Imcivree (setmelanotide) / Rhythm Pharma - LARVOL DELTA

Bardet-Biedl syndrome presenting with early-onset infantile obesity. (PubMed, BMJ Case Rep) - "On follow-up after 2 years of age, setmelanotide is planned to be initiated for his weight management. Infantile obesity, a rare and early manifestation, played a pivotal role in suspecting syndromic obesity, leading to targeted genetic investigations. The case highlights the importance of recognising early-onset obesity as a diagnostic clue for genetic syndromes by performing next-generation sequencing critical to make firm diagnosis of BBS."

Journal • Bardet–Biedl Syndrome • Developmental Disorders • Endocrine Disorders • Genetic Disorders • Inherited Retinal Dystrophy • Mental Retardation • Obesity • Ophthalmology • Pediatrics • Renal Disease

Setmelanotide-mediated MC4R activation improves hypothalamic obesity via CaMKK2/AMPK pathways. (PubMed, Front Pharmacol) - "Crucially, administration of setmelanotide restored CaMKK2/AMPK activity, reactivated MC4R neurons, and normalized appetite and feeding behavior during fasting-refeeding and the long-term treatment of obese rats (60% reduction in food intake), ultimately reversing obesity (23% weight loss). These findings underscore the critical role of MC4R dysfunction in hypothalamic injury and highlight the strategies to pharmacologically activate MC4R via CaMKK2/AMPK signaling to restore metabolic homeostasis, proposing a translatable therapeutic agent to manage obesity caused by CNS injury."

Journal • CNS Disorders • Genetic Disorders • Hypothalamic Injury-associated Obesity • Obesity • Oncology • CAMKK2 • MC4R

Modulating food intake by nasal application of peptides targeting melanocortin 4 receptor and ghrelin receptor systems. (PubMed, Brain Commun) - "Although no significant changes in body weight were observed, we detected differences in the daily change in food intake: this parameter was reduced for mice treated with setmelanotide variants and increased for mice treated with GhrR agonists compared to a control group. Taken together, our findings clearly underline the high potential of intranasal peptide administration for modulating food intake."

Journal • Cachexia • Genetic Disorders • Obesity • MC4R

Current Approaches and Therapeutic Strategies for Hypothalamic Syndrome in Patients with Childhood-onset Craniopharyngioma. (PubMed, J Clin Res Pediatr Endocrinol) - "Several pharmacologic interventions, such as centrally acting stimulants, glucagon-like peptide-1 receptor agonists, and the melanocortin-4 receptor agonist setmelanotide, have demonstrated potential in promoting weight reduction. Bariatric surgery may also yield clinical benefit; however, the use of irreversible procedures in pediatric populations presents substantial ethical and legal challenges. There remains an urgent need for therapeutic strategies that emphasize preservation of hypothalamic structure and function, alongside continued research into targeted and emerging interventions for more effective management of hypothalamic syndrome."

Journal • Brain Cancer • Cardiovascular • CNS Tumor • Genetic Disorders • Germ Cell Tumors • Glioma • Hypothalamic Injury-associated Obesity • Langerhans Cell Histiocytosis • Metabolic Disorders • Obesity • Oncology • Pediatrics • Solid Tumor

Hormones and skin pigmentation: fundamentals and clinical relevance (PubMed, Dermatologie (Heidelb)) - "Two synthetic melanocortins, afamelanotide (NDP-α-MSH) and setmelanotide, are currently approved in Germany. Autoimmune thyroid disorders and diabetes are associated with non-segmental vitiligo. Melatonin appears to have a lightening effect on skin pigmentation by melanin."

Journal • Review • Dermatology • Dermatopathology • Diabetes • Endocrine Disorders • Immunology • Metabolic Disorders • Rare Diseases • Vitiligo • IGF1

Anticipated Upcoming Milestones (The Manila Times) - "Announce topline data in the 12-patient Japanese cohort of the setmelanotide Phase 3 trial in acquired HO in the first quarter of 2026...Complete enrollment in the setmelanotide Phase 3 trial substudy in congenital HO in the first half of 2026...Pending further feedback from U.S. and European regulatory agencies, initiate a pivotal Phase 3 trial evaluating bivamelagon in acquired HO in 2026....Complete enrollment in the Phase 1, Part C trial evaluating the weekly, MC4R agonist RM-718 in patients with acquired HO in the first quarter of 2026."

