rm-493 and Obesity

Examine Setmelanotide use in patients with rare genetic variants that disrupt the melanocortin pathway.. Between February 2017 and September 2018, 10 participants with pro-opiomelanocortin (POMC)/ proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency and 11 participants with leptin receptor (LEPR) deficiency were enrolled in open-label, phase 3 trials at 10 centers in the United States and internationally to assess the efficacy and safety of the melanocortin-4 receptor (MC4R) agonist Setmelanotide. 80% of POMC participants and 45% of LEPR participants achieved at least 10% weight loss at 1 year. Significant changes in hunger scores were seen for both cohorts as well. Setmelanotide was well tolerated with injection site reactions and hyperpigmentation being the most common adverse events reported. As a result, Setmelanotide was approved by the U.S. FDA in 2020 for chronic weight management in adult and pediatric patients ≥6 years of age with POMC, LEPR, or PCSK1 deficiency. In 2022, its approval was extended to include patients with Bardet-Biedel syndrome (BBS) after phase 3 trial data showed that, on average, Setmelanotide treatment resulted in a BMI loss of 7.9% for the 44 BBS participants.. Rare genetic variants such as POMC, LEPR, and PCSK1 deficiency disrupt MC4R pathway signaling, resulting in severe early-onset obesity, hyperphagia, and increased risk for metabolic co-morbidities. Patients with BBS also demonstrate severe early-onset obesity and hyperphagia, due in part to defective MC4R signaling. Setmelanotide has shown promising benefits in improving satiety scores and weight-related outcomes in patients with these early-life genetic obesity conditions, although longer-term studies are needed.

Topics: Child; Clinical Trials, Phase III as Topic; Humans; Hyperphagia; Obesity; Pediatric Obesity; Pro-Opiomelanocortin

Topics: alpha-MSH; Animals; Anti-Obesity Agents; Clinical Trials as Topic; Humans; Injections, Subcutaneous; Loss of Function Mutation; Obesity; Receptor, Melanocortin, Type 4

Setmelanotide (IMCIVREE™, Rhythm Pharmaceuticals) is a melanocortin-4 (MC4) receptor agonist developed for the treatment of obesity arising from proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. The drug has received its first approval in the USA for chronic weight management in patients 6 years and older with obesity caused by POMC, PCSK1 and LEPR deficiency and has been granted PRIority MEdicines (PRIME) designation by the European Medicines Agency for the treatment of obesity and the control of hunger associated with deficiency disorders of the MC4 receptor pathway. Setmelanotide is also being developed in other rare genetic disorders associated with obesity including Bardet-Biedl Syndrome, Alström Syndrome, POMC and other MC4R pathway heterozygous deficiency obesities, and POMC epigenetic disorders. This article summarizes the milestones in the development of setmelanotide leading to this first approval for obesity caused by POMC, PCSK1 and LEPR deficiency.

Topics: alpha-MSH; Humans; Molecular Conformation; Obesity; Receptor, Melanocortin, Type 4

Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency.. Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target.. Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.

Topics: alpha-MSH; Animals; Anti-Obesity Agents; Drug Approval; Drug Discovery; Energy Metabolism; History, 20th Century; History, 21st Century; Homeostasis; Humans; Melanocortins; Mice; Obesity; Receptor, Melanocortin, Type 4; Signal Transduction; United States

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review.

Topics: alpha-MSH; Animals; Anti-Obesity Agents; Bariatric Surgery; Disease Models, Animal; Heterozygote; Humans; Hyperphagia; Mice; Mutation; Obesity; Receptors, Leptin

Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For some clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: (i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome and (ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin-melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients' early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity.

Topics: Adult; alpha-MSH; Anti-Obesity Agents; Bariatric Surgery; Endocrinology; Female; Genetic Predisposition to Disease; Humans; Male; Obesity; Obesity, Morbid; Syndrome

