Rhythm Pharmaceuticals, Inc. (Rhythm) operates as a global, commercial-stage biopharmaceutical company dedicated to transforming the lives of patients living with rare neuroendocrine diseases.
The company is focused on advancing its melanocortin-4 receptor (MC4R) agonists, including its lead asset, IMCIVREE (setmelanotide), as precision medicines designed to treat hyperphagia and severe obesity caused by rare MC4R pathway diseases. While obesity affects hundreds of millions of people worldwide,...
Rhythm Pharmaceuticals, Inc. (Rhythm) operates as a global, commercial-stage biopharmaceutical company dedicated to transforming the lives of patients living with rare neuroendocrine diseases.
The company is focused on advancing its melanocortin-4 receptor (MC4R) agonists, including its lead asset, IMCIVREE (setmelanotide), as precision medicines designed to treat hyperphagia and severe obesity caused by rare MC4R pathway diseases. While obesity affects hundreds of millions of people worldwide, the company is developing therapies for a subset of individuals who have hyperphagia, a pathological, insatiable hunger and impaired satiety accompanied by persistent and abnormal food-seeking behaviors, decreased energy expenditure, and severe obesity due to diseases, such as acquired or congenital hypothalamic obesity, Bardet-Biedl syndrome (BBS), or other diseases caused by impaired MC4R pathway signaling. The MC4R pathway is a neuro-endocrine pathway in the brain that is responsible for regulating hunger, caloric intake, and energy expenditure, which consequently affect body weight. IMCIVREE, an MC4R agonist for which the company holds worldwide rights, is the first-ever therapy that is marketed in the United States, European Union (EU), United Kingdom, Canada, and several other countries and regions for certain rare MC4R pathway diseases, including BBS.
The company’s late-stage clinical development program in acquired hypothalamic obesity presents a meaningful expansion opportunity for setmelanotide. Acquired hypothalamic obesity is a rapid-onset, severe obesity caused by injury to the hypothalamus, which may impair MC4R pathway signaling. With setmelanotide, the company observed positive efficacy results in its Phase 2 trial, with a clinically meaningful BMI reduction of 25.5% in 11 patients who reached 12 months or more on therapy through the extension phase of the trial. In addition, similar positive data suggesting potential efficacy have been reported from a pre-approval, early-access program in France. The company has completed enrollment in its Phase 3 trial in patients with acquired hypothalamic obesity and is on track to disclose topline data in the second quarter of 2025. During the first quarter of 2025, the company completed enrollment in a supplemental, 12-patient Japanese cohort of the global Phase 3 trial in acquired hypothalamic obesity, designed to enable potential registration of setmelanotide in Japan for this rare disease.
In addition, the company added an independent substudy to its ongoing global trial, in order to evaluate setmelanotide in patients with congenital hypothalamic obesity, a rare disease caused by certain brain abnormalities that may impair the function of the MC4R pathway, with enrollment of the first patients in this substudy expected in the first quarter of 2025. The company’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, and this is in addition to the prevalence for acquired hypothalamic obesity above.
For IMCIVREE, which was first approved in the United States in 2020, the company has demonstrated success in achieving regulatory approvals and securing market access in approved indications in more than 15 countries in addition to the United States, and it continues to seek access in additional markets. IMCIVREE is approved by the U.S. Food and Drug Administration (FDA) to reduce excess body weight and maintain weight reduction long term in adult and pediatric patients aged 2 years and older with syndromic or monogenic obesity due to BBS or pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (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). The European Commission (EC) and the United Kingdom’s Medicines & Healthcare Products Regulatory Agency (MHRA) have authorized IMCIVREE 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.
The company’s Phase 3 EMANATE trial, comprises four independent substudies evaluating setmelanotide in genetically caused MC4R pathway diseases, is ongoing. Following the completion of its Phase 2 DAYBREAK trial, the company identified six genetically defined cohorts. Additionally, the company is evaluating setmelanotide for the treatment of Prader-Willi syndrome (PWS) in a 26-week, open-label Phase 2 trial, which was initiated at a single site in the United States during the first quarter of 2025.
In addition to setmelanotide, the company has two earlier-stage investigational MC4R agonists in clinical development, RM-718, designed for weekly administration, and bivamelagon (formerly LB54640), an oral small molecule, which are each advancing in Phase 1 and 2 clinical trials, respectively. These investigational assets are designed to be highly selective for the MC4R and MC1R sparing, and thereby not cause hyperpigmentation. The company completed enrollment in its Phase 2 trial evaluating bivamelagon in acquired hypothalamic obesity in the first quarter of 2025. With RM-718, the company anticipates initiating Part C of its Phase 1 trial to evaluate this weekly MC4R agonist in patients with acquired hypothalamic obesity in the first quarter of 2025.
The company’s sequencing-based epidemiology estimates show that each of these genetically defined MC4R pathway deficiencies is considered a rare disease, according to established definitions based on patient populations. The company’s epidemiology estimates are approximately 4,600 to 7,500 for U.S. patients in initial FDA-approved indications, including obesity due to BBS and biallelic POMC, PCSK1, or LEPR deficiencies. The company’s epidemiology estimates for the two more prevalent indications being studied in its Phase 3 EMANATE trial (SH2B1 and POMC/PCSK1) suggest that approximately 29,000 U.S. patients with one of these genetically driven obesities have the potential to respond well to setmelanotide. Similarly, the company’s epidemiology estimates for patients with genetic indications who demonstrated an initial response following stage 1 of its Phase 2 DAYBREAK trial is approximately 65,300. All these patients face similar challenges as other patients with rare diseases, namely lack of awareness, resources, tests, tools, and especially therapeutic options.
