RegulationPriority Review (US), Rare Pediatric Disease (US), Orphan Drug (EU), PRIME (EU), Priority Review (CA), Breakthrough Therapy (US), Orphan Drug (US)

Structure

Molecular FormulaC51H72N18O11S2

InChIKeyBAJXLDXHOOSXOU-GZRAWZNHSA-N

CAS Registry1504602-49-6

Gene Sequence

Sequence Code 9118544

Source: *****

Clinical Trials associated with Setmelanotide Acetate

NCT06596135 / Enrolling by invitationPhase 3

Open-Label Extension Study of Setmelanotide in Patients With a Rare Genetic, Syndromic or Acquired Disease of the MC4R Pathway

This is an open-label extension study designed to evaluate the long-term safety and tolerability of continued setmelanotide treatment in male and female patients ≥2 years of age who have completed or transitioned from a previous study with setmelanotide for rare genetic, syndromic, or acquired diseases of obesity upstream of the MC4R pathway.

Start Date21 Oct 2024

Sponsor / Collaborator

Rhythm Pharmaceuticals, Inc.

NCT05774756 / Enrolling by invitationPhase 3

A Phase 3, Double Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Setmelanotide in Patients With Acquired Hypothalamic Obesity

The goal of this trial is to learn how well Setmelanotide works to improve weight reduction, hunger, and quality of life in patients 4 years of age and older with acquired Hypothalamic Obesity (HO). To determine how well setmelanotide works and how safe it is, patients with HO will take a daily injection of either setmelanotide or placebo and complete trial assessments for up to 60 weeks.

Start Date26 Apr 2023

Sponsor / Collaborator

Rhythm Pharmaceuticals, Inc.

EUCTR2021-004167-27-ES / Not yet recruitingPhase 3

A Phase 3 Multi-Center, One-Year, Open-Label study of Setmelanotide in Pediatric Patients Aged 2 to <6 years of age with Rare Genetic Causes of Obesity

Start Date05 May 2022

Sponsor / Collaborator-

100 Clinical Results associated with Setmelanotide Acetate

100 Translational Medicine associated with Setmelanotide Acetate

100 Patents (Medical) associated with Setmelanotide Acetate

Literatures (Medical) associated with Setmelanotide Acetate

01 Feb 2025·RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY

The MC4R agonist, setmelanotide, is associated with an improvement in hypercapnic chemosensitivity and weight loss in male mice

Article

Author: Arble, Deanna M. ; Arble, Deanna M ; Framnes-DeBoer, Sarah N. ; Rivera, Athena ; Framnes-DeBoer, Sarah N

Obesity increases the risk of respiratory diseases that reduce respiratory chemosensitivity, such as Obesity Hypoventilation Syndrome and sleep apnea. Recent evidence suggests that obesity-related changes in the brain, including alterations in melanocortin signaling via the melanocortin-4 receptor (MC4R), may underly altered chemosensitivity. Setmelanotide, an MC4R agonist, causes weight loss in both humans and animal models. However, it is unknown the extent to which setmelanotide affects respiratory chemosensitivity independent of body weight loss. The present study uses diet-induced obese, male C57bl/6 J mice to determine the extent to which acute setmelanotide treatment affects the hypercapnic ventilatory response (HCVR). We find that ten days of daily setmelanotide treatment at 1 mg/kg, but not 0.2 mg/kg, is sufficient to cause weight loss and increase HCVR. In a separate group of animals, we find that we can emulate setmelanotide's effect on weight loss by restricting daily calories to match the hypophagia triggered by setmelanotide. These pair-fed animals exhibit improvements in HCVR similar to those who receive setmelanotide. We conclude that acute treatment with setmelanotide is as effective as weight loss at improving respiratory hypercapnic chemosensitivity.

01 Dec 2024·AMERICAN JOURNAL OF HUMAN GENETICS

Monoallelic pathogenic variants in LEPR do not cause obesity

Article

Author: Leloire, Audrey ; Toussaint, Bénédicte ; Buse Falay, Emmanuel ; Henriques, Emma ; Balkau, Beverley ; Marre, Michel ; Vaillant, Emmanuel ; Le Collen, Lauriane ; Delplanque, Jérôme ; Franc, Sylvia ; Bonnefond, Amélie ; Derhourhi, Mehdi ; Loiselle, Hélène ; Froguel, Philippe ; Charpentier, Guillaume