Bardet-Biedl syndrome is a rare genetic disease associated with hyperphagia and early-onset, severe obesity. There is limited evidence on how hyperphagia and obesity affect health-related quality of life in patients with Bardet-Biedl syndrome, and on how management of these symptoms may influence disease burden. This analysis evaluated changes in health-related quality of life in adults and children with Bardet-Biedl syndrome in a Phase 3 trial following 1 year of setmelanotide treatment (ClinicalTrials.gov identifier: NCT03746522).. Patients with Bardet-Biedl syndrome and obesity received 52 weeks of treatment with setmelanotide and completed various self-reported health-related quality of life measures. Patients aged < 18 years or their caregiver completed the Pediatric Quality of Life Inventory (PedsQL; meaningful improvement, 4.4-point change); adults aged ≥ 18 years completed the Impact of Weight on Quality of Life Questionnaire-Lite (IWQOL-Lite; meaningful improvement range, 7.7-12-point change). Descriptive outcomes were reported in patients with data both at active treatment baseline and after 52 weeks of treatment.. Twenty patients (< 18 years, n = 9; ≥ 18 years, n = 11) reported health-related quality of life at baseline and 52 weeks. For children and adolescents, PedsQL score mean change from baseline after 52 weeks was + 11.2; all patients with PedsQL impairment at baseline (n = 4) experienced clinically meaningful improvement. In adults, IWQOL-Lite score mean change from baseline was + 12.0. Of adults with IWQOL-Lite impairment at baseline (n = 8), 62.5% experienced clinically meaningful improvement. In adults, IWQOL-Lite score was significantly correlated with changes in percent body weight (P = 0.0037) and body mass index (P = 0.0098).. After 1 year of setmelanotide, patients reported clinically meaningful improvements across multiple health-related quality of life measures. This study highlights the need to address the impaired health-related quality of life in Bardet-Biedl syndrome, and supports utility of setmelanotide for reducing this burden. Trial Registration NCT03746522. Registered November 19, 2018, https://clinicaltrials.gov/ct2/show/NCT03746522 .

Topics: Adolescent; Adult; Bardet-Biedl Syndrome; Child; Humans; Hyperphagia; Obesity; Quality of Life

Individuals with proopiomelanocortin (POMC) or leptin receptor (LEPR) deficiency are young and experience severe obesity, hyperphagia, and comorbidities, which can impair quality of life (QOL).. Two pivotal Phase 3 trials explored the effect of setmelanotide on body weight and hunger in individuals with obesity due to POMC (NCT02896192) or LEPR (NCT03287960) deficiency. QOL and depression were investigated in parallel using the disease-specific, age-appropriate Impact of Weight on Quality of Life-Lite (IWQOL-Lite), Pediatric Quality of Life Inventory (PedsQL), and Patient Health Questionnaire-9 (PHQ-9).. In total, the POMC and LEPR trials enrolled 21 patients. Adults (≥ 18 years old; n = 7) had moderate-to-severe impairment in QOL at baseline, with mean (standard deviation [SD]) IWQOL-Lite total score 60.3 (13.2; maximum IWQOL-Lite total score = 100). The effect of setmelanotide on IWQOL-Lite total score was observed as soon as Week 5. Among those with scores at Week 52, 5 of 6 adults experienced a clinically meaningful improvement, with mean (SD) total scores increased from baseline by 24.2 (12.1) points. Children (6-12 years old; n = 2) and adolescents (13-17 years old; n = 4) had impaired QOL at baseline, with mean (SD) self-reported PedsQL total scores 53.3 (6.2) and 63.3 (29.1), respectively (maximum PedsQL total score = 100). Three of 5 patients experienced clinically meaningful improvement in PedsQL, with 2 children whose PedsQL total score increased by 28.3 and 3.3 points and 3 adolescents whose mean (SD) total score increased from baseline by 5.8 (18.3) points. Baseline mean (SD) PHQ-9 score (in those ≥ 12 years old) was 5.3 (3.8) and was generally maintained through Week 52.. Patients with POMC or LEPR deficiency had impaired, and in some cases severely impaired, QOL before setmelanotide treatment. Setmelanotide improved QOL in patients as early as Week 5, with some patients no longer experiencing impaired QOL at Week 52. Improvements in QOL may be related to a reduction in hunger and body weight associated with setmelanotide. Because of the highly complex psychological consequences of rare genetic diseases of obesity, some patients may require a long period of treatment to improve QOL and benefit from interdisciplinary care.

Topics: Adolescent; Adult; alpha-MSH; Child; Humans; Obesity; Pro-Opiomelanocortin; Quality of Life; Receptors, Leptin; Surveys and Questionnaires

Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients.. This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m. Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment.. Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome.. Rhythm Pharmaceuticals.

Topics: Alstrom Syndrome; Bardet-Biedl Syndrome; Humans; Obesity; Receptor, Melanocortin, Type 4; Treatment Outcome

The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity.. These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960.. Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials.. Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency.. Rhythm Pharmaceuticals.