The company is working to expand access to IMCIVREE globally. Its disease awareness and patient finding efforts are aligned with a singular focus on building a community of caregivers and healthcare providers dedicated to transforming the treatment of these diseases. The company has multiple field teams in the United States and Europe engaging with physicians who treat patients with severe obesity, and it plans to build out its own team in Japan in preparation for potential registration of setmelanotide for acquired hypothalamic obesity. The company continues to bring together healthcare providers, patients, and families through educational and awareness events. Its genetic testing programs fuel MC4R pathway research, disease education and awareness, and patient finding.
The company is focused on changing the paradigm for the treatment of rare MC4R pathway diseases. The company's focused disease awareness and patient finding efforts fuel the key elements of the company's strategy, including prepare for potential global launch of IMCIVREE in hypothalamic obesity; continue to increase global access to IMCIVREE; and advance MC4R-focused pipeline.
MC4R Pathway Program
IMCIVREE (setmelanotide)
IMCIVREE is approved by the FDA to reduce excess body weight and maintain weight reduction long term in adult and pediatric patients aged 2 years and older with syndromic or monogenic obesity due to BBS, or 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 VUS. The EC and the United Kingdom’s 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 2 years of age and above. IMCIVREE also was approved by Health Canada, where it is indicated in adults and pediatric patients 6 years of age and older with impairments in the MC4R pathway due to genetic diseases, for the treatment of obesity and control of hunger in BBS or biallelic POMC, PCSK1, or LEPR deficiency.
IMCIVREE is the only therapeutic specifically approved for patients with these diseases. As an MC4R agonist, IMCIVREE is designed to address impaired MC4R pathway activity arising due to genetic impairments upstream of the MC4R. IMCIVREE contains setmelanotide acetate, an MC4R agonist. Setmelanotide is an 8 amino acid cyclic peptide analog of endogenous melanocortin peptide a-MSH. The chemical name for setmelanotide acetate is acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidinyl-D-phenylalanyl-L-arginyl-L-tryptophanyl-L-cysteinamide cyclic (2?8)-disulfide acetate. Its molecular formula is C49H68N18O9S2 (anhydrous, free-base), and molecular mass is 1117.3 Daltons (anhydrous, free-base).
IMCIVREE injection is a sterile, clear to slightly opalescent, colorless to slightly yellow solution. Each 1 mL of IMCIVREE contains 10 mg of setmelanotide provided as setmelanotide acetate, which is a salt with 2 to 4 molar equivalents of acetate, and the following inactive ingredients: 100 mg N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl- glycero-3- phosphoethanolamine sodium salt, 8 mg carboxymethylcellulose sodium (average MWt 90,500), 11 mg mannitol, 5 mg phenol, 10 mg benzyl alcohol, 1 mg edetate disodium dihydrate, and Water for Injection. The pH of IMCIVREE is 5 to 6.
Obesity due to POMC, PCSK1 or LEPR deficiency are ultra-rare diseases caused by variants in POMC, PCSK1 or LEPR genes that impair the MC4R pathway. People living with obesity due to POMC, PCSK1 or LEPR deficiency struggle with hyperphagia, an extreme, insatiable hunger, beginning at a young age and resulting in early-onset, severe obesity.
Pivotal Phase 3 Clinical Trial Evaluating Setmelanotide in Bardet-Biedl Syndrome (BBS)
Approvals and marketing authorizations for BBS in the United States, the EU, the United Kingdom, and Canada were based on data from the company’s pivotal Phase 3 clinical trial of setmelanotide in patients with BBS. As the company first reported in December 2020, the trial met its primary endpoint and all key secondary endpoints, with statistically significant and clinically meaningful reductions in weight and hunger at 52 weeks on therapy.
The pivotal data that formed the basis for IMCIVREE’s approvals in BBS were published in the peer-reviewed journal The Lancet Diabetes and Endocrinology in November 2022.
The safety results observed in this study were consistent with that observed with setmelanotide in previous clinical trials in patients with other rare MC4R pathway diseases. Skin hyperpigmentation (n=23; 60.5%) was the most common adverse event (AE). Two patients experienced serious AEs, neither of which was considered related to setmelanotide treatment.
Pivotal Phase 3 Clinical Trials Evaluating Setmelanotide in Biallelic POMC and LEPR Deficiency Obesities
The company assessed the safety and efficacy of IMCIVREE in two pivotal trials that were identically designed: one-year, open-label studies, each with an eight-week, double-blind withdrawal period. The studies enrolled patients with homozygous or presumed compound heterozygous pathogenic, likely pathogenic variants, or VUS, for either the POMC, PCSK1, or LEPR gene. In both studies, adult patients had a body mass index (BMI) of =30 kg/m2. Weight in pediatric patients was =95th percentile using growth chart assessments.
Efficacy analyses were conducted in 21 patients who had completed at least one year of treatment at the time of a pre-specified data cutoff. Of the 21 patients included in the efficacy analysis in both pivotal studies, 62% were adults and 38% were aged 16 years or younger. In Study 1, 50% of patients were female, 70% were White, and the median baseline BMI was 40.0 kg/m2 (range: 26.6-53.3). In Study 2, 73% of patients were female, 91% were White, and the median baseline BMI was 46.6 kg/ m2 (range: 35.8-64.6).
In the POMC/PCSK1 study, 80% of patients with obesity due to POMC or PCSK1 deficiency met the primary endpoint, achieving a =10% weight loss after one year of treatment with IMCIVREE. In the LEPR study, 46% of patients with obesity due to LEPR deficiency met the primary endpoint by achieving a =10% weight loss after 1 year of treatment with IMCIVREE.