Individuals with obesity caused by biallelic pathogenic LEPR (leptin receptor) variants can benefit from setmelanotide, the novel MC4R agonist. An ongoing phase 3 clinical trial (NCT05093634) includes individuals with obesity who carry a heterozygous LEPR variant, although the obesogenic impact of these variants remains incompletely evaluated. The aim of this study was to functionally assess heterozygous variants in LEPR and to evaluate their effect on obesity. We sequenced LEPR in ∼10,000 participants from the French RaDiO study. We found 86 rare heterozygous variants. Each identified variant was then investigated in vitro using luciferase and western blot assays. Using the criteria of the American College of Medical Genetics and Genomics (ACMG), including the strong criterion related to functional assays, we found 12 pathogenic LEPR variants. Most heterozygotes did not present with obesity, and we found no association between these pathogenic variants and body mass index (BMI). This lack of association between pathogenic LEPR variants and obesity risk or BMI was confirmed using exome data from 200,000 individuals in the UK Biobank. In the literature, among 55 reported heterozygotes for of a rare pathogenic LEPR variant, only 27% had obesity. In conclusion, monoallelic pathogenic LEPR variants were functionally tested, and they do not elevate the risk of obesity or BMI levels. This raises questions about the use of setmelanotide, a costly drug with potential side effects, based solely on the presence of a heterozygous LEPR variant.

01 Nov 2024·Molecular Metabolism

Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice

Article

Author: Lund, Jens ; Holm, Stephanie ; Clemmensen, Christoffer ; Merrild, Christoffer ; Petersen, Jonas

OBJECTIVES:

The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether "lead-in" calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models.

METHODS:

Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy.

RESULTS:

Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide.

CONCLUSIONS:

Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care.

160

News (Medical) associated with Setmelanotide Acetate

18 Nov 2024

·www.globenewswire.com

Rhythm Pharmaceuticals Announces Five Presentations at ESPE 2024, including New Real-world Data in Pediatric Patients with Acquired or Congenital Hypothalamic Obesity Treated with Setmelanotide

