Imcivree (setmelanotide) / Rhythm Pharma - LARVOL DELTA

Rhythm Pharmaceuticals Receives Positive CHMP Opinion for IMCIVREE (setmelanotide) for the Treatment of Obesity and Control of Hunger in Patients with Acquired Hypothalamic Obesity due to Hypothalamic Injury or Impairment (The Manila Times) - "The CHMP opinion will now be reviewed by the European Commission (EC), which has the authority to grant and expand marketing authorizations for medicinal products in the European Union. A final decision is anticipated in the second quarter of 2026."

CHMP • EMA approval • Hypothalamic Injury-associated Obesity

Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE (setmelanotide) for Patients with Acquired Hypothalamic Obesity (GlobeNewswire) - "With this label expansion, IMCIVREE is indicated to reduce excess body weight and maintain reduction long term in adults and pediatric patients aged 4 years and older with acquired HO....The approval is supported by the positive pivotal Phase 3 TRANSCEND trial of setmelanotide in 142 patients with acquired HO. The global study met its primary endpoint, with a statistically significant -18.4% placebo-adjusted reduction in body mass index (BMI)."

FDA approval • Hypothalamic Injury-associated Obesity

Rhythm Pharmaceuticals Announces Additional Positive Data from Phase 3 TRANSCEND trial of Setmelanotide in Patients with Acquired Hypothalamic Obesity (GlobeNewswire) - "18.8% placebo-adjusted difference in BMI reduction (N=142); Primary endpoint of mean BMI reduction of -16.4% from baseline for all patients on setmelanotide therapy (n=94) compared with +2.4% BMI change for patients on placebo (n=48) at 52 weeks (95% CI; p<0.0001); and Among patients aged 12 and older (n=98), the setmelanotide group (n=66) showed an average weekly reduction of 2.5 points in the weekly average most hunger score, compared with a 1.3‑point reduction in the placebo group (n=32) (p=0.0015)....The Company anticipates the Committee for Medicinal Products for Human Use (CHMP) would issue an opinion to the European Commission (EC) in the second quarter of 2026 with potential marketing authorization in the second half of 2026. The Company will also submit the full data package to Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) and plans to seek marketing authorization for setmelanotide to treat acquired hypothalamic obesity there, as well."

CHMP • EMA approval • Japan filing • P3 data • Obesity

Joint TOS/OMA/OAC Expert Guidance Statement on the Pharmacological Management of United States Adults With Overweight or Obesity Using the GRADE Approach. (PubMed, Obesity (Silver Spring)) - "Obesity is a chronic, often progressive, disease requiring comprehensive, long-term, and person-centered care. Effective obesity medications exist but remain underutilized due to systemic barriers. Expanding access, reducing stigma, and ensuring equitable coverage are essential to translating scientific advances into population health gains. Future priorities include access and integration of comprehensive obesity care in the primary care setting, improving affordability, addressing research gaps, conducting head-to-head trials, and updating guidance as evidence evolves."

Journal • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Obstructive Sleep Apnea • Osteoarthritis • Pain • Respiratory Diseases • Rheumatology • Sleep Disorder • Type 2 Diabetes Mellitus

Rhythm Pharmaceuticals Announces Topline Results from Phase 3 EMANATE Trial (GlobeNewswire) - "The four substudies of this global, Phase 3 trial evaluating setmelanotide did not meet primary endpoints....Topline results include: POMC / PCSK1 Hets (N=78): –4.3% placebo-adjusted reduction in BMI (p=0.15); LEPR Hets (N=23): –3.6% placebo-adjusted reduction in BMI (p=0.94); SRC1 (NCOA1) (N=73): –4.0% placebo-adjusted reduction in BMI (p=0.12); and SH2B1 (N=121): –1.7% placebo-adjusted reduction in BMI (p=0.43). According to post hoc analyses based on last observation carried forward (LOCF) for missing values, setmelanotide achieved statistically significant and clinically meaningful BMI reductions at Week 52 in the modified intent-to-treat patient populations in the POMC/PCSK1 Hets and SRC1 substudies..."

P3 data • Obesity

Real-world efficacy and safety of setmelanotide in German paediatric patients with Bardet-Biedl syndrome – changes in hyperphagia, body weight and lipid profile (ECO 2026) - No abstract available

Clinical • Real-world • Real-world effectiveness • Real-world evidence • Bardet–Biedl Syndrome • Inherited Retinal Dystrophy • Ophthalmology • Pediatrics

Rhythm expects to achieve the following near-term milestones (The Manila Times) - "Launch IMCIVREE in the United States for the treatment of acquired HO pending FDA approval; the FDA’s assigned PDUFA goal date is March 20, 2026...Announce topline data in the Phase 3 EMANATE trial evaluating setmelanotide in genetically caused MC4R pathway diseases in March 2026."