Phase 3 Trial Results in Patients Between 2 Years Old and Younger than 6
The hyperphagia and severe obesity of rare, genetically caused MC4R pathway diseases can present early in life. In 2023, the company completed its 52-week, Phase 3 pediatrics trial and demonstrated that setmelanotide met the primary endpoint and achieved clinically meaningful weight reduction in patients within this age range. This trial was a multi-center, one-year, open-label trial in pediatric patients with obesity due to biallelic POMC, PCSK1, or LEPR deficiency, or a clinical diagnosis of BBS with genetic confirmation. The primary efficacy endpoint was a responder analysis, based on the proportion of patients who experience a decrease from baseline in BMI-Z score of =0.2.
Based on these data, IMCIVREE received authorization as the first-ever precision medicine in the EU 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 on July 31, 2024. The UK’s MHRA also expanded marketing authorization for IMCIVREE to include patients as young as 2 years with BBS or POMC, PCSK1 or LEPR deficiency on December 3, 2024. In addition, on December 20, 2024, the FDA also approved an expanded indication for IMCIVREE to include children as young as 2 years old.
Development of Setmelanotide for Additional Indications
Acquired Hypothalamic Obesity
The company is on track and plans to read out topline data from its ongoing Phase 3 clinical trial evaluating setmelanotide as a treatment for acquired hypothalamic obesity in the second quarter of 2025. Acquired hypothalamic obesity is characterized by rapid-onset, severe obesity caused by injury to the hypothalamic region, which may impair MC4R pathway signaling, leading to hyperphagia, decreased energy expenditure, and severe obesity. It occurs most frequently after hypothalamic damage resulting from craniopharyngioma or other intracranial tumors, traumatic brain injury, stroke, or surgical resection or radiation of brain tumors. There are no known approved therapies for this disease.
In 2022, setmelanotide demonstrated potential to transform the care of individuals living with the rapid onset of extreme weight gain of hypothalamic obesity with clinical data that suggested setmelanotide treatment resulted in significant, durable weight loss. On the basis of these results, the company requested, and setmelanotide received, Breakthrough Therapy Designation from the FDA for the treatment of acquired hypothalamic obesity in 2022.
Lesions of the hypothalamus can derive from various types of tumors (e.g., craniopharyngiomas, gliomas, pituitary adenomas, hamartomas) or may be caused by surgeries and/or radiotherapies for the treatment of these same tumor types. These hypothalamic lesions, whether caused by the tumor itself and/or the treatment of the tumor, can disrupt the MC4R pathway. Moreover, patients with acquired hypothalamic obesity display a high degree of hyperleptinemia and hyperinsulinemia. Alpha-melanocortin stimulating hormone (MSH) can be detectable in blood, and its levels can change depending on different energy states; however, in patients with craniopharyngioma or post-surgical treatment for it, a-MSH levels are significantly reduced. Reduced serum a-MSH levels may suggest melanocortin pathway deficiency, which might explain obesity in these patients.
The company completed enrollment in its global Phase 3, 120-patient trial of setmelanotide in acquired hypothalamic obesity, with patients aged 4 years or older with hypothalamic obesity randomized 2:1 to setmelanotide therapy or placebo for a total of 60 weeks, including up to eight weeks for dose titration. The company enrolled a total of 131 patients in this trial; however, as discussed with both the FDA and the EMA, the company expects its planned regulatory submissions will be based on data from the pivotal, 120-patient cohort. The primary endpoint is the percent change in BMI after 52 weeks on a therapeutic regimen of setmelanotide versus placebo. The company is on track to report top-line study results in the second quarter of 2025.
On January 10, 2025, the company announced that it completed enrollment in a supplemental cohort of 12 Japanese patients, which it added to its global Phase 3 trial in acquired hypothalamic obesity. Based on discussions with Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), the company plans to use data from this cohort as part of its planned registration package seeking approval from Japan’s Ministry of Health, Labor and Welfare. In addition to efficacy data, the company will plan to collect and submit pharmacokinetic (PK) data from Japanese patients in an effort to expedite the typical pathway of collecting such data in an earlier-stage trial in Japanese subjects.
The pivotal Phase 3 trial follows positive efficacy results from the company’s 16-week Phase 2 trial, as well as data demonstrating durable and deepening weight loss in patients who transitioned from the Phase 2 trial to its open-label, long-term extension trial. The company enrolled 18 patients in its open-label, 16-week Phase 2 trial designed to evaluate setmelanotide in acquired hypothalamic obesity in patients with a body mass index (BMI) =95th percentile (children 6 to <18 years) or =35 kg/m2 (adults =18 years). The primary endpoint was the proportion of patients who achieved a 5% or greater reduction in BMI after 16 weeks of treatment. Hunger was also assessed daily, as self-reported by individual patients.
The publication also included preliminary data from the company’s long-term extension of the Phase 2 study that were disclosed at ObesityWeek 2023. These data show that patients with hypothalamic obesity (n=12) achieved a mean BMI reduction of approximately 26% at one year on setmelanotide treatment. Consistent with prior experience, setmelanotide was generally well tolerated. The most common adverse events (AEs) in the primary trial included nausea (61.1%), vomiting (33.3%), skin hyperpigmentation (33.3%), diarrhea (22.2%), and COVID-19 (22.2%). Two patients discontinued due to AEs, and a third patient was non-compliant. No new safety concerns were observed during the long-term extension trial.
In addition, a poster presentation was delivered at ObesityWeek in San Antonio, TX, in November 2024, with new, real-world data showing improvements in hunger scores and BMI reductions in adult patients in France with acquired hypothalamic obesity who were treated with setmelanotide. These data were generated from eight patients with acquired hypothalamic obesity age 18 years or older with a previous resection of a tumor in the hypothalamus who were being treated with setmelanotide for three months or longer in five different hospitals in France under pre-marketing early access authorization.
