NASDAQ: RYTM

In 2026, pending regulatory approval, we anticipate launching IMCIVREE in the United States as the first and only therapy specifically to treat patients living with acquired hypothalamic obesity. This represents a meaningful, near-term expansion opportunity. Acquired hypothalamic obesity is a rare disease characterized by accelerated and sustained weight gain caused by injury to the hypothalamus, which may impair MC4R pathway signaling. We believe there are approximately 10,000 patients in United States living with acquired hypothalamic obesity with an annual incidence of 500 new cases, with similar prevalence and incidence in Europe, as well as between 5,000 and 8,000 patients in Japan. We believe this represents a significant global unmet need as there are no therapies specifically approved for hypothalamic obesity. We are seeking regulatory approval in the United States and the European Union based on statistically significant and clinically meaningful placebo-adjusted BMI reduction of 19.8% achieved in our 120-patient, Phase 3 trial. In addition, we added an independent substudy to our ongoing global trial, in order to evaluate setmelanotide in patients with congenital hypothalamic obesity, a constellation of rare diseases caused by certain brain abnormalities that may impair the function of the MC4R pathway, with enrollment of the first patients in this substudy expected to be complete in the second half of 2026. Our 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. Also, we plan to initiate a Phase 3 registrational trial to evaluate bivamelagon in patients with hypothalamic obesity by year-end 2026, and we are evaluating RM-718 in an ongoing Phase 1/2 trial, also in acquired hypothalamic obesity. On February 26, 2026 we announced we completed a positive end-of-Phase-2 meeting with FDA regarding bivamelagon in acquired HO and disclosed open-label extension data from our Phase 2 trial that showed bivamelagon achieved persistent BMI reductions at six and nine months of therapy.

For IMCIVREE, which was first approved in the United States in 2020, we have demonstrated success in achieving regulatory approvals and/or securing market access or named patient sales in more than 25 countries in addition to the United States, and we continue 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. Reviews of our regulatory submissions seeking approval and marketing authorization for setmelanotide as a treatment for acquired hypothalamic obesity are ongoing in the United States and Europe, with an FDA-assigned Prescription Drug User Fee Act (PDUFA) goal date of March 20, 2026. We anticipate disclosing topline data from a 12-patient Japanese cohort of our Phase 3 trial evaluating setmelanotide for acquired hypothalamic obesity in March 2026, and pending positive data, completing a new drug application submission in Japan. Regulatory decisions in Europe and Japan are anticipated later in 2026 or 2027.

Following our disclosure in December 2025 of positive preliminary data from our ongoing, exploratory, open-label Phase 2 trial with setmelanotide in patients with PWS, we believe there is potential for an MC4R agonist to be a future treatment option for patients with PWS, a rare genetic disorder that results in a number of physical, mental and behavioral problems. A key feature of PWS is a constant sense of hunger that usually begins in early childhood. PWS is estimated to affect approximately 400,000 people worldwide and approximately 20,000 people in the United States. There are currently limited therapeutic options that effectively reduce the extreme hyperphagia and address low resting energy expenditure associated with PWS. Following the disclosure of these positive preliminary results in December 2025, we announced plans to further develop setmelanotide and RM-718 for PWS.

We are advancing what we believe is the most comprehensive clinical research and development program ever initiated in MC4R pathway diseases, with setmelanotide, bivamelagon and RM-718 in multiple ongoing and planned clinical trials. Our MC4R pathway program is designed to expand the total number of patients who we believe could benefit from setmelanotide therapy or from one of our new drug candidates. Our Phase 3 EMANATE trial, comprised of four independent substudies evaluating setmelanotide in genetically caused MC4R pathway diseases, is ongoing with topline data expected in March 2026. Following the completion of our Phase 2 DAYBREAK trial, we identified six genetically-defined cohorts that we believe merit further investigation for potential setmelanotide efficacy.

We are leveraging what we believe is the largest known DNA database focused on obesity—with approximately 120,000 sequencing samples as of December 31, 2025—to improve the understanding, diagnosis and care of people living with severe obesity due to certain variants in genes associated with the MC4R pathway. Our sequencing-based epidemiology estimates show that each of these genetically-defined MC4R pathway deficiencies we are focused on are considered rare diseases, according to established definitions based on patient populations. Our 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. Our epidemiology estimates for the SH2B1 insufficiency and heterozygous POMC/PCSK1 insufficiency being studied in our Phase 3 EMANATE trial suggest that approximately 29,000 U.S. patients with one of these genetically driven obesities have the potential to respond well to setmelanotide. Similarly, our epidemiology estimates for patients with genetic indications who demonstrated an initial response in our Phase 2 DAYBREAK trial is approximately 65,300. All these patients face similar challenges to other patients with rare diseases, namely lack of awareness, resources, tests, tools and especially therapeutic options.

