Imcivree (setmelanotide) / Rhythm Pharma - LARVOL DELTA

Efficacy and Safety of Setmelanotide in Acquired Hypothalamic Obesity: Results from a Double-Blind, Multicenter, Placebo-Controlled, Randomized Phase 3 Trial (Rhythm Press Release) - P3 | N=120 | TRANSCEND (NCT05774756) | Sponsor: Rhythm Pharmaceuticals, Inc. | "In a live oral presentation, Susan Phillips, M.D., Pediatric Endocrinology, University of California San Diego/Rady Children’s Hospital, San Diego, presented data from Rhythm’s pivotal Phase 3 TRANSCEND trial evaluating setmelanotide, the largest randomized, placebo-controlled trial in acquired hypothalamic obesity to date. Highlights from the presentation include: 19.8% placebo-adjusted difference in BMI reduction (N=120); Statistically significant BMI reductions following setmelanotide treatment were consistently observed across subgroups stratified by age (<12, 12 to 17, <18, and 18 years and older; ranging from -15.6% to -17.2%) and by sex (-16.3% female; -16.8% male)....There was significant reduction in weight-related measures in participants <18 years of age with setmelanotide at week 52, with a -26.2% change in the 95th percentile for BMI."

P3 data • Hypothalamic Injury-associated Obesity • Obesity

Rhythm Pharmaceuticals Announces Oral MC4R Agonist Bivamelagon Achieved Statistically Significant, Clinically Meaningful BMI Reductions in Placebo-controlled Phase 2 Trial in Acquired Hypothalamic Obesity (Rhythm Press Release) - "In a post-hoc analysis comparing the randomized Phase 2 results to results from prior setmelanotide trials, bivamelagon demonstrated BMI reductions...In this post-hoc comparison of the subset of setmelanotide patients who demonstrated study compliance and were not on concomitant GLP1 therapy (no patients who enrolled in the Phase 2 bivamelagon trial were on concomitant GLP1 therapy), setmelanotide and bivamelagon achieved: -9.7% and -10.5% mean BMI reductions achieved in a pooled patient population (n=59; n=64) from Phase 2 and Phase 3 trials of setmelanotide therapy at 12 weeks and 16 weeks, respectively; as compared to: -8.8% and -10.1% mean BMI reductions achieved in patients (400mg n=6; 600mg n=7) at 14 weeks of bivamelagon therapy....A total of 27 patients completed the 14-week, placebo-controlled portion of the trial, and 26 of them transitioned into the open-label extension of the trial and remained in that portion of the trial, as of July 7, 2025."

Retrospective data • Trial status • Hypothalamic Injury-associated Obesity • Obesity

Efficacy And Safety Of Setmelanotide In Acquired Hypothalamic Obesity: Results From A Double-blind, Multicenter, Placebo-controlled, Randomized Phase 3 Trial (ENDO 2025) - P3 | "In the SET arm, there was 1 serious treatment-related AE of hypernatremia due to vomiting and an inability to tolerate their desmopressin. In the largest randomized, PBO-controlled trial in aHO to date, SET demonstrated significant effects over PBO in the primary and all key secondary efficacy endpoints at 52 weeks, with no new safety signals. SET may represent an important treatment option for pts with aHO aged ≥4 y, for which there are no currently approved treatments."

Clinical • Late-breaking abstract • P3 data • CNS Disorders • Epilepsy • Genetic Disorders • Hypothalamic Injury-associated Obesity • Obesity • Oncology • Pain • Vascular Neurology • MC4R

Experiences And Observations With Acquired Hypothalamic Obesity: A Qualitative Interview Sub-study (ENDO 2025) - P3 | "Setmelanotide is being investigated as a treatment for aHO in an ongoing Phase 3, randomized, placebo-controlled trial (TRANSCEND; NCT05774756)... Experiences and observations with aHO before the TRANSCEND trial and post hypothalamic injury were characterized by substantial hunger, accelerated weight gain, fatigue, and reductions in physical activity/function, which had severe impacts on trial participants' and caregivers' overall quality of life. This study's findings support the assessment of these concepts in the evaluation of treatment benefit in aHO studies."