Clinical data • Enrollment status • New P3 trial • Hypothalamic Injury-associated Obesity • Obesity

Setmelanotide-Mediated MC4R Activation Improves Hypothalamic Obesity via CaMKK2/AMPK Pathways (Frontiers) - "We established a rat hypothalamic injury model to replicate human HO symptoms, such as hyperphagia (50% increase in food intake), elevated Lee index, and more than 25% weight gain. Immunofluorescence and immunoblot analysis showed that HO disrupted the PVN neuropeptides, leading to the inhibition of MC4R via calmodulin-dependent protein kinase kinase 2 (CaMKK2) and AMP-activated protein kinase (AMPK) signaling. Crucially, administration of setmelanotide restored CaMKK2/AMPK activity, reactivated MC4R neurons, and normalized appetite and feeding behavior during fasting-refeeding and the long-term treatment of obese rats (60% reduction in food intake), ultimately reversing obesity (23% weight loss)."

Preclinical • Hypothalamic Injury-associated Obesity

The effect of melanocortin-4 receptor agonist drugs on obesity and metabolic risk factors: a systematic review and meta-analysis. (PubMed, Diabetol Metab Syndr) - No abstract available

Journal • Retrospective data • Review • Genetic Disorders • Obesity

Rate of Age-Related Macular Degeneration in Patients Prescribed Glucagon-Like Peptide-1 Receptor Agonists or Other Weight Loss Therapy. (PubMed, Ophthalmol Retina) - "Among non-diabetic adults ≥ 50 years old eligible for weight loss pharmacotherapy, prescriptions for GLP-1 RAs were associated with a lower incidence of nonexudative and any (nonexudative, exudative, or unspecified) AMD diagnoses compared with other weight loss medications. The difference in new exudative AMD diagnoses was not statistically significant."

Journal • Age-related Macular Degeneration • Cardiovascular • Dry Age-related Macular Degeneration • Dyslipidemia • Genetic Disorders • Hypertension • Macular Degeneration • Metabolic Disorders • Obesity • Ophthalmology • Retinal Disorders

Targeted Next-Generation Sequencing of the Leptin-Melanocortin Pathway in Severe Obesity. (PubMed, Obesity (Silver Spring)) - "This supports the relevance of expanded genetic testing in severe obesity. Early-onset obesity remains a key clinical feature to guide genetic investigation and identify patients who may benefit from early personalized care and targeted treatments."

Biomarker • Journal • Next-generation sequencing • Behavior Disorders • Genetic Disorders • Mental Retardation • Obesity • Psychiatry • LEP • PCSK1

Beyond metabolism: sexual dysfunction and weight-loss drugs. (PubMed, Sex Med Rev) - "Pharmacological weight-loss therapies influence sexual health through multiple direct and indirect pathways. However, current evidence is inconsistent, and sex-specific data are scarce. Future clinical trials should systematically include validated sexual function measures as primary endpoints and stratify results by sex and comorbidities to better guide clinical practice in sexual medicine."

Journal • Erectile Dysfunction • Genetic Disorders • Obesity • Sexual Disorders

SAR investigation and synergistic optimization of setmelanotide yields a potent, selective, and soluble MC4R agonist. (PubMed, Bioorg Chem) - "In a diet-induced obesity model, SC19 demonstrated robust efficacy comparable to setmelanotide in reducing weight gain and improving lipid profiles, affirming its therapeutic potential. This work not only presents a promising lead compound but also validates a synergistic optimization blueprint for concurrently enhancing the pharmacological and drug-like properties of therapeutic peptides."

Journal • Genetic Disorders • Obesity • MC4R

The Obesity Drug Revolution: New Frontiers in Pharmacotherapy. (PubMed, Cureus) - "The current FDA-approved pharmacotherapy consists of orlistat, setmelanotide, phentermine-topiramate, naltrexone-bupropion, liraglutide, semaglutide, and tirzepatide...Orforglipron, a non-peptide oral glucagon-like peptide-1 receptor agonist, offers parenteral efficacy with convenient dosing...Innovative therapeutic approaches, multidisciplinary care, and a patient-centered plan are required for better clinical outcomes. This review highlights the current and emerging therapies designed to enhance long-term outcomes in obesity care."