Congenital Hypothalamic Obesity
Clinical Development to Address Additional MC4R Pathway Diseases
The company is also advancing a broad clinical development program evaluating setmelanotide, and it is leveraging the largest known DNA database focused on obesity—with approximately 100,000 sequencing samples as of December 2024—to improve the understanding, diagnosis, and care of people living with hyperphagia and severe obesity due to certain variants in genes associated with the MC4R pathway. There remains a significant unmet need with no effective therapeutic options for patients with these rare MC4R pathway diseases.
Phase 3 EMANATE Trial
The ongoing pivotal Phase 3 EMANATE clinical trial is a randomized, double-blind, placebo-controlled trial, designed to evaluate setmelanotide therapy over a 52-week period in four independent substudies in patients with obesity due to: a heterozygous variant of the POMC/PCSK1 genes or LEPR gene and certain variants of the SRC1 gene or the SH2B1 gene.
On January 10, 2025, the company announced enrollment completion in this 52-week trial. It considers the two most encouraging substudies to be SH2B1 (n=121) and POMC and/or PCSK1 (n=79). The epidemiology estimates for these two genetic indications suggest that approximately 29,000 U.S. patients with one of these genetic deficiencies have the potential to respond to setmelanotide. The epidemiology for the additional two genetic indications enrolled in this trial, SRC1 (n=73) and LEPR (n=23), suggests as many as 24,000 U.S. patients with one of these genetic deficiencies may have the potential to respond to setmelanotide. However, the vast majority of genetic variants of the SRC1 gene are classified as VUS and mostly benign; similarly, pathogenic or likely pathogenic variants of the LEPR gene are ultra-rare. The trial design with four independent substudies allows for independent data readouts and potential registration for each genetic cohort on its own. As the SRC1 and LEPR substudies are under-enrolled and therefore underpowered, it is likely that the company would need to complete additional studies in order to seek regulatory approval for these genetic indications. The primary endpoint for each substudy is the difference in mean percent change in BMI from baseline to 52 weeks in the setmelanotide arm compared to the placebo arm. The company anticipates reporting topline data in the first half of 2026.
Proof of Concept Achieved in Exploratory Phase 2 Basket Study
In January 2021, the company announced proof-of-concept data from its exploratory Phase 2 Basket Study in multiple patient cohorts of patients with severe obesity due to a variant in one of the two alleles in the POMC, PCSK1, or LEPR genes (PPL HET obesity), as well as the SRC1 and SH2B1 genes. The company subsequently furnished updated data in multiple presentations at medical meetings throughout 2021. The exploratory Phase 2 Basket Study was an open-label study designed to evaluate setmelanotide in patients with obesity defined as BMI = 30 kg/m² for patients 16 years of age or older, or BMI = 95th percentile for age and gender for patients between 6 and 16 years old. Patients were stratified by cohort according to their genetic variant. The primary endpoint of the study was the percent of patients in each subgroup showing at least a 5% loss of body weight over three months (such patients are referred to as clinical responders for this study).
In its analyses, the company is applying variant classification guidelines from the American College of Medical Genetics, or ACMG (as described in Richards, et al., 2015), to patient cohort stratification. Specific variants of the POMC, LEPR, PCSK1, SRC1, or SH2B1 gene may be classified based on published data as being pathogenic, likely pathogenic, likely benign, or benign, or classified as a variant of unknown significance or VUS. As the genetics of obesity remains an emerging field, the vast majority of variants in genes associated with the MC4R pathway are classified as VUS. The company’s hypothesis was that patients with genetic variants that indicate a higher degree of pathogenicity would be more likely to have impaired pathway signaling and therefore more likely to respond to setmelanotide.
Phase 2 DAYBREAK Trial
In 2024, the company completed its Phase 2 DAYBREAK trial, a signal- finding study with a two-stage design, that successfully identified six cohorts of interest for further study. This trial was designed to evaluate setmelanotide in patients with hyperphagia and severe obesity caused by variants in one of 31 pre-identified genes known to have strong relevance to the MC4R pathway.
Stage 1 of the trial ruled out several genes for further exploration based on patient prevalence or lack of response. The company designed Stage 1 to evaluate setmelanotide in patients who carry a confirmed variant in one or more genes with strong or very strong relevance to the MC4R pathway. This first stage of the study consisted of a 16-week open-label treatment period; patients 18 years or older who achieved a body mass index (BMI) at least 3% less than the Baseline BMI at the end of Stage 1 and patients <18 years old who achieved a BMI at least 3% less than the Baseline BMI or a decrease in BMI Z-score of at least 0.05 at the end of Stage 1 were eligible for enrollment in the second stage of the study.
A total of 49 patients who completed Stage 1 with a response to setmelanotide (as detailed below) were randomized into Stage 2 of the trial. Stage 2 was a 24-week, double-blind, placebo-controlled withdrawal study. These patients were stratified into genetically defined cohorts and randomized 2:1 to receive setmelanotide or placebo. After analyzing the results from Stage 2, the company deemed the following genes or gene families to merit further study with MC4R agonism: SEMA3 family, PHIP, and TBX3 or PLXNA family.