Interview • Late-breaking abstract • Fatigue • Genetic Disorders • Hypothalamic Injury-associated Obesity • Obesity

Role Of Ligand- And Genetic Variant Dependent Melanocortin 4 Receptor (mc4r) Bias Signaling For The Individual Risk To Develop Obesity (ENDO 2025) - "Additionally, the MC4R agonist setmelanotide has recently been approved as a pharmacological treatment option for patients with certain rare monogenic forms of obesity... Our findings emphasize the critical role of differential (bias) signaling for MC4R function. Cryo-EMStructural data- combined with in vitro functional data allowed to gain further insights into the structural regulation of the MC4R, which can be relevant to optimized MC4R agonists as a treatment option for patients with certain forms of obesity."

Clinical • Late-breaking abstract • Genetic Disorders • Obesity • ARRB1 • LEP • MC4R

Genetic Screening Yields Positive Results In 75% Of Patients With Early-onset Morbid Obesity And Identified Patients Who Can Benefit From A Personalized Approach To Treatment (ENDO 2025) - "Genetic screening revealed positive results in 75 % of cases. According to the FDA guidelines, 9% of positive cases and 6.7 % of total cases were eligible for treatment with Setmelanotide. Genes involved in cilia signaling play a significant role in obesity, and they were found to be positive in 80% of 399 cases."

Clinical • Late-breaking abstract • Genetic Disorders • Obesity • AFF4 • BBS9 • CEP290 • CREBBP • CUL4B • DNMT3A • DYRK1B • EP300 • GNAS • KIDINS220 • LEP • LZTFL1 • NCOA1 • NRP1 • NRP2 • NTRK2 • PCSK1 • PHF6 • PLXNA1 • PLXNA2 • PPARG • RPS6KA3 • SEMA3A • SEMA3G • TBX3 • TRIM32

Setmelanotide Treatment Of The Child With Morbid Obesity Secondary To A Combination Of Magel2 And Bbs19 (ift27) Genes Dramatically Improved Morbid Obesity, Liver Function, Hyperlipidemia, And Prediabetes (ENDO 2025) - "Setmelanotide therapy was effective in the case of BBS 19 (IFT27) and MAGEL 2 heterozygous polymorphism.. BMI decreased 15 %, and Hb A1c went from 5.9 to 5.7.The child tolerated therapy well. Only mild skin pigmentation was noted."

Clinical • Late-breaking abstract • Autism Spectrum Disorder • Bardet–Biedl Syndrome • Cognitive Disorders • Developmental Disorders • Dyslipidemia • Genetic Disorders • Hypertriglyceridemia • Inherited Retinal Dystrophy • Metabolic Disorders • Obesity • Obstructive Sleep Apnea • Ophthalmology • Pain • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Efficacy And Safety Of Once-daily Oral Bivamelagon In Acquired Hypothalamic Obesity: Results From A Double-blind, Multicenter, Placebo-controlled, Randomized Phase 2 Trial (ENDO 2025) - P2 | "The favorable results from the Phase 3 trial of the injectable MC4R agonist setmelanotide suggest that this mechanism of action has therapeutic utility in aHO. At the time of submission, 21 of 28 participants completed the 14-week trial (1 discontinuation), 20 of whom continued to receive treatment in the OLE. Overall, 46.4% were female, mean (SD; range) age at baseline was 25.4 (16.8; 12-68) years, mean (SD) BMI was 38.7 (8.4) kg/m2, and mean (SD) BMI-Z (<18 years) was 3.13 (1.21). The most common etiology of aHO was craniopharyngioma (82.1%), and the mean (SD) time from confirmed hypothalamicinjury to enrollment was 7.0 (5.0) years."