We are working to expand access to IMCIVREE globally. Our disease awareness and patient finding efforts are aligned with a singular focus on building a community of caregivers and healthcare providers focused on transforming the treatment of these diseases. We have multiple field teams in the United States and Europe engaging with physicians who treat patients with severe obesity, and we have a team in Japan preparing for the potential registration and launch of setmelanotide for acquired hypothalamic obesity. We continue to bring together health care providers, patients and families with educational and awareness events. Our genetic testing programs fuel MC4R pathway research, disease education, awareness, and patient finding.

As of February 1, 2026, we had 414 employees, including 126 employees in 11 countries outside of North America and with an ever-expanding network of key opinion leaders, and an increasing number of identified, diagnosed and treated patients, we are focused on changing the paradigm for the treatment of rare MC4R pathway diseases. Rhythm is executing a strategy to build a durable, global biopharmaceutical company focused on transforming the lives of patients with rare neuroendocrine diseases by rapidly advancing care and precision medicines that address the root cause. We have established a strong global foundation with IMCIVREE (setmelanotide), which has achieved regulatory approvals and marketing authorization, reimbursed access or named patient sales in more than 25 countries, including the United States, the European Union and the United Kingdom. With RM-718 and bivamelagon in addition to setmelanotide, we are advancing what we believe is the most comprehensive portfolio of MC4R agonists. Leveraging our expertise, we plan to maximize the value of our MC4R agonists by aligning our clinical development, commercial and life-cycle management strategies around three key disease areas where patients are currently underserved:

1. Hypothalamic dysfunction

We are preparing for global commercialization of setmelanotide for the treatment of patients with acquired hypothalamic obesity beginning in 2026, if approved, in the United States, Europe, Japan and more regions and countries. In parallel, we expect to initiate a registrational Phase 3 program for bivamelagon, our oral MC4R agonist, by year-end 2026, and continue to evaluate RM‑718, our weekly MC4R agonist, in an ongoing Phase 1/2 trial in patients with hypothalamic obesity. We also are evaluating setmelanotide in congenital hypothalamic obesity.

2. Prader-Willi syndrome (PWS)

With encouraging preliminary results from the ongoing exploratory Phase 2 PWS trial of setmelanotide, we believe MC4R agonism has the potential to address the profound hyperphagia and severe obesity associated with PWS. We also are advancing RM‑718 in an ongoing Phase 1/2 trial in PWS. There remains a significant unmet need to treat hyperphagia, diminished energy expenditure and obesity associated with PWS.

3. Rare genetic MC4R pathway diseases

We are leveraging our global leadership in MC4R pathway genetics to deepen our knowledge of the genetics underlying these rare diseases and the number of patients who may benefit from MC4R agonism. EMANATE, our pivotal Phase 3 program comprised of four independent substudies across genetically defined MC4R‑pathway diseases, is expected to deliver topline results from each substudy in March 2026. We believe, these results, if positive, could have the potential to support regulatory approval for setmelanotide in up to four additional indications. We also expect EMANATE results, in combination with results from our completed DAYBREAK trial, to advance our understanding of which genetic variants are associated with loss of function and to inform on our approach to future clinical development. We are evaluating our next‑generation MC4R agonists, including bivamelagon and RM‑718, for further development in these populations. While each genetic MC4R pathway disease may be ultra-rare, when combined this set of diseases represents a meaningful expansion opportunity for setmelanotide and/or our next-generation assets.

In addition to our commercial and clinical priorities, we are advancing pre‑clinical research and exploring new potential indications and potential therapeutic benefits of MC4R agonism. We are advancing new product candidates for congenital hyperinsulinism (CHI), a rare genetic disease. Together, these efforts support our long‑term objective: to develop a scientifically differentiated, globally scaled company capable of delivering first‑in‑class or best‑in‑class MC4R‑mediated therapeutics to patients with rare neuroendocrine diseases across multiple geographies and therapeutic categories.