-- Four Pediatric patients treated in French early-access program achieved meaningful weight reduction at three months on setmelanotide therapy -- -- Rhythm announced plans for a new substudy to evaluate setmelanotide therapy in patients with congenital hypothalamic obesity -- BOSTON, Nov. 18, 2024 (GLOBE NEWSWIRE) -- Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a commercial-stage biopharmaceutical company focused on transforming the lives of patients living with rare neuroendocrine diseases, today announced the presentation of new, real-world data that showed four pediatric patients with acquired hypothalamic obesity or congenital hypothalamic obesity achieved >5% weight reduction at three months on setmelanotide, a melanocortin-4 receptor (MC4R) agonist. These data were among five Rhythm-related presentations delivered during the 62nd annual meeting of the European Society for Paediatric Endocrinology (EPSE) in Liverpool, England. “Patients living with hypothalamic obesity – whether acquired or congenital –are mostly refractory to lifestyle programs and anti-obesity medicines that do not address the underlying cause,” said David Meeker, M.D., Chairman, Chief Executive Officer and President of Rhythm. “Based on these case reports and insight generated through our pre-approval early-access program for setmelanotide in France, we look forward to exploring the potential efficacy of setmelanotide to offer a new therapy for these patients.” 3-month real-world setmelanotide hunger and weight outcomes in four French pediatric patients with acquired or congenital hypothalamic obesityThe presentation includes results from four case reports of patients <18 years old, two with acquired hypothalamic obesity and two with congenital hypothalamic obesity, at month three on setmelanotide therapy: Congenital hypothalamic obesity: Female, age 15, with septo-optic dysplasia as cause of hypothalamic obesity, achieved a body weight decrease of 9.6% from baseline (94 kg) at month 3 and BMI-Z score change from 3.1 at baseline to 2.8;Male, age 9, with pituitary stalk interruption syndrome (PSIS) as cause of hypothalamic obesity, achieved a body weight decrease of 5.2% from baseline (64 kg) at month 3 and BMI-Z score change from 3.7 at baseline to 3.5; Acquired hypothalamic obesity: Male, age 13, with acquired hypothalamic obesity related to craniopharyngioma resected at age 9, achieved a body weight decrease of 5.6% from baseline (116 kg) at month 3 and 9.5% weight reduction at month 6, and BMI-Z score change from 3.7 at baseline to 3.4 at month six of setmelanotide therapy; andMale, age 13, with acquired hypothalamic obesity related to radiotherapy for juvenile pilocytic astrocytoma, achieved a body weight decrease of 8.3% from baseline (88.3 kg) at month 3 and BMI-Z score change from 3.1 at baseline to 2.8. These patients were treated with setmelanotide at four different hospitals in France under a pre-marketing, early-access authorization program. All four patients remain on therapy, as of November 15, 2024, and there were no new safety signals observed. “These patients present with differences and complexities associated with hypothalamic obesity, but these conditions share the same disrupted MC4R pathway signaling,” said Dr. Ahlam Azar-Kolakez, MD, Endocrinology-Diabetology Department, Reference Center for Endocrine Growth and Developmental Diseases, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, France. “These real-world results are the first reported evidence of setmelanotide treatment for patients with congenital hypothalamic obesity demonstrating that it may be an effective, targeted therapy for both acquired and congenital hypothalamic obesity despite differences in etiology.” Also today, Rhythm announced plans for a new, 34-week substudy designed to evaluate setmelanotide in 39 patients with congenital hypothalamic obesity aged 4 years and older. Rhythm is seeking approval from the U.S. Food and Drug Administration (FDA) for the independent substudy for congenital hypothalamic obesity as a protocol amendment to the Company’s ongoing Phase 3 trial evaluating setmelanotide in patients with acquired hypothalamic obesity. Rhythm anticipates enrolling the first patients with congenital hypothalamic obesity in the first quarter of 2025. The substudy in congenital hypothalamic obesity is independent from Rhythm’s pivotal Phase 3 trial in acquired hypothalamic obesity. The Company remains on track to disclose topline data from that pivotal trial in the first half of 2025. About Congenital Hypothalamic ObesityCongenital hypothalamic obesity is a rare disease caused by certain inborn brain abnormalities that may impair the function of the MC4R pathway, which regulates satiety or food intake and energy expenditure. The hallmark features of this disease include hyperphagia and early-onset, refractory obesity that is often linked to an impairment in the MC4R pathway associated with several pituitary deficiencies. Rare diseases that may cause congenital hypothalamic obesity include septo-optic displasia (or de Morsier syndrome), optic nerve hypoplasia, multiple pituitary hormone deficiency (also known as combined pituitary hormone deficiency) and pituitary stalk interruption syndrome. Each of these diseases is considered rare, and between 12% and 40% of patients with these diseases may have congenital hypothalamic obesity. Rhythm’s preliminary estimate of the prevalence of congenital hypothalamic obesity is in excess of 1,000 patients in the United States with a similar prevalence in Europe. Additional Presentations at ESPE 2024In a poster entitled, “Evaluating Setmelanotide Treatment for 12 Months in Pediatric Age Groups With Rare Melanocortin-4 Receptor Pathway–Related Obesity: Efficacy in Weight Reduction and Safety Outcomes,” presenters highlighted the importance of early intervention in young patients with rare MC4R pathway diseases. A cross-sectional analysis of 50 patients aged 2 to 17 years with rare MC4R pathway diseases who participated in one of five different clinical trials of setmelanotide was presented showing that patients regardless of age achieved clinically meaningful weight reductions, and that children between 2 and 5 years old achieved a greater absolute BMI Z reduction. Additionally, the Company delivered three oral presentations based on analyses of more than 5,000 sequencing samples from the Company’s European genetic testing program for individuals with suspected rare MC4R pathway diseases, Rare Obesity Advanced Diagnosis or ROAD®. Genetic testing of individuals with early-onset obesity can help improve disease etiology understanding and identify patients who may benefit from specialized care. Highlights from these three presentations included: 1.74% of individuals tested carried a biallelic variant in one of 22 tested genes related to Bardet-Biedl syndrome (BBS), and the frequency in Turkey was 5.82%, potentially due to consanguinity rates;22.5% of tested individuals with early-onset