P3 data: top line • PDUFA • Hypothalamic Injury-associated Obesity • Obesity

Recent Business Highlights (The Manila Times) - "Fourth quarter 2025 net product revenue from global sales of IMCIVREE (setmelanotide) of $57.3 million."

Sales • Bardet–Biedl Syndrome • Obesity

Setmelanotide in Bardet-Biedl Syndrome: A 52-Week Comparison of Phase 3 Trial Participants With a Matched Registry Cohort. (PubMed, Obesity (Silver Spring)) - P3 | "This indirect comparison provides additional strong evidence that setmelanotide significantly improves weight outcomes in patients with BBS. These findings further support its clinical benefit over 52 weeks in managing obesity associated with BBS."

Journal • P3 data • Bardet–Biedl Syndrome • Genetic Disorders • Inherited Retinal Dystrophy • Obesity • Ophthalmology • Pediatrics

b-FL022 Daybreak Study: Preliminary results of the phase 2 double-blind, randomized, placebo-controlled trial evaluating setmelanotide in patients with variants on specific genes of the leptin-melanocortin pathway. (HMGC 2026) - P2 | "The results of this randomized phase 2 support the efficacy of setmelanotide in patients carrying variants in the genes or gene families involved in the leptin-melanocortin pathway identified in the first open-label phase of the DAYBREAK study. These results suggest that these variants are likely to respond to targeted management with setmelanotide."

Clinical • P2 data • LEP • TBX3

Clinical characteristics of patients aged 2 to 5 years with hyperphagia and obesity secondary to different pathologies of the leptin-melanocortin pathway and response after one year of treatment with setmelanotide. (HMGC 2026) - "In various pediatric populations aged 2 to 5 years with obesity, treated for 52 weeks, setmelanotide resulted in weight reduction and improvement in body size class, although with varying degrees of intensity depending on the type of disease related to the leptin-melanocortin pathway. This could be due to the diversity of mechanisms and the location of dysfunction within this pathway."

Clinical • Bardet–Biedl Syndrome • Genetic Disorders • Inherited Retinal Dystrophy • Leptin Receptor Deficiency Obesity • Obesity • Ophthalmology • POMC-null Obesity • LEP • LEPR

Effect of setmelanotide on body mass change in patients with obesity associated with Bardet-Biedl syndrome (BBS). (HMGC 2026) - "In adult and pediatric patients with hyperphagia and obesity associated with BBS, setmelanotide decreased BMI, improved body weight, and reduced hunger. The improvement in body weight category was associated with improved quality of life and a reduction in the incidence of comorbidities. These data in pediatric and adult patients reinforce existing evidence in favor of using setmelanotide as a targeted therapy in patients ≥ 2 years old with BBS-related obesity, and support early initiation in pediatric patients."

Clinical • Bardet–Biedl Syndrome • Genetic Disorders • Inherited Retinal Dystrophy • Obesity • Ophthalmology • LEP

Biochemical data on loss of function of the SIM1 gene increase the likelihood of a favorable clinical response in terms of weight loss to setmelanotide, a melanocortin type-4 receptor (MC4R) agonist. (HMGC 2026) - "These data demonstrate the importance of functional characterization of SIM1 VSIs to interpret their clinical significance and assess their potential benefit in the context of setmelanotide treatment."

Clinical • Genetic Disorders • Obesity • MC4R

A Study of Setmelanotide in Patients With Prader-Willi Syndrome (clinicaltrials.gov) - P2 | N=18 | Active, not recruiting | Sponsor: Rhythm Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity • Prader–Willi syndrome

A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756) (clinicaltrials.gov) - P3 | N=39 | Recruiting | Sponsor: Rhythm Pharmaceuticals, Inc. | Trial completion date: Sep 2027 ➔ Mar 2028 | Trial primary completion date: Sep 2026 ➔ Mar 2027

Trial completion date • Trial primary completion date • Genetic Disorders • Hypothalamic Injury-associated Obesity • Obesity

Current and Future Pharmacological Interventions for Acquired Hypothalamic Obesity. (PubMed, Drugs) - "These agents include stimulants, incretin-based therapies (e.g., glucagon-like peptide-1 receptor agonists), insulin modulators, and melanocortin receptor agonists such as setmelanotide...Although challenging, aHO is no longer untreatable. Patients should be referred and managed at specialized centers, with pharmacological treatment preferably conducted within research settings to optimize and personalize care, and to develop evidence-based protocols for this debilitating condition."

Journal • Brain Cancer • CNS Tumor • Genetic Disorders • Hypothalamic Injury-associated Obesity • Obesity • Oncology • LEP

EMANATE: A Study of Setmelanotide in Patients With Specific Gene Variants in the MC4R Pathway (clinicaltrials.gov) - P3 | N=296 | Active, not recruiting | Sponsor: Rhythm Pharmaceuticals, Inc. | Trial completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Genetic Disorders • Obesity • NCOA1 • PCSK1

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