Market Overview

Severe Obesity, Hyperphagia, and the MC4R Pathway

Rare MC4R pathway diseases are distinct from general obesity. The hallmark characteristics of rare MC4R pathway diseases are severe obesity and hyperphagia, a pathological and insatiable hunger that drives a severe preoccupation with food and extreme food-seeking behaviors. Lifestyle interventions are not effective in patients with these diseases because they fail to address the underlying genetic or acquired impairment of central energy regulation and satiety. Accordingly, the discovery that the MC4R pathway regulates both energy intake (hunger) and energy expenditure has made it an important target for therapeutics. Studies have shown that injuries to the hypothalamus region of the brain in patients with certain tumors impair MC4R signaling, leading to increased hunger, reduced energy expenditure and accelerated and sustained weight gain. With a deeper understanding of this critical signaling pathway, we are taking a different approach to drug development by focusing on specific genetic variants and acquired injury affecting the MC4R pathway. We believe that this approach has the potential to provide clinically meaningful improvements in the treatment of rare obesity and hyperphagia by addressing lost function in the MC4R pathway.

Rare MC4R Pathway Diseases

The MC4R pathway has been the focus of extensive scientific investigation for many years. This neuro-endocrine pathway in the hypothalamus is a key signaling pathway responsible for regulating hunger, caloric intake, and energy expenditure, which consequently affects body weight. It is known to be a critical component in the regulation of energy balance. The critical role of the MC4R pathway in weight regulation is supported by the observation that single gene variants at various points in this pathway may result in early-onset, severe obesity.

The MC4R pathway, through its regulation of energy intake and energy expenditure, is the key physiological determinant of body weight. Genetic variants or anatomical injury or insults may lead to MC4R pathway impairment and result in severe obesity, hyperphagia (an extreme and unrelenting hunger) and reduced energy expenditure. Such MC4R pathway diseases include POMC, PCSK1, LEPR genetic deficiencies, Bardet-Biedl syndrome, Prader-Willi syndrome, acquired and congenital hypothalamic obesity. Additionally, variants of several genes may be associated with MC4R pathway disease, including SH2B1 and SRC1/NCOA1.

The MC4R pathway is illustrated in the figure below. Under normal conditions, POMC neurons are activated by adiposity and satiety signals, including the hormone leptin acting through the LEPR. POMC neurons produce a protein, which is processed by the PCSK1 enzyme, into melanocyte stimulating hormone, or MSH, the natural agonist, or activator of the MC4R. When upstream genetic variants, traumatic injuries or lesions disrupt this pathway, it can lead to insufficient MC4R activation and downstream signaling, the result of which can be hyperphagia, reduced energy expenditure and severe obesity.

The figure below also illustrates some of the genes that are upstream of the MC4R and the potential effect variants in those genes can have on the activation of the MC4R, which regulates food intake and energy expenditure.

MC4R Agonism Development Targets: Upstream Deficiencies Affecting the MC4R Pathway

AgRP, agouti-related protein; LEPR, leptin receptor; MC4R, melanocortin-4 receptor; MSH, melanocyte-stimulating hormone; ACTH, adrenocorticotropic hormone; PCSK1, proprotein convertase subtilisin/kexin-type 1; POMC, proopiomelanocortin. Reference: Yazdi FT et al. PeerJ. 2015;3:e856.

We are focused on developing our MC4R agonists, including our lead asset setmelanotide, as precision treatments for certain rare MC4R pathway diseases. In addition to acquired hypothalamic obesity, congenital hypothalamic obesity and PWS, we are evaluating setmelanotide for the treatment of obesity due to variants in a number of genes associated with the MC4R pathway. Setmelanotide has the potential to restore lost function in this pathway by activating the intact MC4R-expressing neuron downstream of the genetic impairment. In this way, we believe setmelanotide may act as restorative therapy, to restore lost signaling of the MC4R pathway.

Epidemiology Estimates of Rare MC4R Pathway Diseases

While obesity is a global epidemic, we are focused on rare MC4R pathway diseases. Impairment of the MC4R pathway is characterized by hyperphagia and rapid-onset obesity or the presence of early-onset, severe obesity. Of the tens of millions of individuals with obesity in the United States, the U.S. Center for Disease Control (CDC) estimates that there are approximately 5 million individuals whose severe obesity had onset between the ages of 2 and 5 years old. The tables below summarize the estimated prevalence for indications currently approved or under clinical investigation. These calculations rely on internal and proprietary sequencing data and current estimated responder rates to setmelanotide therapy, and they assume a U.S. population of 327 million, of which 1.7% have early-onset, severe obesity (Hales et al in JAMA – April 2018: Trends in Obesity and Severe Obesity Prevalence in US Youth and Adults by Sex and Age, 2007-2008 to 2015-2016).