Topics: Adolescent; Adrenal Insufficiency; Adult; alpha-MSH; Anti-Obesity Agents; Child; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Obesity; Pro-Opiomelanocortin; Prognosis; Receptor, Melanocortin, Type 4; Receptors, Leptin; Young Adult

Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.. We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.. In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.. Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.

Topics: Adrenal Insufficiency; Adult; alpha-MSH; Amino Acid Sequence; Animals; Female; HEK293 Cells; Humans; Male; Mice; Mice, Knockout; Middle Aged; Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4

Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).

Topics: Adult; alpha-MSH; Blood Pressure; Female; Humans; Hyperphagia; Metabolism, Inborn Errors; Obesity; Phenotype; Pilot Projects; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4; Young Adult

Activation of the melanocortin-4 receptor (MC4R) with the synthetic agonist RM-493 decreases body weight and increases energy expenditure (EE) in nonhuman primates. The effects of MC4R agonists on EE in humans have not been examined to date.. In a randomized, double-blind, placebo-controlled, crossover study, we examined the effects of the MC4R agonist RM-493 on resting energy expenditure (REE) in obese subjects in an inpatient setting.. Twelve healthy adults (6 men and 6 women) with body mass index of 35.7 ± 2.9 kg/m(2) (mean ± SD) received RM-493 (1 mg/24 h) or placebo by continuous subcutaneous infusion over 72 hours, followed immediately by crossover to the alternate treatment. All subjects received a weight-maintenance diet (50% carbohydrate, 30% fat, and 20% protein) and performed 30 minutes of standardized exercise daily. Continuous EE was measured on the third treatment day in a room calorimeter, and REE in the fasting state was defined as the mean of 2 30-minute resting periods.. RM-493 increased REE vs placebo by 6.4% (95% confidence interval, 0.68-13.02%), on average by 111 kcal/24 h (95% confidence interval, 15-207 kcal, P = .03). Total daily EE trended higher, whereas the thermic effect of a test meal and exercise EE did not differ significantly. The 23-hour nonexercise respiratory quotient was lower during RM-493 treatment (0.833 ± 0.021 vs 0.848 ± 0.022, P = .02). No adverse effect on heart rate or blood pressure was observed.. Short-term administration of the MC4R agonist RM-493 increases REE and shifts substrate oxidation to fat in obese individuals.

Topics: Adult; alpha-MSH; Anti-Obesity Agents; Combined Modality Therapy; Cross-Over Studies; Double-Blind Method; Energy Metabolism; Female; Humans; Male; Middle Aged; Obesity; Receptor, Melanocortin, Type 4; Rest; Weight Reduction Programs; Young Adult

Bardet-Biedl Syndrome (BBS) is a rare, multisystemic ciliopathy with an incidence of obesity of 89%. Mutations in genes encoding BBS proteins are linked to reduced leptin sensitivity of hypothalamic POMC neurons and reduced activation of the melanocortin-4 receptor (MC4R) pathway due to deficient α-MSH production by hypothalamic POMC neurons. The MC4R pathway is involved in controlling body weight and energy metabolism, and its disruption is linked to hyperphagia and obesity. Setmelanotide is an MC4R agonist that counteracts deficiencies in the MC4R pathway of individuals with BBS.. Data from clinical trials were reviewed along with information available from setmelanotide's approval for treatment of obesity in people ages ≥6y with a clinical diagnosis of BBS.. Setmelanotide is available as a daily injectable that can be used for amelioration of obesity in people with Bardet-Biedl syndrome. Its cost is substantial, which may limit its use, but among those who respond, setmelanotide can reduce body mass dramatically and potentially improve comorbid conditions associated with obesity. Setmelanotide treatment has generally tolerable side effects, primarily injection site reactions and nausea/vomiting that generally improve with continued use; almost all people using setmelanotide experience marked skin darkening due to off-target activation of cutaneous MC1R.