obesity carried a variant classified as pathogenic, likely pathogenic or of unknown significance (VUS) of one or more genes closely associated with MC4R pathway function: SIM1, SEMA3 family, PLXNA family, POMC, PCSK1, LEPR, SH2B1 and NCOA1; and4.9% of tested individuals carried a biallelic or heterozygous pathogenic, likely pathogenic or VUS variant in one or more of these genes: ALMS1, BBS, MAGEL2, PHIP, or TBX3 genes. These genes are associated with certain debilitating syndromes. All of the Rhythm-related presentations from ESPE 2024 are available here: https://hcp.rhythmtx.com/publications-presentations/. About Rhythm PharmaceuticalsRhythm is a commercial-stage biopharmaceutical company committed to transforming the lives of patients and their families living with rare neuroendocrine diseases. Rhythm’s lead asset, IMCIVREE® (setmelanotide), an MC4R agonist designed to treat hyperphagia and severe obesity, is approved by the U.S. Food and Drug Administration (FDA) for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency confirmed by genetic testing, or patients with a clinical diagnosis of Bardet-Biedl syndrome (BBS). Both the European Commission (EC) and the UK’s Medicines & Healthcare Products Regulatory Agency (MHRA) have authorized setmelanotide for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. The EC has also authorized setmelanotide for control of hunger and treatment of obesity in children as young as 2 years old, living with BBS or POMC, PCSK1, or LEPR deficiency. Additionally, Rhythm is advancing a broad clinical development program for setmelanotide in other rare diseases, as well as investigational MC4R agonists LB54640 and RM-718, and a preclinical suite of small molecules for the treatment of congenital hyperinsulinism. Rhythm’s headquarters is in Boston, MA. Setmelanotide IndicationIn the United States, setmelanotide is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to POMC, PCSK1 or LEPR deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1 or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) or BBS. In the European Union, setmelanotide is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 2 years of age and above. In Europe, setmelanotide should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology. Limitations of UseSetmelanotide is not indicated for the treatment of patients with the following conditions as setmelanotide would not be expected to be effective: Obesity due to suspected POMC, PCSK1 or LEPR deficiency with POMC, PCSK1 or LEPR variants classified as benign or likely benign.Other types of obesity not related to POMC, PCSK1 or LEPR deficiency, or BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity. ContraindicationPrior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. WARNINGS AND PRECAUTIONS Skin Pigmentation and Darkening of Pre-Existing Nevi: Generalized increased skin pigmentation and darkening of pre-existing nevi have occurred because of its pharmacologic effect. Full body skin examinations prior to initiation and periodically during treatment should be conducted to monitor pre-existing and new pigmentary lesions. Heart rate and blood pressure monitoring: In Europe, heart rate and blood pressure should be monitored as part of standard clinical practice at each medical visit (at least every 6 months) for patients treated with setmelanotide. Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Patients who have an erection lasting longer than 4 hours should seek emergency medical attention. Depression and Suicidal Ideation: Depression and suicidal ideation have occurred. Patients should be monitored for new onset or worsening depression or suicidal thoughts or behaviors. Consideration should be given to discontinuing setmelanotide if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur. Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue setmelanotide. Pediatric Population: The prescribing physician should periodically assess response to setmelanotide therapy. In growing children, the impact of weight loss on growth and maturation should be evaluated. In Europe, the prescribing physician should monitor growth (height and weight) using age- and sex-appropriate growth curves. Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs. ADVERSE REACTIONSMost common adverse reactions (incidence ≥20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection. USE IN SPECIFIC POPULATIONS Lactation: Not recommended when breastfeeding.To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at +1 (833) 789-6337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See section 4.8 of the Summary of Product Characteristics for information on reporting suspected adverse reactions in Europe. Please see the full U.S. Prescribing Information and EU Summary of Product Characteristics for additional Important Safety Information. Forward-looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the potential, safety, efficacy, and regulatory and clinical progress, potential regulatory submissions, approvals and timing thereof of setmelanotide and other product candidates; the timing of results from our global Phase 3 trial evaluating setmelanotide in patients with acquired hypothalamic obesity; the planned new substudy to the ongoing Phase 3 trial evaluating setmelanotide in patients with acquired hypothalamic obesity that would add and evaluate patients with congenital hypothalamic obesity and the timing of enrollment for the substudy; the potential benefits of any of the Company’s products or product candidates for any specific disease indication or at any dosage, including the potential benefits of setmelanotide for patients with acquired hypothalamic obesity or congenital hypothalamic obesity, POMC, PCSK1, or LEPR variants or genetically confirmed Bardet-Biedl syndrome (BBS); expectations surrounding potential clinical trial results, regulatory submissions and approvals; our participation in upcoming events and presentations, the content thereof and the timing of any of the foregoing . Statements using words such as “expect”, “anticipate”, “believe”, “may”, “will” and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to, our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the impact of competition, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our ability to successfully commercialize setmelanotide, our liquidity and expenses, our ability to retain our key employees and consultants, and to attract, retain and motivate qualified personnel, and general economic conditions, and the other important factors discussed under the caption “Risk Factors” in Rhythm’s Quarterly Report on Form 10-Q for the three months ended September 30, 2024 and other filings with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise. Corporate Contact:David ConnollyHead of Investor Relations and Corporate CommunicationsRhythm Pharmaceuticals, Inc.857-264-4280dconnolly@rhythmtx.com Media Contact:Sheryl SeapyReal Chemistry(949) 903-4750sseapy@realchemistry.com