Approved by the U.S. FDA and authorized by the EC and United Kingdom’s MHRAa

Estimated U.S. prevalence

Estimated European prevalence

Bardet-Biedl syndrome

4,000 – 5,000b

4,000 – 5,000b

Obesity due to POMC or LEPR deficiency caused by biallelic variants in the POMC, PCSK1 or LEPR gene

~600 – 2,500

Similar prevalence as U.S.c

a.Authorized by the EC and MHRA for use in patients 2 years of age and older. Approved by the FDA for use in patients 2 years of age and older with monogenic or syndromic obesity.

b.For BBS, prevalence estimates vary between populations, from 1 in 100,000 in northern European populations with higher prevalence rates in some additional regions throughout the world. We estimate the number of patients with BBS in the United States is between 4,000 and 5,000, with a similar number in continental Europe and the United Kingdom (UK). These estimates are based on our patient identification efforts in the United States and Europe and our proprietary genetic sequencing data, as well as our belief that BBS, like most rare diseases, is underdiagnosed. We believe the BBS health care provider network in EU member states and the UK is particularly well-established and more advanced than in the United States, and based on field work, we believe there are approximately 1,500 patients diagnosed and being cared for at academic centers in Europe. Applying these population-adjusted identified patient populations to the United States and other countries with comparable population genetics supports our epidemiology estimates.

c.For POMC or LEPR deficiencies, we estimate European prevalence is similar to the United States. While our sequencing data include patients from the United States and Europe, at the time, we did not have a comparable number of sequencing samples from European countries, and these estimates are therefore based on applying relative population percentages to the Rhythm-derived estimates described above.

Separately, in Canada, where IMCIVREE is approved for weight management in adult and pediatric patients 6 years of age and older with obesity due to BBS or biallelic POMC, PSCK1 or LEPR deficiency, we estimated at the time of our filing for approval with Health Canada that there are approximately 300 – 400 individuals with BBS. This was based on data on file, a range of prevalence estimates for BBS in Canada between 1 in 125,000 to 1 in 160,000, and a population in Canada of 38,929,902 as of July 1, 2022, according to StatsCan. Also, our prevalence estimate accounted for a reported founder effect in the province of Newfoundland, where estimated prevalence is approximately 1 in 17,500 (Forsythe E, Beales PL. Eur J Hum Genet. 2013;21(1):8-13). The prevalence of POMC, PCSK1, and LEPR deficiency obesity in Canada is not well characterized as very little data are available.

Setmelanotide currently being evaluated in Phase 3 trials

Estimated U.S. population

Estimated European population

Acquired hypothalamic obesity

~10,000d

~10,000e

Congenital hypothalamic obesity

>1,000f

>1,000f

Obesity due to POMC insufficiency caused by heterozygous variants in the POMC or PCSK1 genes

6,000g

Similar prevalence as U.S. g

Obesity due to LEPR insufficiency caused by heterozygous variants in the LEPR gene

4,000 g

Similar prevalence as U.S. g

Obesity due to SRC1 deficiency caused by a variant in the NCOA1 gene (SRC1 deficiency obesity)

~20,000 g

Similar prevalence as U.S. g

Obesity due to SH2B1 deficiency caused by a variant in the SH2B1 gene or 16p11.2 deletion encompassing the SH2B1 gene (SH2B1 deficiency obesity)

~23,000 g

Similar prevalence as U.S. g

Setmelanotide currently being evaluated in Phase 2 trial

Prader-Willi syndrome

~20,000

~400,000 world wide

Obesity due a deficiency in the MC4R pathway caused by variants in the SEMA3 family, PHIP, TBX3 or PLXNA family

~65,300g,h

Similar prevalence as U.S.f

d.For acquired hypothalamic obesity in the United States, our internal Company estimates are based on reported incidence of hypothalamic obesity following craniopharyngioma and long-term survival rates, (Zacharia, et al., Neuro-Oncology 14(8):1070–1078, 2012. doi:10.1093/neuonc/nos142; and Muller, et al., Neuro-Oncology 17(7), 1029–1038, 2015 doi:10.1093/neuonc/nov044.)

e.Our European prevalence estimate for acquired hypothalamic obesity is limited to the EU4 (Germany, France, Spain, Italy), UK and the Netherlands. The total 2020 population estimates for the six key countries (EU4, the Netherlands, and UK) of 339,295,304 was used to reach a final prevalence of 0.1-0.3 in 10,000 patients. In addition, we estimate the prevalence of acquired hypothalamic obesity in Japan to be approximately 5,000 to 8,000 based on our review of tumor registries and claims data.