Phase 2 Trial in Prader-Willi Syndrome
Prader-Willi syndrome (PWS) is a rare genetic disorder that results in a number of physical, mental and behavioral problems. Key features of PWS include an excess weight gain due to a combination of low resting energy expenditure and a severe, constant hyperphagia with onset in early-mid childhood. There are no approved therapies that effectively reduce the extreme hyperphagia or address low resting energy expenditure experienced by patients with PWS, which, if not managed by stringent food restrictions and environmental controls, often results in life-threatening obesity. Approximately 20,000 people in the United States and approximately 400,000 people worldwide are estimated to be living with this disease. There are no approved therapies for the treatment of PWS.
While the underlying etiology of the hyperphagia and excess weight gain in PWS is multifactorial, there remains a logical biological justification for MC4R agonism in this patient population. The critical chromosomal region relevant for PWS contains genetic regions that may impact signaling within the MC4R pathway. Notably, deletions in this region have been shown to be associated with decreased expression of PCSK1, which encodes a key prohormone convertase enzyme in the MC4R pathway. Finally, patients with PWS may have a reduced response to leptin on POMC neurons and consequently reduced MC4R pathway activity (Miller 2020).
In 2016, the company completed a Phase 2 trial that evaluated setmelanotide in patients [N=40] with PWS 16-65 years of age. The study had co-primary endpoints of weight and hyperphagia after 4 weeks of placebo or one of three arms on setmelanotide therapy (0.5mg, 1.5mg or 2.5mg). No statistically significant treatment differences were observed for the co-primary endpoints. The AEs reported in this study were consistent with those reported in other setmelanotide trials. The most common AEs reported thought to be related to setmelanotide were injection site reactions.
On January 10, 2025, the company announced its plan to initiate a new, 26-week, open-label Phase 2 trial evaluating setmelanotide for the treatment of PWS. Unlike the design of its earlier trial, this new trial design calls for an increased dose of setmelanotide and a longer duration of administration. The company plans to enroll up to 20 patients with PWS and obesity aged 6 to 65 years old. Patients will be dose escalated up to 3 mg/day (ages 6 to <12) and up to 5 mg/day as tolerated (ages 12-65) and will receive a daily subcutaneous dose of setmelanotide. The primary endpoints are safety and tolerability. Key secondary endpoints will assess weight, hyperphagia, behavior, and pharmacokinetics. This trial is being conducted at a single site in the United States.
Weekly Formulation of Setmelanotide
In collaboration with Camurus AB, or Camurus, the company has developed a once-weekly, long-acting formulation of setmelanotide using FluidCrystal technology. When injected subcutaneously, aqueous body fluid may be absorbed by the excipient lipid phase, which may then form a gel-like depot consisting of liquid crystals formed in situ, leading to slow diffusion of setmelanotide from the depot. In the event RM-718 shows positive efficacy and safety results, the company will discontinue development of the weekly formulation of setmelanotide. Concurrently, the company is engaging with applicable regulatory authorities to address the impact of its discontinuing development of the weekly formulation of setmelanotide, which was a component of its pediatric investigation plan, or PIP, in the EU (and the United Kingdom). In January 2025, the company submitted a request to modify the PIP to remove elements related to the weekly formulation, and it expects to receive a decision sometime in Q2 2025.
The company has completed one Phase 3 trial evaluating the weekly formulation of setmelanotide in patients with rare MC4R pathway diseases. This weekly switch trial was a randomized, double-blind switch trial in patients with obesity due to biallelic or heterozygous POMC, PCSK1, or LEPR deficiency, or a clinical diagnosis of BBS with genetic confirmation, who were previously enrolled in its long-term, open-label extension trial. Patients were randomized 1:1 to receive once-weekly setmelanotide and once-daily placebo, or once-daily setmelanotide and once-weekly placebo for 13 weeks. Following the 13-week randomized treatment period, patients crossed over to an open-label, 13-week study in which all patients received once-weekly setmelanotide. The study was intended to provide detailed pharmacokinetic characterization of the weekly formulation.
Safety and Tolerability Results
Setmelanotide was generally well-tolerated in the company’s Phase 1, Phase 2 and Phase 3 clinical trials to date. Overall, except as outlined below, the number and patterns of AEs were generally low, and the intensity of the AEs was generally mild, and only infrequently led to clinical trial discontinuation.
In the majority of the company’s trials, it observed a small increase in frequency of penile erections in male patients, as well as signs of sexual arousal in a small number of female patients. These symptoms were infrequent, generally mild, not painful, and short-lived. Most often these symptoms were reported in the first week of treatment. There was a small incidence of nausea and vomiting, as well as injection site reactions, both of which usually were reported as mild, early in treatment, and short-lived. A small number of patients had dose reductions and/or discontinued treatment due to nausea and vomiting.
The company also noted darkening of skin and skin lesions, such as moles and freckles, in approximately half of the patients who received setmelanotide. This was likely caused by activation of the closely related MC1 receptor, the receptor that mediates skin darkening in response to sun exposure. This was observed generally after one to two weeks of treatment, most often plateaued by two to four weeks of treatment, and like sun-related tanning, generally returned to baseline after cessation of exposure.
Life Cycle Management and Pipeline Expansion
In 2024, the company made significant strides in its development of two new clinical programs designed to expand the company’s MC4R agonist product portfolio. RM-718 and bivamelagon are being evaluated in hypothalamic obesity in Phase 1 and 2 trials, respectively. In addition, the company is advancing potential candidates for CHI, a rare genetic disease.
Bivamelagon, an Oral MC4R Agonist
On January 4, 2024, the company announced that it entered into a global licensing agreement with LG Chem, Ltd., or LGC, a leading global company headquartered in South Korea that specializes in life sciences as one of its core businesses, for bivamelagon, an investigational oral small molecule MC4R agonist now in a Phase 2 clinical trial. The development of an effective oral therapy for treating MC4R pathway diseases has been a major goal for the industry.