Topics: Adult; alpha-MSH; Bardet-Biedl Syndrome; Child; Humans; Obesity; Pro-Opiomelanocortin

Recessive deficiency of proopiomelanocortin (POMC) causes childhood-onset severe obesity. Cases can now benefit from the melanocortin 4 receptor agonist setmelanotide. Furthermore, a phase 3 clinical trial is evaluating setmelanotide in heterozygotes for POMC. We performed a large-scale genetic analysis to assess the effect of heterozygous, pathogenic POMC variants on obesity.. A genetic analysis was performed in a family including 2 cousins with childhood-onset obesity. We analyzed the obesity status of heterozygotes for pathogenic POMC variants in the Human Gene Mutation Database. The association between heterozygous pathogenic POMC variants and obesity risk was assessed using 190,000 exome samples from UK Biobank.. The 2 cousins carried a compound heterozygous pathogenic variant in POMC. Six siblings were heterozygotes; only 1 of them had obesity. In Human Gene Mutation Database, we identified 60 heterozygotes for pathogenic POMC variants, of whom 14 had obesity. In UK Biobank, heterozygous pathogenic POMC variants were not associated with obesity risk, but they modestly increased body mass index levels.. Heterozygous pathogenic POMC variants do not contribute to monogenic obesity, but they slightly increase body mass index. Setmelanotide use in patients with obesity, which would only be based on the presence of a heterozygous POMC variant, can be questioned.

Topics: Anti-Obesity Agents; Body Mass Index; Child; Heterozygote; Humans; Mutation; Obesity; Pediatric Obesity; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4

Setmelanotide (Imcivree™) was developed as a daily injectable therapeutic peptide for the treatment of rare forms of syndromic obesity, such as POMC deficiency and leptin receptor deficiency. The important option of poly(lactic-co-glycolic acid) (PLGA) controlled release microspheres has become more attractive for this class of drugs upon the discovery that net positively charged peptides can be remote-loaded rapidly from aqueous peptide solution into blank microspheres at high loading and encapsulation efficiency. Here we sought to remote-load setmelanotide in PLGA microspheres and examine its potential for long-term controlled release and body weight control. The influence of PLGA microsphere porosity was investigated with respect to morphology, drug loading, and in vitro release profiles. Increased density of the microspheres inhibited the progress of encapsulation of the dicationic peptide. A diet-induced obese murine model was then used to determine the pharmacokinetic profile and to evaluate long-term efficacy of an optimal formulation. Remote loaded PLGA formulations encapsulated setmelanotide as high as ∼63% (∼6.3% w/w loading) and exhibited slow and continuous peptide release over ∼6 weeks in vitro largely independent of microsphere porosity. The obtained in vivo release pattern from deconvolution of the pharmacokinetics after subcutaneous microsphere injection was consistent with the in vitro release profile but with a lower initial burst release and overall slightly faster release rate. After a single injection of remote-loaded setmelanotide, continuous long-term inhibition of food intake and body weight control was observed over 17 and 30 days, respectively. The improvement in body weight control over drug-free microsphere vehicle-treated control groups matched the observed PK profile. This study provides the first report of long-acting release formulation for 1-month controlled release of setmelanotide and body weight control in a diet induced obese murine model, and supports the further development of long-acting treatment options for obese patients.

Topics: alpha-MSH; Animals; Body Weight; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Glycols; Humans; Lactic Acid; Mice; Microspheres; Obesity; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer

Melanocortin 4 receptor (MC4R) has a well-established role in regulating appetite, food intake and energy homeostasis. Setmelanotide is an MC4R agonist currently approved for weight loss in obese adults and children with mutations in components of the leptin-melanocortin pathway. This study aims to compare structural and functional aspects of the physiological MC4R agonist α-melanocyte-stimulating hormone (α-MSH) with setmelanotide. We also aim to show the binding affinity of setmelanotide to known MC4R human missense mutations associated with obesity.. AutoDock Vina was used in the structural analysis to calculate induced fit docking scores of ligand binding to MC4R wild type or the selected variants. HEK293-MC4R were utilized in the functional analysis of MC4R-actiavted pathways upon stimulating with α-MSH or setmelanotide.. Our data shows that setmelanotide has a higher potency for cAMP formation and a weaker effect on ERK1/2 phosphorylation when compared to α-MSH indicating functional selectivity otherwise known as biased agonism. We also present structural data showing that setmelanotide has a higher binding affinity to MC4R compared to α-MSH. Lastly, we show that two loss-of-function and two gain-of-function MC4R variants change the conformation not only of the ligand binding pocket of the receptor but also of the peptide when bound to the receptor because the interaction network and the residues involved in the binding are altered.. Taken together, our study provides important insights into the diversity of MC4R signaling pathways which will facilitate the development of personalized anti-obesity drugs via refining MC4R agonists.