f.Epidemiology of congenital hypothalamic obesity is expected to be comparable between the United States and EU4 (Germany, France, Spain, Italy), United Kingdom and the Netherlands combined in the absence of specific regional data. Our internal Company estimate is driven mainly by septo-optic dysplasia (Garne, et al., European Journal of Medical Genetics 61(9):483–488, 2018. doi: 10.1016/j.ejmg.2018.05.010; and Cerbone, et al., EClinicalMedicine 19, 2020. doi: 10.1016/j.eclinm.2019.11.017.)

g.For patients with genetic variants of the MC4R pathway, the rarity and the genetic pathophysiology of our target indications means that there is no comprehensive patient registry or other method of establishing with precision the actual number of patients. As a result, we have had to rely on other available sources to derive clinical prevalence estimates for these monogenic indications. For the four rare MC4R pathway diseases we are studying on the Phase 3 EMANATE trial (POMC insufficiency, LEPR insufficiency, SRC1 deficiency and SH2B1 deficiency), we believe that the patient populations in continental Europe and UK are at least as large as those in the United States. While our sequencing data include patients from the United States and Europe, we do not have comparable sequencing data from European countries and these estimates are therefore based on applying relative population percentages to the Rhythm-derived estimates described above. Because the published epidemiology studies for these genetic deficiencies are based on relatively small population samples, and are not amenable to robust statistical analyses, it is possible that these projections may significantly under- or overestimate the addressable population. While our projected estimates of the aggregate total addressable population continue to expand with the addition of new genes, the addressable population faces the challenges of a rare disease population. As announced on December 6, 2023, during our ‘Update on MC4R Pathway Programs’ event for investors and analysts. U.S. prevalence estimates based on results from our URO genetic testing program with samples from more than 36,000 participants, classification of variants for pathogenic, likely pathogenic and 20% of VUS and applied to established estimate of approximately 5 million people in the United States with early-onset obesity; 1. van der Klaauw et al. Cell. 2019;176:729-742.e18. 2. Marenne et al. Cell Metab. 2020;31:1107-1119.e12. 3. Bamshad et al. Am J Hum Genet.1999;64:1550-1562. 4. Ackinci et al. J Clin Res Pediatr Endocrinol. 2019;11:341-349..i. Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi Syndrome. In: Adam MP, Bick S, Mirzaa GM, et al, eds. GeneReviews®. 1998:1-41. Updated December 5, 2024. Accessed December 10, 2025. https://www.ncbi.nlm.nih.gov/books/NBK1330/

Separately, there is a higher per-capita prevalence rate for hypothalamic obesity in Japan. We estimate the prevalence of acquired hypothalamic obesity in Japan to be approximately 5,000 to 8,000 based on our review of the literature, tumor registries and claims data. (https://doi.org/10.1038/s41572-022-00351- z).

Limitations of Current Therapies

Although drugs approved for general obesity potentially can be used in patients with obesity and rare MC4R pathway diseases, all currently available obesity products have limited efficacy and treat symptoms without addressing the underlying biology of MC4R impairment. For example, drugs which delay gastric emptying may cause a patient to feel full and eat less, but are also often associated with nausea and vomiting as a consequence of the delayed emptying. In the case of individuals with rare MC4R pathway diseases, these therapies also do not address the impaired signaling in this central

energy regulating pathway. Similarly, metabolic and bariatric surgery which has been shown to be quite effective in the general population with obesity, may be unsuccessful in patients with rare MC4R pathway diseases for the same reason.

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 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 α-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).

The chemical structure of setmelanotide is:

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. Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a life-threatening, ultra-rare orphan disease. BBS is a disease that causes hyperphagia and severe obesity beginning in early childhood, as well as vision loss, polydactyly, kidney abnormalities, and

other signs and symptoms. For patients with BBS, hyperphagia and obesity can have significant health consequences. BBS is part of a class of disorders called ciliopathies, or disorders associated with the impairment of cilia function in cells. Cilia are hair-like cellular projections that play a fundamental role in the regulation of several biological processes, including satiety signaling. Cilia dysfunction in the hypothalamus, including in the MC4R pathway, is thought to contribute to hyperphagia and obesity in BBS. BBS is a genetically heterogeneous disease that has been associated with mutations in 29 genes, to date. All result in a similar syndrome of clinical manifestations. Recent scientific studies identify deficiencies affecting the MC4R pathway as a potential cause of the hyperphagia and obesity associated with BBS, and demonstrate that an MC4R agonist can directly impact these symptoms.