In a Phase 1 trial in healthy overweight adults, bivamelagon demonstrated dose-dependent weight reduction. Bivamelagon also demonstrated favorable safety results in the trial, with no changes in blood pressure or heart rate observed and no hyperpigmentation observed. In addition, bivamelagon has received orphan drug designation from FDA for the treatment of LEPR deficiency.
The company completed enrollment in its Phase 2 trial evaluating bivamelagon in acquired hypothalamic obesity in the first quarter of 2025. The Phase 2 trial is a randomized, placebo-controlled, double-blind study to assess the effect of bivamelagon on safety, weight reduction, hunger, and quality of life measures in patients 12 years of age and older (N=28) with acquired hypothalamic obesity. Patients will take an oral daily dose of either bivamelagon (low, middle, or high dose) or placebo for 14 weeks. The primary endpoint of the study is the change from baseline in body mass index after 14 weeks of treatment, and patients may continue on therapy for up to 52 weeks.
RM-718, a Next Generation MC4R Peptide Agonist
The company’s MC4R peptide agonist for weekly administration, the new chemical entity, RM-718, has demonstrated the potential to reduce body weight and hunger, with favorable safety results observed in preclinical studies. RM-718 is designed to be more highly targeted and MC1R sparing with the potential to not cause hyperpigmentation. In a series of pre-clinical studies, RM-718 reduced overall body weight, body weight gain and food consumption in animal models. The company initiated a Phase 1 in-human trial in the first quarter of 2024, including a multiple-ascending dose study in patients with hypothalamic obesity.
RM-718 is an investigational, synthetic, cyclic heptamer (7-amino acid-containing) peptide, and is designed as a selective and potent MC4R agonist that spares other melanocortin receptors. The RM-718 formulation is a sustained release depot designed for once weekly (QW), subcutaneous (SC) injection, consisting of RM-718 and excipients. The major components are phospholipids (PL) that are a natural part of the cell membrane, and once injected into tissue and coming into contact with aqueous body fluids and tissues, can precipitate and trap a co-administered drug to form a drug-PL co-precipitate (nanometer-sized phospholipid particles) that functions as a depot. Over time, this depot slowly diffuses into the surrounding tissue and/or is degraded by local phospholipase (slowly hydrolyzing phospholipids) resulting in a slow and controlled release of RM-718 over time.
On March 25, 2024, the company announced that the first participants had been dosed in its Phase 1 clinical trial of RM-718. This Phase 1 trial is a three-part study to evaluate safety, tolerability, and PK. The study consists of Part A: single ascending doses (SAD) of RM-718 in healthy participants aged 18 to 55 years old with obesity; Part B: multiple ascending doses (MAD) of RM-718 in healthy participants aged 18 to 55 years old with obesity; and Part C: MAD of RM-718 in patients 12 to 65 years old with hypothalamic obesity. Cohorts in Parts A and B are double-blind, placebo-controlled, and randomized 2:1. Study participants will receive one weekly dose of either RM-718 or placebo in Part A, four weekly doses of either RM-718 or placebo in Part B, and 16 weekly doses of open-label RM-718 in Part C. In all Parts, RM-718 or placebo doses are administered weekly via subcutaneous injection.
The company completed a protocol amendment in December 2024 and the company expects to begin enrolling patients with acquired hypothalamic obesity in Part C of the Phase 1 trial evaluating RM-718 in the first quarter of 2025. It plans to enroll up to 30 patients with acquired hypothalamic obesity for 16 weeks in Part C of this Phase 1 trial, and patients may continue on therapy for up to 52 weeks. The anticipated total enrollment for all of Parts A, B, and C of this study is up to 120 participants.
In safety pharmacology studies evaluating potential adverse effects on the cardiovascular and respiratory systems in cynomolgus monkeys, RM-718 produced no treatment-related changes in effects on heart rate, blood pressure, electrocardiographic changes, or respiratory parameters up to the 30 mg/kg weekly dose. Moreover, the MC4R peptide agonist LY2112688 (formulated by Eli Lilly and Company), continuous SC infusion for 3 days of LY2112688 at 0.5 and 1 mg/kg/day, resulted in a slight increase in blood pressure at the 1 mg/kg/day dose level, relative to the reference item (saline), with effects being more pronounced during the night cycle, with no definitive effect on heart rate. These changes were not noted following continuous administration of RM-718 at doses of 1 and 5 mg/kg/day for 3 days, with heart rate and blood pressure remaining comparable to the reference item (saline) up to 96 hours post start of infusion. A slight, non-dose dependent decrease in body temperature was seen in all test article-treated groups over the course of the study, all within normal variation for monkeys and it was not considered adverse.
Congenital Hyperinsulinism Program
In February 2023, the company completed the acquisition of Xinvento B.V., or Xinvento, a Dutch private limited liability company based in the Netherlands, through the company's wholly owned subsidiary Rhythm Pharmaceuticals Netherlands B.V., a Dutch private limited liability company. The company anticipates nominating a candidate by the end of 2025.
Genetic Sequencing and Patient Finding
The company continues to expand its sequencing efforts in individuals living with early-onset, severe obesity to support research, patient finding, and community building efforts to better understand rare MC4R pathway diseases. Its obesity DNA database contains sequencing data from approximately 100,000 individuals, as of December 31, 2024. The company’s sequencing data has come from four distinct sources in recent years: the Genetic Obesity ID | Genotyping Study, a global network of collaborations with obesity researchers with individual sample collections, institutional biobanks and Uncovering Rare Obesity (URO) or Rare Obesity Advanced Diagnosis (ROAD) programs.