Clinical • Late-breaking abstract • P2 data • Brain Cancer • Cardiovascular • CNS Tumor • Endocrine Disorders • Genetic Disorders • Hypothalamic Injury-associated Obesity • Obesity • Oncology

The Impact of MC4R Agonist Therapy for Obesity in Bardet-Biedl Syndrome: A Case Study of Puerto Rican Siblings (ENDO 2025) - "MC4R agonist therapy (Setmelanotide) offers a novel treatment for hyperphagia and obesity, reducing cardiometabolic risk...MC4R agonist therapy is a significant advancement in treating BBS-related obesity by targeting the underlying neuroendocrine dysfunction. Although BBS management requires a multidisciplinary approach, endocrinologists play a crucial role in managing hormonal imbalances, metabolic disorders, and cardiovascular risks, improving patient outcomes."

Case study • Clinical • Bardet–Biedl Syndrome • Cardiovascular • Developmental Disorders • Dyslipidemia • Endocrine Disorders • Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Hypertension • Immunology • Inherited Retinal Dystrophy • Mental Retardation • Metabolic Disorders • Nephrology • Obesity • Obstructive Sleep Apnea • Ocular Inflammation • Ophthalmology • Renal Disease • Respiratory Diseases • Retinal Disorders • Retinitis Pigmentosa • Sleep Disorder • MC4R • PDE6A

Weight Loss with Topiramate and Phentermine Combination Therapy in a Patient with Bardet-Biedl Syndrome (BBS) (ENDO 2025) - "This case report highlights the excellent weight loss response (25% total weight loss) and significant improvement in metabolic profile with phentermine and topiramate combination therapy in a patient with BBS. The effects of this combination therapy have not been formally studied in BBS, emphasizing the need for further research to evaluate the efficacy of conventional anti-obesity medications—used alone, sequentially, or in combination with setmelanotide—to optimize weight and metabolic outcomes. Keywords: Bardet-Biedl Syndrome, obesity, topiramate, phentermine, weight loss."

Clinical • Combination therapy • Bardet–Biedl Syndrome • CNS Disorders • Constipation • Developmental Disorders • Dyslipidemia • Endocrine Disorders • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Inherited Retinal Dystrophy • Metabolic Disorders • Migraine • Obesity • Obstructive Sleep Apnea • Ophthalmology • Pain • Respiratory Diseases • Sleep Disorder • MC4R

Exploring Adverse Drug Reactions Associated With Setmelanotide- A Pharmacovigilance Study (ENDO 2025) - "These findings suggest that Setmelanotide continues to be a valuable treatment option for patients with rare genetic conditions associated with obesity. Further studies and post market surveillance is needed to assess the long-term effects of Setmelanotide especially with patients having comorbidities."

Adverse drug reaction • Adverse events • Bardet–Biedl Syndrome • Genetic Disorders • Inherited Retinal Dystrophy • Obesity • Ophthalmology • POMC-null Obesity • LEP • LEPR

Rhythm Pharmaceuticals Announces Three Late-breaking Data Abstracts Accepted for Presentation at ENDO 2025 (GlobeNewswire) - "Rhythm Pharmaceuticals...today announced that three late-breaking abstracts have been accepted for presentation at The Endocrine Society’s Annual Meeting (ENDO 2025) taking place July 12-15 in San Francisco, CA...In a live oral presentation, Susan Phillips, M.D., Pediatric Endocrinology, University of California San Diego/Rady Children’s Hospital, San Diego, will present data from Rhythm’s pivotal Phase 3 TRANSCEND trial evaluating setmelanotide in the largest randomized, placebo-controlled trial in acquired hypothalamic obesity to date....Vidhu Thaker, M.D., Pediatric Endocrinology, Columbia University, New York City will present a poster from the 14-week, multicenter, international, randomized, double-blind, placebo-controlled Phase 2 trial of bivamelagon, an oral MC4R agonist (formerly LB54640), in participants with acquired hypothalamic obesity."