Journal • Review • Cardiovascular • Diabetes • Dyslipidemia • Genetic Disorders • Hypertension • Inflammation • Metabolic Disorders • Obesity • Psychiatry • Transplantation

Evidence Supporting the Use of Optically Pure S-(+)-Indoxacarb: Discovery and Toxicokinetic Characterization of Two New Pairs of Metabolite Enantiomers in Rats. (PubMed, Chirality) - "In this study, two new pairs of enantiomeric metabolites were identified from indoxacarb metabolism in rats: S-IN-RM493 and S-IN-RM541 derived from S-(+)-indoxacarb, and R-IN-RM493 and R-IN-RM541 derived from R-(-)-indoxacarb...Overall, S-(+)-indoxacarb demonstrates a more favorable safety profile than R-(-)-indoxacarb with respect to mammals. These findings provide valuable insights into the toxicology of indoxacarb in mammals, thereby paving the way for the informed agricultural application of its optically pure S-(+)-indoxacarb."

Journal • Preclinical

Resolution of chronic idiopathic urticaria with setmelanotide in a patient with Bardet-Biedl Syndrome: A case report. (PubMed, Obes Pillars) - "Adjunct phentermine 18.75 mg daily was later added to optimize appetite control. Setmelanotide produced durable remission of refractory CIU in a patient with BBS, suggesting MC4R agonism may exert immunomodulatory effects beyond weight regulation. This finding underscores the broader potential of precision therapies for rare obesity syndromes to reveal new mechanisms of inflammation control."

Journal • Bardet–Biedl Syndrome • Chronic Spontaneous Urticaria • Dermatology • Developmental Disorders • Genetic Disorders • Immunology • Inflammation • Inherited Retinal Dystrophy • Obesity • Ophthalmology • Renal Disease • Urticaria • BBS9 • MC4R

Efficacy of Semaglutide in Pediatric Patients With Bardet-Biedl Syndrome and Alström Syndrome. (PubMed, JCEM Case Rep) - "While setmelanotide, a melanocortin-4 receptor agonist, may be an effective therapy for obesity in these conditions (especially BBS), its cost limits accessibility for many patients. We describe two pediatric cases (one with BBS and another with AS) demonstrating significant metabolic improvements with semaglutide, a glucagon-like peptide-1 receptor agonist. These observations suggest that some cases of BBS and AS may be treated with semaglutide."

Journal • Alstrom Syndrome • Bardet–Biedl Syndrome • Genetic Disorders • Inherited Retinal Dystrophy • Obesity • Ophthalmology • Pediatrics • LEP

Survey of Drugs Induced Skin Pigmentation (Hyper and Hypo Pigmentation). (PubMed, Clin Cosmet Investig Dermatol) - "Minocycline (ROR 115.66) and setmelanotide (ROR 1506.82) showed high RORs for hyperpigmentation, while triamcinolone (ROR 37.20) and ribociclib (ROR 60.20) were strongly linked to hypopigmentation. Several drugs, including dupilumab, tretinoin, and clobetasol, exhibited bidirectional pigmentary modulation...These findings emphasize the importance of early recognition and dermatologic monitoring during prolonged therapy. Considering the odds ratio and analysis results, the drugs found to be associated with hyperpigmentation or hypopigmentation warrant further investigation."

Journal

Cardiometabolic Results From a Phase 3 Trial of Setmelanotide in Acquired Hypothalamic Obesity (Rhythm Press Release) - "Jennifer Miller, M.D., University of Florida Division of Endocrinology, Department of Pediatrics in the College of Medicine, was the lead author on a poster that showed setmelanotide treatment was associated with significant improvement across most cardiometabolic parameters and proteomic biomarkers. Results showed improvements across nonambulatory blood pressure, lipid levels, and hematologic and chemistry parameters."

P3 data • Hypothalamic Injury-associated Obesity

Dr. Roth delivered an oral presentation detailing previously disclosed results from a post-hoc analysis of Phase 3 TRANSCEND data of setmelanotide in patients with acquired hypothalamic obesity who received concomitant GLP-1 therapy during the trial. (Rhythm Press Release) - "-27.1% (p<0.0001) mean placebo-adjusted difference in BMI reduction in patients (n=9) treated with setmelanotide and GLP-1 therapy concurrently compared with GLP-1 therapy and placebo (n=6); and -19.0% (p<0.0001) mean placebo-adjusted difference in BMI reduction in patients treated with setmelanotide (n=72) compared with placebo (n=33); none of these patients were on GLP-1 therapy during the trial....The results from interviews with 14 trial participants and 16 caregivers of trial participants younger than 12 showed that patients consistently reported meaningful and beneficial changes in hunger, weight, energy levels, and physical activity with setmelanotide therapy."