Pivotal Phase 3 Clinical Trial Evaluating Setmelanotide in BBS

Approvals and marketing authorizations for BBS in the United States, the EU, the United Kingdom, and Canada were based on data from our pivotal Phase 3 clinical trial of setmelanotide in patients with BBS. As we 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. As previously disclosed, treatment with setmelanotide resulted in significant weight and hunger reductions after one year of treatment among patients with BBS. The primary endpoint was achieved by 32.3% (95% confidence interval (CI), 16.7%, 51.4%; p=0.0006) of patients ≥12 years old, all of whom were patients with BBS. Data highlights in patients with BBS (n=32) after 52 weeks of setmelanotide include:

•Fifteen (15) patients ≥18 years achieved a mean (SD) percent reduction in BMI of -9.1% (6.8%; 95% CI, −13.4%, −4.8%);

•Fourteen (14) patients <18 years achieved a mean (SD) change in BMI Z score of −0.8 (0.5; 95% CI, −1.0, −0.5), and 12 patients (85.7%) achieved ≥0.2-point reduction in BMI Z; and

•Fourteen (14) patients ≥12 years who reported hunger scores achieved reduction of -30.5% in maximal hunger score.

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

We 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. Therefore, we believe access to treatment earlier in life will lead to better outcomes for children. In 2023, we completed our 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.

These data were published in the peer-reviewed journal The Lancet Diabetes & Endocrinology in November 2024:

•83 percent of all patients (10 of 12) achieved ≥ 0.2 reduction in BMI-Z score from baseline to week 52;

•18 percent mean reduction from baseline in BMI at week 52 (N=12);

•3.04 mean reduction from baseline in BMI-Z score at week 52 (N=12); and

•The safety profile was consistent with past trials evaluating setmelanotide.

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

Acquired hypothalamic obesity is a rare disease characterized by accelerated and sustained weight gain caused by injury to the hypothalamic region which may impair MC4R pathway signaling leading to hyperphagia, decreased energy expenditure, and severe obesity. There is an urgent need for effective treatments, as current approaches - including lifestyle interventions and general obesity pharmacotherapy - have shown limited long-term effectiveness.

Acquired hypothalamic obesity occurs most frequently after hypothalamic damage resulting from craniopharyngioma or other intracranial tumor, traumatic brain injury, stroke, or surgical resection or radiation of brain tumors. Based on results from Phase 2 and Phase 3 trials evaluating setmelanotide to treat patients with acquired hypothalamic obesity and interactions with regulatory agencies in the United States, Europe and Japan, we anticipate receiving regulatory decisions regarding potential approval and marketing authorization for acquired hypothalamic obesity in 2026 and 2027.

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 (α-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, α-MSH levels are significantly reduced. Reduced serum α-MSH levels may suggest melanocortin pathway deficiency, which might explain obesity in these patients.

In 2025, the Phase 3 TRANSCEND trial evaluating setmelanotide for the treatment of acquired hypothalamic obesity met its primary endpoint with statistically significant and highly clinically meaningful results. This global, double-blinded, placebo-controlled, 52-week trial enrolled a primary cohort of 120 patients, an additional 11 supplemental patients and a further 12 patients in Japan and is believed to be the largest and longest study of its kind for this rare disease. Key results included:

•Patients on setmelanotide achieved a mean BMI reduction of 16.5% from baseline, compared to a 3.3% increase for placebo, resulting in a placebo-adjusted difference of 19.8% (p<0.0001);

•In adults (≥18 years), the placebo-adjusted BMI reduction was 19.2%; in patients younger than 18, it was 20.2%;

•80% of patients on setmelanotide achieved a BMI reduction of 5% or greater at 52 weeks;

•Eighty-three percent of patients achieved a 5% or greater reduction in BMI (≥18 years) or a BMI Z-score reduction of 0.2 or greater (<18 years);

•Patients 12 years and older experienced a placebo-adjusted mean change in weekly average daily maximal hunger score of -1.4 (p=0.003); and

•No new safety signals were observed; Setmelanotide was generally well tolerated, with the most common adverse events (>20% of participants) being nausea, vomiting, diarrhea, injection site reaction, skin hyperpigmentation, and headache.

Our regulatory submissions seeking label expansion for IMCIVREE to treat patients in acquired hypothalamic obesity in the United States and Europe currently are under review. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) goal date of March 20, 2026, an extension from the original assigned goal date of December 20, 2025. The FDA in October 2025 requested additional sensitivity analyses of clinical efficacy data from the Phase 3 pivotal trial in acquired hypothalamic obesity. No new data were requested. The additional information was deemed a ‘major amendment,’ which allows for additional time for the FDA to review. The major amendment did not include any information relating to the safety or manufacturing of setmelanotide. The EMA confirmed validation of our Type II variation submission to the Marketing Authorization Application (MAA) for setmelanotide for the same indication. The application review began on August 16, 2025, by the Committee for Medicinal Products for Human Use (CHMP), which will issue an opinion to the European Commission (EC) regarding potential approval.