URO, the company’s sponsored genetic testing program designed to increase access to genetic testing and help determine if individuals have an underlying genetic cause of their severe obesity, is the primary driver of how the company collects sequencing samples and identify patients in the North America region. As obesity has reached epidemic levels in the United States, the company is focused on identifying people with early-onset obesity that may be caused by certain rare genetic variants.
The company’s U.S. partner, Prevention Genetics, a subsidiary of Exact Sciences Corp., a Clinical Laboratory Improvement Amendments-College of American Pathologists of CLIA/CAP-certified independent laboratory, conducts the genetic testing for URO. This program covers the cost of the test and excludes office visit, copay, sample collection, and any other related costs to a participant. In addition, as part of the program, licensed genetic counselors from PWN Health, a leading provider of professional guidance for diagnostic and genetic testing, are available to advise participating individuals.
The ROAD program outside the United States mirrors the URO program as it is designed to increase awareness of rare MC4R pathway diseases caused by genetic variants and support patient identification in the International region. The company collects samples from individuals with severe obesity from seven countries, including Spain, Italy, Ireland, Israel, Turkey and Germany. The company’s partner CGC Genetics Unilabs conducts the genetic testing for ROAD. This program covers the cost of the test, the kit and shipment.
As of the end of 2024, the company has collected samples from approximately 100,000 individuals with severe obesity, primarily through the company’s URO and ROAD programs, which now are the company’s primary source of sequencing samples.
Commercial Efforts for IMCIVREE
The company is focused on developing its global commercial infrastructure to make IMCIVREE available in as many markets as possible.
IMCIVREE, an MC4R agonist for which the company holds worldwide rights, is the first-ever precision medicine developed for patients with certain rare MC4R-pathway diseases approved or authorized in the United States, the EU, the United Kingdom, Canada, and other countries and regions. IMCIVREE is approved by the FDA to reduce excess body weight and maintain weight reduction long term in adult and pediatric patients aged 2 years and older with syndromic or monogenic obesity due to BBS or 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 VUS. The EC and the MHRA have authorized IMCIVREE 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.
The company has achieved market access for IMCIVREE for BBS or POMC and LEPR deficiencies, or both, in more than 15 countries outside the United States, and the company continues to collaborate with authorities to achieve access in additional markets.
While the company is focused on commercial access for IMCIVREE for BBS and POMC and LEPR deficiencies, it is working with the broader community of patients and families, physicians, scientists, and more to engage with them on the impact of hyperphagia and severe obesity caused by rare MC4R pathway diseases. Individually, populations with each of these MC4R pathway diseases are rare, and affected patients face many of the same challenges as any classically rare disease patient populations. There is little or no awareness about rare MC4R pathway diseases, and the patients suffering from them are lost in the healthcare system, with limited educational resources and no effective treatments for their condition. All the company’s efforts and services described above are designed to address the challenges of rare diseases and lay the groundwork for potential future launches, with a focus on scalability.
Licensing Agreements
Ipsen Pharma S.A.S.
Pursuant to its March 21, 2013 license agreement with Ipsen Pharma S.A.S., or Ipsen, the company has an exclusive, sublicensable, worldwide license to certain patents and other intellectual property rights to research, develop, and commercialize compounds that were discovered or researched by Ipsen in the course of conducting its MC4R program or that otherwise were covered by the licensed patents. Rights under the license included the right to research, develop, and commercialize setmelanotide. Pursuant to the license, the company has a non-exclusive, sublicensable, worldwide license to certain patents and other intellectual property rights that were licensed by Ipsen from a third party or that Ipsen may develop in the future, to research, develop, and commercialize any of the compounds exclusively licensed by Ipsen pursuant to the license.
Camurus
In January 2016, the company entered into a license agreement for the use of Camurus' drug delivery technology, FluidCrystal, to formulate setmelanotide with Camurus. Under the terms of the agreement, Camurus granted the company a worldwide license to the FluidCrystal technology to formulate setmelanotide and to develop, manufacture, and commercialize this new formulation for once-weekly dosing, administered as a subcutaneous injection. The license granted to the company is specific to the FluidCrystal technology incorporating setmelanotide. Under the terms of the license agreement, the company is responsible for manufacturing, development, and commercialization of the setmelanotide FluidCrystal formulation worldwide. In addition, Camurus is eligible to receive tiered, mid to mid-high, single-digit royalties on future sales of the product.
RareStone Group Ltd.
In December 2021, the company entered into an exclusive license agreement with RareStone, or the RareStone License. Pursuant to the RareStone License, the company granted to RareStone an exclusive, sublicensable, royalty-bearing license under certain patent rights and know-how to develop, manufacture, commercialize and otherwise exploit any pharmaceutical product that contains setmelanotide in the diagnosis, treatment or prevention of conditions and diseases in humans in China, including mainland China, Hong Kong and Macao. RareStone has a right of first negotiation in the event that Rhythm chooses to grant a license to develop or commercialize the licensed product in Taiwan.
According to the terms of the RareStone License, RareStone has agreed to seek local approvals to commercialize IMCIVREE for the treatment of obesity and hyperphagia due to POMC, PCSK1, or LEPR deficiency, as well as Bardet-Biedl and Alström syndromes. Additionally, RareStone agreed to fund efforts to identify and enroll patients from China in Rhythm’s global EMANATE trial, a Phase 3, randomized, double-blind, placebo-controlled trial to evaluate setmelanotide in four independent sub-studies in patients with obesity due to a heterozygous variant of POMC/PCSK1 or LEPR; certain variants of the SRC1 gene, and certain variants of the SH2B1 gene.