Clinical data • Obesity

Clinical, Functional, and Therapeutic Implications of a Novel Monogenic Obesity Trait (ADA 2025) - "The identification of 20 patients indicates a relatively high frequency of the new monogenic trait with the implication to rethink screening algorithms. Patient phenotypes mimick the agouti-mouse phenotype. Our findings from the humanized mouse model indicate that the obesity phenotype is caused by ectopic ASIP and might be treatable with the MC4R agonist setmelanotide."

Clinical • Late-breaking abstract • Metabolic Disorders • Obesity • MC4R

Three-Year Setmelanotide Outcomes in Patients with POMC/LEPR Deficiency or BBS and Obesity (ADA 2025) - P2/3 | "Long-term Tx with setmelanotide demonstrated sustained weight-related efficacy. These findings support continuous Tx with setmelanotide in patients with POMC/LEPR deficiency or BBS and obesity."

Clinical • Late-breaking abstract • Leptin Receptor Deficiency Obesity • Metabolic Disorders • Obesity • POMC-null Obesity • LEP • LEPR • PCSK1

Three-Year Setmelanotide Outcomes in Patients with POMC/LEPR Deficiency or BBS and Obesity (ADA 2025) - P2/3 | "Long-term Tx with setmelanotide demonstrated sustained weight-related efficacy. These findings support continuous Tx with setmelanotide in patients with POMC/LEPR deficiency or BBS and obesity."

Clinical • Late-breaking abstract • Leptin Receptor Deficiency Obesity • Metabolic Disorders • Obesity • POMC-null Obesity • LEP • LEPR • PCSK1

The effects of anti-obesity medications on bone metabolism: A critical appraisal. (PubMed, Diabetes Obes Metab) - "The bone effects of opioid receptor antagonists and setmelanotide are largely unknown, while the impact of the combination of phentermine with topiramate is assumed to be negative. Finally, very limited clinical evidence suggests that orlistat may have a neutral effect on bone metabolism."

Journal • Review • Addiction (Opioid and Alcohol) • Genetic Disorders • Musculoskeletal Diseases • Obesity • Orthopedics • Osteoporosis • Rheumatology • ACVR2A

The management of hypothalamic obesity in craniopharyngioma. (PubMed, Best Pract Res Clin Endocrinol Metab) - "The use of dextroamphetamine in some HO patients has proved effective. Emerging therapies include melanocortin-4 receptor (MC4R) agonists such as setmelanotide, which restore anorexigenic signalling, glucagon-like peptide-1 (GLP-1) receptor agonists that enhance satiety and energy expenditure, and combination strategies integrating adrenergic modulation (Tesomet). Despite promising preliminary data, long-term efficacy and safety profiles require further validation. Optimizing precision medicine approaches incorporating polypharmacotherapy and neuroendocrine modulation may redefine therapeutic paradigms for HO management."

Journal • Review • Brain Cancer • CNS Disorders • CNS Tumor • Genetic Disorders • Hypothalamic Injury-associated Obesity • Metabolic Disorders • Obesity • Sleep Disorder • LEP

Biallelic pathogenic variants in POMC can cause combined pituitary hormonal deficiency associated with severe obesity. (PubMed, Eur J Endocrinol) - "These findings underscore the potential for CPHD to occur in carriers of biallelic pathogenic POMC variants. Sequencing the full POMC, including coding and regulatory regions, is crucial in CPHD cases, alongside evaluating all pituitary axes in neonatal hypocortisolism. Beyond weight regulation, Setmelanotide may modulate hypothalamic-pituitary function, with implications for fertility."