Topics: Adult; alpha-MSH; Anti-Obesity Agents; Child; HEK293 Cells; Humans; Leptin; Ligands; Melanocortins; Obesity; Receptor, Melanocortin, Type 4

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-G

Topics: alpha-MSH; Anti-Obesity Agents; Appetite; Binding Sites; Calcium; Cryoelectron Microscopy; Drug Design; HEK293 Cells; Humans; Ligands; Mutation; Obesity; Protein Conformation, alpha-Helical; Protein Domains; Receptor, Melanocortin, Type 4; Satiation; Signal Transduction

Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine-another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice.

Topics: alpha-MSH; Animals; Antipsychotic Agents; Female; Hyperphagia; Hypothalamus; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Models, Animal; Neurons; Obesity; Olanzapine; Potassium; Receptor, Melanocortin, Type 4; Risperidone; Synaptic Potentials; Transcriptome; Weight Gain

Work in recent decades has established that metabolic hormones released by endocrine cells and diverse other cell types serve to regulate nutrient intake and energy homeostasis. Tsukushi (TSK) is a leucine-rich repeat-containing protein secreted primarily by the liver that exerts an inhibitory effect on brown fat sympathetic innervation and thermogenesis. Despite this, physiological regulation of TSK and the mechanisms underlying its effects on energy balance remain poorly understood. Here we show that hepatic expression and plasma concentrations of TSK are induced by feeding and regulated by melanocortin-4 receptor (MC4R) signaling. We generated TSK and MC4R-double-knockout mice to elucidate the nature of cross talk between TSK and the central regulatory circuit of energy balance. Remarkably, TSK inactivation restores energy balance, ameliorates hyperphagia, and improves metabolic health in MC4R-deficient mice. TSK ablation enhances thermogenic gene expression in brown fat, dampens obesity-association inflammation in the liver and adipose tissue, and protects MC4R-null mice from diet-induced nonalcoholic steatohepatitis. At the cellular level, TSK deficiency augments feeding-induced c-Fos expression in the paraventricular nucleus of the hypothalamus. These results illustrate physiological cross talk between TSK and the central regulatory circuit in maintaining energy balance and metabolic homeostasis.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; alpha-MSH; Animals; Anti-Obesity Agents; Energy Metabolism; Hypothalamus; Liver; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Obesity; Proteoglycans; Receptor, Melanocortin, Type 4; Signal Transduction; Thermogenesis

To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS).. Individuals aged 12 years and older with BBS received once-daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes.. From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was -5.5% (90% CI, -9.3% to -1.6%; n = 8); change from baseline was -11.3% (90% CI, -15.5% to -7.0%; n = 8) at 6 months and -16.3% (90% CI, -19.9% to -12.8%; n = 7) at 12 months. All participants reported at least one treatment-emergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points.. Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.

Topics: alpha-MSH; Bardet-Biedl Syndrome; Humans; Obesity; Receptor, Melanocortin, Type 4

Topics: alpha-MSH; Humans; Obesity; Obesity, Morbid; Pro-Opiomelanocortin; Receptor, Melanocortin, Type 4

Human melanocortin-4 receptor (hMC4R) mutations have been implicated as the cause for about 6-8% of all severe obesity cases. Drug-like molecules that are able to rescue the functional activity of mutated receptors are highly desirable to combat genetic obesity among this population of patients. One such molecule is the selective MC4R agonist RM-493 (setmelanotide). While this molecule has been shown to activate mutated receptors with 20-fold higher potency over the endogenous agonist, little is known about its binding mode and how it effectively interacts with hMC4R despite the presence of mutations. In this study, a MC4R homology model was constructed based on the X-ray crystal structure of the adenosine A2A receptor in the active state. Four MC4R mutations commonly found in genetically obese patients and known to effect ligand binding in vitro were introduced into the constructed model. RM-493 was then docked into the wild-type and mutated models in order to better elucidate the possible binding modes for this promising drug candidate and assess how it may be interacting with MC4R to effectively activate receptor polymorphisms. The results reflected the orthosteric interactions of both the endogenous and synthetic ligands with the MC4R, which is supported by the site-directed mutagenesis studies. Meanwhile it helped explain the decremental affinity and potency of these ligands with the receptor polymorphisms. More significantly, our findings indicated that the structural characteristics of RM-493 may allow for enhanced receptor-ligand interactions, particularly through those with the putative allosteric binding sites, which facilitated the ligand to stabilize the active state of native and mutant MC4Rs to maintain reasonably high affinity and potency.