In addition to the United States and Europe, we plan to seek marketing authorization in Japan for setmelanotide to treat patients with acquired hypothalamic obesity given the significant unmet need there. Our review of certain tumor registries and claims data in Japan point to a higher per-capita prevalence and incidence rate of this disease than in Europe and the United States. We estimate there are approximately 5,000 to 8,000 patients in Japan with acquired hypothalamic obesity. In January 2025, we announced that we completed enrollment in a supplemental cohort of 12 Japanese patients, which we added to our global Phase 3 trial in acquired hypothalamic obesity. We expect to read out topline results for these data from this Japanese cohort in March 2026. We plan to use efficacy and pharmacokinetic (PK) data from this cohort as part of our registration package seeking approval from Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). We aligned on this approach based on previous discussions with PMDA. In March 2025, we received orphan drug designation from Japan’s Ministry of Health, Labor and Welfare (MHLW) for setmelanotide as a treatment for acquired hypothalamic obesity.

The pivotal Phase 3 trial followed positive efficacy results from our 18-patient, 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 our open-label, long-term extension trial. 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. These data were published in the peer-reviewed journal The Lancet Diabetes & Endocrinology in April 2024. In this trial, we observed a consistent reduction in body weight and hunger in all adherent patients. Results demonstrated:

•89% (16 of 18) of patients achieved the primary endpoint;

•78% (14 of 18) of patients achieved a 10% or greater reduction in BMI at 16 weeks;

•Mean percent reduction in BMI was 15% from baseline;

•In pediatric patients (n=13), the mean (standard deviation (SD)) BMI Z score at Week 16 was 2.7 (1.3), a reduction of 1.3 (1.0) points from baseline; and

•Mean (SD) most hunger score at baseline was 6.6 (1.6), compared with 3.7 (2.5) at Week 16, for a reduction of –2.9 (2.3) points or 45% for patients ≥12 years of age (n=11).

The publication also included preliminary data from our long-term extension of the Phase 2 study . These data show patients with hypothalamic obesity (n=12) achieved 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.

Based on the efficacy data from the Phase 2 trial, setmelanotide was granted pre-marketing early-access authorization (AP1) for use in patients with hypothalamic obesity in France in 2023, a program which has provided real-world evidence supporting the potential efficacy of setmelanotide in this patient population. This approval was issued by the French National Agency for Medicines and Health Products Safety (ANSM) and the French National Authority for Health (HAS) under the AP1 program, which allows early access to innovative therapies prior to European regulatory approval when no alternative treatments exist, and a positive benefit-risk profile is recognized. In May 2025, physicians from Sorbonne University in Paris presented data from patients in the early-access programs in France at the first-ever Joint Congress between the European Society for Paediatric Endocrinology and the European Society of Endocrinology (ESPE-ESE). These presentations detailed real-world data from 30 patients with acquired hypothalamic obesity (10 patients younger than 18; 20 patients 18 or older) on setmelanotide therapy for up to nine months at 14 different treatment centers in France.

Of the 20 adult patients with acquired hypothalamic obesity treated with setmelanotide therapy in France:

•Across all patients, there was an overall -11.9% mean change in body mass index (BMI) from baseline at month 3;

•Ten (n=10) who reached month 6 on therapy achieved -19.2% mean change in BMI; and

•Eight (n=8) who reached month 9 on therapy achieved -23.0% mean change in BMI; and

•Adult patients reported meaningful decreases in hunger scores after 3 and 6 months of treatment with setmelanotide.

For pediatric patients with acquired hypothalamic obesity treated with setmelanotide, BMI z-score (a measure that represents standard deviations of a child’s BMI that corrects for age and sex) decreased from baseline at all timepoints analyzed. A clinically meaningful reduction in BMI z-score is defined as a ≥0.2-point reduction. Data from these pediatric patients include:

•Ten (n=10) pediatric patients who reached month 3 on therapy achieved a mean BMI z-score decrease of 0.3 from baseline;

•Seven (n=7) pediatric patients who reached month 6 on therapy achieved a mean BMI z-score decrease of 0.4 decrease from baseline; and

•Two (n=2) pediatric patients who reached month 9 on therapy achieved a mean BMI z-score decrease of 0.4 from baseline.