Journal • Endocrine Disorders • Genetic Disorders • Growth Hormone Deficiency • Obesity • POMC-null Obesity • MC4R

Patient and caregiver experiences with a patient-support program for setmelanotide treatment of patients with Bardet-Biedl syndrome. (PubMed, Orphanet J Rare Dis) - "Based on this real-world survey of patients with BBS and their caregivers, setmelanotide improved key symptoms related to insatiable hunger and obesity. Personalized multidimensional nursing support at the start of treatment can help address unmet support needs in BBS and may contribute to high rates of treatment satisfaction and adherence."

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

Body Composition Improvements with 12 Months of Setmelanotide in Acquired Hypothalamic Obesity (ECO 2025) - P2, P2/3 | "In a heterogeneous population of patients with HO, 12 months of setmelanotide treatment resulted in greater loss of fat mass than lean muscle mass. These results support the beneficial body composition changes associated with previously reported weight reductions."

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

Weight Loss at 18 Months of Setmelanotide in 2-<6-Year-Old Patients with Rare MC4R Pathway Diseases (ECO 2025) - P3 | "In the first trial of setmelanotide in patients <6 years of age, robust reductions in age-appropriate weight measures were seen in all patients at 18 months of treatment, with no new safety concerns. No approved therapies for patients <6 years old with obesity in the studied populations currently exist, despite the need for early intervention with targeted therapy in these patients."

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

Testing for genetic causes of obesity in adults: experience of an NHS adult weight management service (ECO 2025) - "We identified a significant proportion of adults living with obesity in an NHS weight management service with variations within genes associated with obesity. The majority of these were VUOS and further research is needed to understand the influence of these variants on the development of obesity. It is notable the relatively small proportion of patients living with T2DM and hypertension given the degree of adiposity, and analysis of larger cohorts may help identify clinical characteristics that are associated with a genetic cause of obesity and help refine the genetic testing criteria for adults."

Clinical • Autism Spectrum Disorder • Cardiovascular • CNS Disorders • Cognitive Disorders • Depression • Diabetes • Genetic Disorders • Hypertension • Obesity • Obstructive Sleep Apnea • Psychiatry • Respiratory Diseases • Sleep Apnea • Sleep Disorder • Type 2 Diabetes Mellitus • LEP • PCSK1

Adding glucagon-like peptide-1 receptor agonists to long-term lifestyle treatment in two children with leptin receptor deficiency (ECO 2025) - "A childhood intensive lifestyle treatment was successful for two patients with LEPR deficiency, now 16.5 and 18 years old. However, the strenuous and continuous adherence to a treatment regimen was not without difficulties. Novel drugs such as setmelanotide targeting the melanocortin-4 -receptor could help patients maintain successful weight control in adulthood."

Clinical • Genetic Disorders • Leptin Receptor Deficiency Obesity • Obesity • Pediatrics • LEP • LEPR

Precision Medicine: The Role of Genetic Testing in the Treatment of Obesity (ECO 2025) - "While monogenic gene variants causing 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... those with positive results felt emotional relief (e.g., less self-blame) but also diminished perceived personal control over their health, while those with negative results experienced frustration and self-blame but stronger motivation to improve diet and exercise behaviors. Based on this study findings, we have developed standardized clinical workflows and communication strategies for discussing obesity genetic testing and results for patients."

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

Real-world efficacy of setmelanotide in adults living with rare genetic forms of obesity (ECO 2025) - "These real-world data of adult patients with rare genetic forms of obesity who received setmelanotide under pre-marketing early access authorization show improvements in hunger scores and weight outcomes that are consistent with phase 3 data without any new safety signals. Conflicts of interest: CP, KC and SC are clinical trial investigators for Rhythm Pharmaceuticals, Inc. JM has consulted for Rhythm Pharmaceuticals, Inc."

Clinical • Real-world • Real-world effectiveness • Real-world evidence • Bardet–Biedl Syndrome • CNS Disorders • Depression • Genetic Disorders • Inherited Retinal Dystrophy • Mood Disorders • Obesity • Ophthalmology • POMC-null Obesity • Psychiatry • LEP • LEPR • MC4R