On October 28, 2022, the company delivered written notice, or the October 2022 Notice, to RareStone that it has terminated the RareStone License for cause. In accordance with the October 2022 Notice, the company maintains that RareStone has materially breached its obligations under the RareStone License to fund, perform, or seek certain key clinical studies and waivers, including with respect to its global EMANATE trial, among other obligations. On December 21, 2022, RareStone provided written notice to the company that it objects to the claims in the October 2022 Notice, including the company’s termination of the RareStone License for cause. On March 16, 2023, the company provided written notice, or the March 2023 Notice, to RareStone reaffirming its position that RareStone has materially breached its obligations under the RareStone License and that it has terminated the RareStone License for cause and also requested documentation supporting RareStone’s purported dispute notice objecting to the claims in the October 2022 Notice.
On May 10, 2023, RareStone provided written notice to the company reaffirming its objections to the claims in the October 2022 Notice and March 2023 Notice, including to the company’s termination of the RareStone License for cause. On November 29, 2023, RareStone wrote to the company seeking to negotiate and execute a commercial supply agreement as contemplated under the Exclusive License Agreement, and on January 19, 2024, the company responded in writing, again reaffirming its position that RareStone has materially breached its obligations under the RareStone License and that it has terminated the RareStone License for cause. Since the company’s last written response in January 2024, it has engaged in discussions with RareStone in an effort to reach a resolution; however, it cannot predict whether a resolution will ever be reached.
LG Chem
In January 2024, the company entered into a license agreement and share issuance agreement with LG Chem, Ltd, or LGC. Under the terms of the license agreement, it obtained worldwide rights to exploit LGC’s proprietary compound bivamelagon and have assumed sponsorship of two ongoing LGC Phase 2 studies designed to evaluate safety, tolerability, pharmacokinetics and weight loss efficacy of bivamelagon. The SIGNAL trial is a randomized, placebo-controlled, double-blind study designed to enroll and evaluate approximately 28 patients with acquired hypothalamic obesity. Participants will receive one of three doses of bivamelagon by oral administration once daily for up to 52 weeks, and the primary endpoint of the study is the change from baseline in body mass index after 14 weeks of treatment. The open-label, single-arm, 16-week ROUTE trial is designed to enroll five patients with POMC or LEPR deficiency obesity.
In addition and subject to, among other conditions, the completion of Phase 2 development of bivamelagon, the company has agreed to pay LGC royalties of between low-to-mid single-digit percent of net revenues from products covered by its patent portfolio directed toward the MC4R agonists, including setmelanotide, RM-718, and bivamelagon (collectively, the company's ‘MC4R portfolio’), including bivamelagon, commencing in 2029. This is also dependent upon the achievement of various regulatory and indication approvals and is subject to customary deductions and anti-stacking provisions.
Royalties may further increase to a low double-digit percent royalty; however, such royalty would only be applicable on net sales of bivamelagon in a region if bivamelagon is covered by a composition of matter or method of use patent controlled by LGC in that region, and the company’s MC4R portfolio is not covered by any composition of matter or method of use patents controlled by the company in that region. Such increased rate would only apply on net sales of bivamelagon for the limited remainder of the royalty term in the relevant region.
Patents and Proprietary Rights
The company’s MC4R portfolio of licensed and exclusively owned patent families, which includes setmelanotide, RM-718, and bivamelagon, consists of 45 patent families being prosecuted or maintained, which include applications and patents directed to compositions of matter, formulations, and methods of making, and methods of treatment. These patent families have been filed in over 40 jurisdictions, including all major markets, such as the United States, Europe, Australia, Brazil, Canada, China, India, Israel, Japan, Korea, Mexico, New Zealand, Russia, and Singapore.
In the key patent families directed to selected peptide-based MC4R receptor agonists, including the composition of matter for setmelanotide, the company has 10 issued United States patents and over 225 issued non-United States patents in various jurisdictions. Patents issuing in these patent families will have a standard 20-year term and expire between 2026 and 2045, in each instance provided that all appropriate maintenance fees are paid and not including any patent term adjustment, patent term extension, or supplementary protection certificates that may be available on a country-by-country basis. For example, in a key patent family providing composition of matter coverage for setmelanotide, the company has received 5 years of patent term extension in the United States, extending patent protection in that patent family through 2032.
In addition to the patents and patent applications discussed above, the company co-owns one patent family with the University of Strasbourg and the French National Institute of Health and Medical Research, which is directed to specific uses of MC4R agonists. The company also owns three patent families directed to small molecule compounds for use in its CHI program, with patent claims that will expire when issued between 2043 and 2045, without factoring in any available patent term extension.
Manufacturing
The company contracts with various third parties for the manufacture of setmelanotide and intend to continue to do so in the future. The company has entered into process development and manufacturing service agreements with the company's CMOs, Corden Pharma Brussels S.A, or Corden (formerly Peptisyntha SA prior to its acquisition by Corden), PolyPeptide Group, Braine L'Alleud, or Polypeptide, Neuland Laboratories, and Recipharm Monts S.A.S for certain process development and manufacturing services for regulatory starting materials and/or drug substance, or API, and drug product in connection with the manufacture of setmelanotide. The company has also entered into commercial supply agreements with both Polypeptide and Recipharm.
Setmelanotide is distributed in the U.S. through the company's specialty pharmacy and in the EU/U.K. through third-party service providers that deliver the medication to patients. The company plans to continue building out its network for commercial distribution in jurisdictions in which setmelanotide is approved.
Research and Development
The company’s research and development expense were $238.0 million in 2024.
History
The company was founded in 2008. It was incorporated in 2013. The company was formerly known as Rhythm Metabolic, Inc. and changed its name to Rhythm Pharmaceuticals, Inc. in 2015.
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