantoni A … Roth CL, et al. Pilot multi-site and reproducibility study of hypothalamic gliosis in children. Pediatr Obes. 2021;16(4):e12732.
9. Milliken, BT, Elfers C, Chepurny OG … Roth CL, et al. Design and evaluation of peptide dual-agonists of GLP-1 and NPY2 receptors for glucoregulation and weight loss with mitigated nausea and emesis. J Med Chem. 2021;64(2):1127-1138.
10. Schur EA, Melhorn SJ, Scholz K … Roth CL. Child neurobiology impacts success in family-based behavioral treatment for children with obesity. Int J Obes. 2020;44(10):2011-2022.
11. Roth CL, Melhorn SJ, Elfers CT, et al. Central nervous system and peripheral hormone responses to a meal in children. J Clin Endocrinol Metab. 2019;104(5):1471-1483.
12. Chepurny OG, Bonaccorso RL, Leech CA … Roth CL, et al. Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. Sci Rep. 2018;8(1):3749.

Updated April 14, 2026.