Topics: Allosteric Regulation; alpha-MSH; Amino Acid Sequence; Anti-Obesity Agents; Computer Simulation; Humans; Molecular Docking Simulation; Obesity; Point Mutation; Protein Structure, Secondary; Protein Structure, Tertiary; Receptor, Melanocortin, Type 4

The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity.. Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1, and LEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants.. We predict ~650 α-melanocyte-stimulating hormone (MSH)/POMC, 8500 PCSK1, and 3600 LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway-deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants: β-MSH/POMC,PCSK1 N221D, and a PCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in the POMC, PCSK1, and LEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene.. Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.

Topics: Alleles; alpha-MSH; Anti-Obesity Agents; Body Mass Index; Female; Heterozygote; Homozygote; Humans; Loss of Function Mutation; Male; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptors, Leptin; Signal Transduction; United States

We assessed the efficacy of simultaneous agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the melanocortin-4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet-induced obese (DIO) mice were chronically treated with either the long-acting GLP-1R agonist liraglutide, the MC4R agonist RM-493 or a combination of RM-493 and liraglutide. Co-treatment of DIO mice with RM-493 and liraglutide improves body weight loss and enhances glycemic control and cholesterol metabolism beyond what can be achieved with either mono-therapy. The superior metabolic efficacy of this combination therapy is attributed to the anorectic and glycemic actions of both drugs, along with the ability of RM-493 to increase energy expenditure. Interestingly, compared to mice treated with liraglutide alone, hypothalamic Glp-1r expression was higher in mice treated with the combination therapy after both acute and chronic treatment. Further, RM-493 enhanced hypothalamic Mc4r expression. Hence, co-dosing with MC4R and GLP-1R agonists increases expression of each receptor, indicative of minimized receptor desensitization. Together, these findings suggest potential opportunities for employing combination treatments that comprise parallel MC4R and GLP-1R agonism for the treatment of obesity and diabetes.

Topics: alpha-MSH; Animals; Diabetes Mellitus; Drug Synergism; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Liraglutide; Mice, Obese; Obesity; Receptor, Melanocortin, Type 4; Receptors, Glucagon; Treatment Outcome

The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects.

Topics: Adiposity; alpha-MSH; Animals; Anti-Obesity Agents; Blood Pressure; Cardiovascular System; Chronic Disease; Diet, High-Fat; Eating; Glucose Intolerance; Heart Rate; Insulin Resistance; Macaca mulatta; Male; Obesity; Peptides; Receptor, Melanocortin, Type 4; Weight Loss

Melanocortin receptor agonists act in the brain to regulate food intake and body weight and, independently of these actions, affect insulin sensitivity. These experiments investigated the function of novel non-selective melanocortin receptor agonists (BIM-22493, BIM-22511) that cross the blood-brain barrier when administered peripherally. Treatment of diet induced obese C57BL/6J (B6) mice with melanocortin agonists administered peripherally improved obesity, hyperinsulinemia (approximately 50%) and fatty liver disease. Specificity of function was determined using B6 melanocortin-3 and melanocortin-4 receptor knockout mice (MC3RKO, MC4RKO). Chow fed MC4RKO but not MC3RKO used for these tests exhibited obesity, hyperinsulinemia and severe hepatosteatosis associated with increased expression of insulin-stimulated genes involved in lipogenesis. Reduced food intake associated with acute BIM-22493 treatment, and weight loss associated with 14 days of treatment with BIM-22511, required functional MC4R but not MC3R. However, while 14 days of treatment with BIM-22511 did not affect body weight and even increased cumulative food intake in MC4RKO, a significant reduction (approximately 50%) in fasting insulin was still observed. Despite lowering insulin, chronic treatment with BIM-22511 did not improve hepatosteatosis in MC4RKO, and did not affect hepatic lipogenic gene expression. Together, these results demonstrate that peripherally administered melanocortin receptor agonists regulate body weight, liver metabolism and glucose homeostasis through independent pathways. MC4R are necessary for melanocortin agonist-induced weight loss and improvements in liver metabolism, but are not required for improvements in hyperinsulinemia. Agonists with activity at MC4R improve glucose homeostasis at least partially by causing weight loss, however other melanocortin receptors may have potential for treating aberrations in glucose homeostasis associated with obesity.

Topics: alpha-MSH; Animals; Diet; Eating; Energy Metabolism; Female; Glucose; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Weight Loss