Clinical ResultPhase 3Drug Approval

13 Nov 2024

·www.globenewswire.com

Rhythm Pharmaceuticals Announces Publication of Results from Phase 3 Study of Setmelanotide in Patients Between 2 and 5 Years Old in The Lancet Diabetes & Endocrinology

BOSTON, Nov. 13, 2024 (GLOBE NEWSWIRE) -- Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a global commercial-stage biopharmaceutical company focused on transforming the lives of patients living with rare neuroendocrine diseases, today announced the publication of results from its Phase 3 VENTURE trial evaluating setmelanotide, a melanocortin-4 receptor (MC4R) agonist, in children between the ages of 2 and younger than 5 years old with Bardet Biedl syndrome (BBS) or pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. The data are published in the peer-reviewed journal The Lancet Diabetes & Endocrinology. “Severe, early-onset obesity has been shown to have a negative short-term and long-term impact on a child’s health,” said Professor Jesús Argente, M.D., Ph.D., Department of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús and Universidad Autónoma de Madrid, Madrid, Spain. “In this study, setmelanotide demonstrated clinically meaningful reductions in hunger and body weight in patients younger than 5 years of age with severe obesity. We believe these data support the use of this targeted therapy in a patient population that could benefit from intervention as early as possible.” Rhythm enrolled 12 patients in its open-label 52-week Phase 3 VENTURE trial designed to evaluate setmelanotide in patients aged 2 to younger than 6 years with BBS or POMC, PCSK1 or LEPR deficiency. Clinically meaningful improvements were observed in both co-primary endpoints at week 52. Results of the trial demonstrated: 10 of 12 patients (83%)1 achieved ≥0.2-point reduction in body mass index (BMI) Z-score;-18% in mean percent change in BMI from baseline;91% of caregivers reported patients had reduced hunger compared with baseline, and the caregivers also reported feelings of reduced personal burden; andNo new safety signals were observed. Consistent with prior experience, setmelanotide was observed to have been generally well tolerated. No serious adverse events (AEs) leading to study discontinuation or death were reported. The most common treatment-emergent AEs were skin hyperpigmentation (75%), vomiting (58%), nasopharyngitis (42%), upper respiratory tract infection (33%), and injection site bruising (33%). In July 2024, IMCIVREE (setmelanotide) received authorization as the first-ever precision medicine in the European Union for control of hunger and treatment of obesity in adults and children as young as 2 years old, living with BBS or POMC, PCSK1, or LEPR deficiency. In addition, Rhythm has completed submission of its supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) to expand the label of IMCIVREE to treat pediatric patients between the ages of 2 and younger than 6 years old in approved indications in the United States. The FDA has granted Priority Review of the sNDA and assigned a Prescription Drug User Fee Act (PDUFA) goal date of December 26, 2024. About Rhythm PharmaceuticalsRhythm is a commercial-stage biopharmaceutical company committed to transforming the lives of patients with rare neuroendocrine diseases. Rhythm’s lead asset, IMCIVREE® (setmelanotide), an MC4R agonist designed to treat hyperphagia and severe obesity, is approved by the U.S. Food and Drug Administration (FDA) for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency confirmed by genetic testing, or patients with a clinical diagnosis of Bardet-Biedl syndrome (BBS). Both the European Commission (EC) and the UK’s Medicines & Healthcare Products Regulatory Agency (MHRA) have authorized setmelanotide for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. The EC has also authorized setmelanotide for control of hunger and treatment of obesity in children as young as 2 years old, living with BBS or POMC, PCSK1, or LEPR deficiency. Additionally, Rhythm is advancing a broad clinical development program for setmelanotide in other rare diseases, as well as investigational MC4R agonists LB54640 and RM-718, and a preclinical suite of small molecules for the treatment of congenital hyperinsulinism. Rhythm’s headquarters is in Boston, MA. Setmelanotide IndicationIn the United States, setmelanotide is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to POMC, PCSK1 or LEPR deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1 or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) or BBS. In the European Union, setmelanotide