P3 data • Hypothalamic Injury-associated Obesity

Efficacy of Setmelanotide in Patients With Acquired HO Previously or Concurrently on GLP 1 Therapy (OBESITY WEEK 2025) - P3 | "The response to setmelanotide observed in pts receiving prior and/or concurrent GLP1-RAs highlights the improved benefit of other pharmacologic interventions once the deficit in MC4R signaling has been corrected. These data add to the available evidence demonstrating that setmelanotide represents a promising treatment option for patients with aHO aged ≥4 y."

Clinical • Genetic Disorders • Hypothalamic Injury-associated Obesity • Obesity • MC4R

Case Report: Setmelanotide and Urticaria Resolution in Bardet-Biedl Syndrome (OBESITY WEEK 2025) - "She also had a history of chronic idiopathic urticaria (CIU) resistant to dual antihistamine therapy, necessitating daily use of diphenhydramine and cetirizine. This case demonstrates the resolution of chronic idiopathic urticaria with the use of setmelanotide in a patient diagnosed with BBS. BBS is primarily caused by mutations in genes essential for ciliary function, leading to impaired cellular signaling pathways, particularly those involved in development and metabolism. This dysfunction results in a range of clinical manifestations due to disrupted intercellular communication, but is not typically associated with inflammatory or dermatologic conditions."

Case report • Clinical • Bardet–Biedl Syndrome • Chronic Spontaneous Urticaria • Dermatology • Genetic Disorders • Immunology • Inherited Retinal Dystrophy • Obesity • Ophthalmology • Urticaria • BBS9 • KIDINS220

Cardiometabolic Results From a Phase 3 Trial of Setmelanotide in Acquired Hypothalamic Obesity (OBESITY WEEK 2025) - P3 | "Setmelanotide treatment was associated with a significant improvement in cardiometabolic parameters, underscoring the broadly encompassing benefits and impacts of setmelanotide treatment on metabolic health. These cardiometabolic data add to the available evidence of robust, clinically significant, and consistent response to setmelanotide treatment in patients with aHO, suggesting the promising potential of setmelanotide as a treatment option for this patient population."

P3 data • Cardiovascular • Genetic Disorders • Hypothalamic Injury-associated Obesity • Metabolic Disorders • Obesity • LEP

Patient- and Caregiver-Reported Experience With Acquired Hypothalamic Obesity in the TRANSCEND Trial (OBESITY WEEK 2025) - P3 | "This substudy confirms the positive treatment benefits and meaningfulness of improvements associated with setmelanotide in patients with aHO. These results are highly supportive of the Phase 3 TRANSCEND efficacy outcomes seen with setmelanotide."

Clinical • Genetic Disorders • Hypothalamic Injury-associated Obesity • Obesity

Frequency of Genetic Variants Associated With Obesity Among Patients Pursuing Weight Loss Treatment (OBESITY WEEK 2025) - "While monogenic gene variants associated with obesity are rare, identifying these mutations is increasingly justified due to the development of mutation-specific therapies such as setmelanotide, a melanocortin-4 receptor (MC4R) agonist... As there continues to be significant variations in response to clinical treatments for obesity, our findings suggest that genetic testing can provide insight to potential targeted therapies for many patients, possibly improving treatment outcomes."

Clinical • Bardet–Biedl Syndrome • Genetic Disorders • Inherited Retinal Dystrophy • Leptin Receptor Deficiency Obesity • Obesity • Ophthalmology • CEP290 • LEP • PCSK1 • PLXNA1

Craniopharyngioma - What's next. (PubMed, Pituitary) - "Therapeutic interventions such as dextroamphetamine and other centrally acting stimulants, along with glucagon-like peptide-1 receptor (GLP-1R) agonists, and setmelanotide have shown potential in promoting weight reduction. Bariatric surgery has also demonstrated efficacy; however, the use of irreversible surgical techniques in pediatric populations remains ethically and legally contentious. This report summarizes perspectives of future research and clinical progress in diagnostics, treatment, and follow-up of patients with craniopharyngioma."

Journal • Brain Cancer • Cardiovascular • CNS Tumor • Genetic Disorders • Hypothalamic Injury-associated Obesity • Metabolic Disorders • Obesity • Oncology • Pediatrics