is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 2 years of age and above. In Europe, setmelanotide should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology. Limitations of UseSetmelanotide is not indicated for the treatment of patients with the following conditions as setmelanotide would not be expected to be effective: Obesity due to suspected POMC, PCSK1 or LEPR deficiency with POMC, PCSK1 or LEPR variants classified as benign or likely benign.Other types of obesity not related to POMC, PCSK1 or LEPR deficiency, or BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity. ContraindicationPrior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. WARNINGS AND PRECAUTIONS Skin Pigmentation and Darkening of Pre-Existing Nevi: Generalized increased skin pigmentation and darkening of pre-existing nevi have occurred because of its pharmacologic effect. Full body skin examinations prior to initiation and periodically during treatment should be conducted to monitor pre-existing and new pigmentary lesions. Heart rate and blood pressure monitoring: In Europe, heart rate and blood pressure should be monitored as part of standard clinical practice at each medical visit (at least every 6 months) for patients treated with setmelanotide. Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Patients who have an erection lasting longer than 4 hours should seek emergency medical attention. Depression and Suicidal Ideation: Depression and suicidal ideation have occurred. Patients should be monitored for new onset or worsening depression or suicidal thoughts or behaviors. Consideration should be given to discontinuing setmelanotide if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur. Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue setmelanotide. Pediatric Population: The prescribing physician should periodically assess response to setmelanotide therapy. In growing children, the impact of weight loss on growth and maturation should be evaluated. In Europe, the prescribing physician should monitor growth (height and weight) using age- and sex-appropriate growth curves. Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs. ADVERSE REACTIONS Most common adverse reactions (incidence ≥20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection. USE IN SPECIFIC POPULATIONS Lactation: Not recommended when breastfeeding. To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at +1 (833) 789-6337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See section 4.8 of the Summary of Product Characteristics for information on reporting suspected adverse reactions in Europe. Please see the full U.S. Prescribing Information and EU Summary of Product Characteristics for additional Important Safety Information. Forward-looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the potential, safety, efficacy, and regulatory and clinical progress of setmelanotide or other product candidates for any specific disease indication or at any dosage, including the potential benefits of setmelanotide for pediatric patients with BBS or POMC, PCSK1, or LEPR deficiency; potential and completed regulatory submissions, approvals and timing thereof of setmelanotide and other product candidates, including the PDUFA date to expand the label of IMCIVREE; expectations surrounding potential and completed regulatory submissions and approvals, including within the United States, the EU and other regions; the publication of results from the Phase 3 VENTURE trial in a peer-reviewed journal; and the timing of any of the foregoing . Statements using words such as “expect”, “anticipate”, “believe”, “may”, “will” and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to, our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the impact of competition, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our ability to successfully commercialize setmelanotide, our liquidity and expenses, our ability to retain our key employees and consultants, and to attract, retain and motivate qualified personnel, and general economic conditions, and the other important factors discussed under the caption “Risk Factors” in Rhythm’s Quarterly Report on Form 10-Q for the three months ended September 30, 2024 and other filings with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise. Corporate Contact:David ConnollyHead of Investor Relations and Corporate CommunicationsRhythm Pharmaceuticals, Inc.857-264-4280dconnolly@rhythmtx.com Media Contact:Sheryl SeapyReal Chemistry(949) 903-4750sseapy@realchemistry.com 1 One patient from the initial group of 12 did not complete follow-up appointments and discontinued early in the trial

Phase 3Drug ApprovalClinical ResultPriority ReviewNDA

06 Nov 2024

·www.globenewswire.com

Rhythm Pharmaceuticals Announces Participation in Upcoming Investor Conferences

BOSTON, Nov. 06, 2024 (GLOBE NEWSWIRE) -- Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a global commercial-stage biopharmaceutical company focused on transforming the lives of patients living with rare neuroendocrine diseases, today announced that David Meeker, M.D., Chair, President and Chief Executive Officer, will participate in fireside chats at two upcoming investor conferences: Guggenheim Securities Healthcare Innovation Conference on Monday, November 11 at 11:30 a.m. ET Stifel 2024 Healthcare Conference on Monday, November 18, 2024, at 11:30 a.m. ET The fireside chats will be webcasted and available under “Events & Presentations” in the Investor Relations section of the Company’s website at www.rhythmtx.com, and webcast replays will be available for 30 days following the presentations. About Rhythm PharmaceuticalsRhythm is a commercial-stage biopharmaceutical company committed to transforming the lives of patients with rare neuroendocrine diseases. Rhythm’s lead asset, IMCIVREE® (setmelanotide), an MC4R agonist designed to treat hyperphagia and severe obesity, is approved by the U.S. Food and Drug Administration (FDA) for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency confirmed by genetic testing, or patients with a clinical diagnosis of Bardet-Biedl syndrome (BBS). Both the European Commission (EC) and the UK’s Medicines & Healthcare Products Regulatory Agency (MHRA) have authorized setmelanotide for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. The EC has also authorized setmelanotide for control of hunger and treatment of obesity in children as young as 2 years old, living with BBS or POMC, PCSK1, or LEPR deficiency. Additionally, Rhythm is advancing a broad clinical development program for setmelanotide in other rare diseases, as well as investigational MC4R agonists LB54640 and RM-718, and a preclinical suite of small molecules for the treatment of congenital hyperinsulinism. Rhythm’s headquarters is in Boston, MA. Setmelanotide IndicationIn the United States, setmelanotide is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to POMC, PCSK1 or LEPR deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1 or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS) or BBS. In the European Union, setmelanotide is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 2 years of age and above. In Europe, setmelanotide should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology. Limitations of Use Setmelanotide is not indicated for the treatment of patients with the following conditions as setmelanotide would not be expected to be effective: Obesity due to suspected POMC, PCSK1 or LEPR deficiency with POMC, PCSK1 or LEPR variants classified as benign or likely benign.Other types of obesity not related to POMC, PCSK1 or LEPR deficiency, or BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity. ContraindicationPrior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. WARNINGS AND PRECAUTIONS Skin Pigmentation and Darkening of Pre-Existing Nevi: Generalized increased skin pigmentation and darkening of pre-existing nevi have occurred because of its pharmacologic effect. Full body skin examinations prior to initiation and periodically during treatment should be conducted to monitor pre-existing and new pigmentary lesions. Heart rate and blood pressure monitoring: In Europe, heart rate and blood pressure should be monitored as part of standard clinical practice at each medical visit (at least every 6 months) for patients treated with setmelanotide. Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Patients who have an erection lasting longer than 4 hours should seek emergency medical attention. Depression and Suicidal Ideation: Depression and suicidal ideation have occurred. Patients should be monitored for new onset or worsening depression or suicidal thoughts or behaviors. Consideration should be given to discontinuing setmelanotide if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur. Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue setmelanotide. Pediatric Population: The prescribing physician should periodically assess response to setmelanotide therapy. In growing children, the impact of weight loss on growth and maturation should be evaluated. In Europe, the prescribing physician should monitor growth (height and weight) using age- and sex-appropriate growth curves. Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs. ADVERSE REACTIONS Most common adverse reactions (incidence ≥20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection. USE IN SPECIFIC POPULATIONS Lactation: Not recommended when breastfeeding. To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at +1 (833) 789-6337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See section 4.8 of the Summary of Product Characteristics for information on reporting suspected adverse reactions in Europe. Please see the full U.S. Prescribing Information and EU Summary of Product Characteristics for additional Important Safety Information. Forward-looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without including without limitation statements regarding the safety, efficacy, potential benefits of, and clinical design or progress of any of our products or product candidates at any dosage or in any indication, our participation in upcoming events and presentations, and the date, time and content thereof and the timing of any of the foregoing . Statements using words such as “expect”, “anticipate”, “believe”, “may”, “will” and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to, our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the impact of competition, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our ability to successfully commercialize setmelanotide, our liquidity and expenses, our ability to retain our key employees and consultants, and to attract, retain and motivate qualified personnel, and general economic conditions, and the other important factors discussed under the caption “Risk Factors” in Rhythm’s Quarterly Report on Form 10-Q for the three months ended September 30, 2024 and other filings with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise. Corporate Contact:David ConnollyHead of Investor Relations and Corporate CommunicationsRhythm Pharmaceuticals, Inc.857-264-4280dconnolly@rhythmtx.com Media Contact:Sheryl SeapyReal Chemistry(949) 903-4750sseapy@realchemistry.com

Drug Approval

100 Deals associated with Setmelanotide Acetate

External Link

KEGG	Wiki	ATC	Drug Bank
D11927 D11928	Setmelanotide Acetate	A08AX	DB11700

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Bardet-Biedl Syndrome	US	Rhythm Pharmaceuticals, Inc.	16 Jun 2022
Proopiomelanocortin Deficiency	EU	Rhythm Pharmaceuticals Netherlands BV	16 Jul 2021
Proopiomelanocortin Deficiency	IS	Rhythm Pharmaceuticals Netherlands BV	16 Jul 2021
Proopiomelanocortin Deficiency	LI	Rhythm Pharmaceuticals Netherlands BV	16 Jul 2021
Proopiomelanocortin Deficiency	NO	Rhythm Pharmaceuticals Netherlands BV	16 Jul 2021
Obesity	US	Rhythm Pharmaceuticals, Inc.	25 Nov 2020

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypothalamic obesity	Phase 3	US	Rhythm Pharmaceuticals, Inc.	26 Apr 2023
Hypothalamic obesity	Phase 3	JP	Rhythm Pharmaceuticals, Inc.	26 Apr 2023
Hypothalamic obesity	Phase 3	CA	Rhythm Pharmaceuticals, Inc.	26 Apr 2023
Hypothalamic obesity	Phase 3	DE	Rhythm Pharmaceuticals, Inc.	26 Apr 2023
Hypothalamic obesity	Phase 3	NL	Rhythm Pharmaceuticals, Inc.	26 Apr 2023
Hypothalamic obesity	Phase 3	GB	Rhythm Pharmaceuticals, Inc.	26 Apr 2023
Alstrom Syndrome	Phase 3	US	Rhythm Pharmaceuticals, Inc.	23 Nov 2018
Alstrom Syndrome	Phase 3	CA	Rhythm Pharmaceuticals, Inc.	23 Nov 2018
Alstrom Syndrome	Phase 3	FR	Rhythm Pharmaceuticals, Inc.	23 Nov 2018
Alstrom Syndrome	Phase 3	PR	Rhythm Pharmaceuticals, Inc.	23 Nov 2018

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


GlobeNewswire Manual	Not Applicable	Hypothalamic obesity	4	Setmelanotide	dfktkpmgec(qnurmhmthc) = xqulxazbwn vgvrrtmwxs (mhgorviqcq )	Positive	18 Nov 2024
NCT04966741 (VENTURE, Literature) Manual	Phase 3	Bardet-Biedl Syndrome \| Obesity \| Proopiomelanocortin Deficiency	12	Setmelanotide	swrvcjjxcb(ztwilgbbty) = ldgvrcmbmy ocrskkutkv (ccypwlrtlh, 58·7–99·8) View more	Positive	13 Nov 2024
NCT04966741 (VENTURE, Literature) Manual	Phase 3		12	Setmelanotide (POMC deficiency)	swrvcjjxcb(glynqluovh) = kwkhfpxqjm fhabtnktxe (uharyemoxr, 11)	Positive	13 Nov 2024
NCT04963231 (CTgov)	Phase 2	Obesity	164	Setmelanotide (Stage 1: Setmelanotide (Open-Label))	aeovllqxgj(jlviblivbo) = pwsiqrcodp aqmalpaoho (inkngklwbc, eeujrxmcmm - odllvdliti) View more	-	24 Oct 2024
NCT04963231 (CTgov)	Phase 2	Obesity	164	Setmelanotide (Stage 2: Setmelanotide (Double-Blind))	inwtuscmxq(binrozwvmf) = plgqbcuorl kduhyoxkda (iamibsafrf, youzcxfope - klzowltewd) View more	-	24 Oct 2024
NCT04966741 (VENTURE, CTgov)	Phase 3	Bardet-Biedl Syndrome \| Obesity	12	Setmelanotide (Setmelanotide: PPL Group)	xozzpbcgct(yvmmcztjms) = uqmcgbnfpg vqnbgbirwk (rmqsufjcfz, vaoczfxvvq - pbjfdkfxnm) View more	-	10 Jul 2024
NCT04966741 (VENTURE, CTgov)	Phase 3	Bardet-Biedl Syndrome \| Obesity	12	Setmelanotide (Setmelanotide: BBS Group)	xozzpbcgct(yvmmcztjms) = stnkboazan vqnbgbirwk (rmqsufjcfz, bjrsgwamph - wwukqbczps) View more	-	10 Jul 2024
NCT04966741 (Biospace) Manual	Phase 3	Bardet-Biedl Syndrome \| Obesity	12	Setmelanotide	lwnnxsllfe(nkqvgqrnof) = tivkexadgs mqdyppxjil (cpaqhnwhkm ) Met View more	Positive	06 May 2024
NCT04725240 (Pubmed)	Phase 2	Hypothalamic obesity	18	Setmelanotide 3.0 mg	encbuyohvw(taqimvtikn) = 22% cznbxuvche (ukmmpopdoh ) View more	Positive	01 Apr 2024
NCT03746522 (CTgov)	Phase 3	Bardet-Biedl Syndrome \| Alstrom Syndrome \| Obesity	52	Setmelanotide	nlpqwvzhfs(tlvloxcvow) = cbdbiuigcc brkzbpaiyk (rjhfwyxprk, uacswacfmy - tsntsxvpzt) View more	-	01 Dec 2023
Corporate Publications Manual	Not Applicable	Obesity	-	setmelanotide (patients with hypothalamic obesity)	dicsldkssh(yesqjrrcbc) = mdsvzymofb opquixocqt (setybajgrz )	Positive	17 Oct 2023
Corporate Publications Manual	Not Applicable	Obesity	-	setmelanotide (patients with Bardet-Biedl syndrome)	dicsldkssh(wumpkcxshh) = qagmkpppch vyqhqrrvfh (blwoxmhwqz )	Positive	17 Oct 2023
NCT02896192 (CTgov)	Phase 3	Proopiomelanocortin Deficiency	15	Placebo+Setmelanotide	mcxaketzjm(ixjhxcurnf) = jchwzpqvyl nwspcrcnar (sqbkxskewd, orhuumzaym - iblftbcwlp) View more	-	21 Sep 2023

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