Congenital hypothalamic obesity

Congenital hypothalamic obesity is a rare disease caused by certain brain abnormalities that may impair the function of the MC4R pathway, which regulates satiety or food intake and energy expenditure. It is a severe, refractory obesity that is underdiagnosed and not widely understood with high unmet need as there are no approved treatment options. It is often associated with pituitary and hypothalamic dysfunction. Unlike acquired hypothalamic obesity – which is known to be caused by certain brain tumors and their treatment – there is little recognition and/or understanding of congenital hypothalamic obesity and its different causes, as the connection between the severe obesity and MC4R pathway in the hypothalamus may not be evident.

An impairment in the MC4R pathway can lead to reduced energy expenditure and hyperphagia and, consequently, severe obesity. Rare diseases that may cause congenital hypothalamic obesity include septo-optic dysplasia (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. We estimate the prevalence of congenital hypothalamic obesity to be in excess of 1,000 patients in the United States and in excess of 1,000 patients in Europe.

U.S. and European experts have highlighted an urgent, unmet medical need for therapeutic options for patients with congenital hypothalamic obesity, as none are approved for this heterogenous patient population. At French hospitals that are participating in the early-access program mentioned above, physicians have initiated setmelanotide therapy to treat several patients with congenital hypothalamic obesity. In May 2025 at the 32nd annual European Congress on Obesity (ECO), French physicians shared data from five patients with congenital hypothalamic obesity, including four patients who reached six months on setmelanotide therapy, as part of a broader presentation on hypothalamic obesity. Highlights included:

•Four (n=4) pediatric patients who reached month 3 on setmelanotide therapy achieved a mean BMI z-score decrease of -0.2 from baseline; and

•Three (n=3) pediatric patients who reached month 6 on setmelanotide therapy achieved a mean BMI z-score decrease of -0.4 from baseline; and

•One adult patient with congenital hypothalamic obesity achieved a -14.8% BMI reduction baseline at month 6 of setmelanotide therapy.

It was based on early case reports from French hospitals participating in the early-access program that led us to add a 34-week substudy, which is designed to evaluate setmelanotide in approximately 39 patients with congenital hypothalamic obesity aged 4 years and older as a protocol amendment to our ongoing Phase 3 trial evaluating setmelanotide in patients with acquired hypothalamic obesity. We anticipate completing enrollment in this substudy in congenital hypothalamic obesity, which is independent from the pivotal Phase 3 trial cohort in acquired hypothalamic obesity, in the second half of 2026.

Development of Setmelanotide as a Treatment for Prader-Willi Syndrome

In December 2025, we disclosed positive preliminary results from our ongoing, exploratory Phase 2 trial of setmelanotide in patients with PWS. Based on these preliminary results, we are pursuing development of both setmelanotide and RM-718, one of our two next-generation MC4R agonists, for PWS, a rare genetic disease 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 severe, constant hyperphagia with onset in early-mid childhood. There are currently 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.

While the underlying etiology of 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. Relevant mouse models recapitulate the hyperphagia phenotype seen in PWS (Polex-Wolf J et al 2018). Disruption of MAGEL2 expression, a gene within the PWS region, leads to defective leptin sensing in POMC neurons (Mercer et al. PLoS Genet. 2013;9:e1003207. 7. Pravdivyi et al. Hum Mol Genet. 2015;24:4276-4283). Interestingly, there was a potential efficacy signal in some patients with a MAGEL2 variant in our Phase 2 DAYBREAK trial (Ortiz et al 2024). Finally, patients with PWS may have a reduced response to leptin on POMC neurons and consequently reduced MC4R pathway activity (Miller 2020). 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 (https://pubmed.ncbi.nlm.nih.gov/27941249/). We believe setmelanotide, a potent MC4R agonist, has the potential to restore signaling and regulation of hunger, energy expenditure, and weight.

In 2016, we 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. We came to believe that this 2016 trial was too short, enrolled too few patients and used sub-optimal dosing levels of setmelanotide to be conclusive. Therefore, in early 2025, we initiated a new open-label, exploratory trial. We enrolled 18 patients with PWS aged 6-65 years old with a BMI ≥30 kg/m2 for patients ≥18 years of age or BMI ≥95th percentile for age and sex for patients younger than 18.

On December 11, 2025, we disclosed preliminary results that showed setmelanotide therapy demonstrated potential therapeutic benefit with BMI and hyperphagia reductions in patients with PWS at Month 3 (n=8) and Month 6 (n=5); Highlights from these preliminary results, as of a cut-off date of Nov. 14, include:

•Six (6) of 8 patients who reached Month 3 of setmelanotide therapy achieved BMI reductions from baseline;

•Three (3) of 5 patients who reached Month 6 of setmelanotide therapy achieved reductions in BMI, with two seeing deeper reductions versus Month 3 and one unchanged;

•Six (6) of 7 evaluable patients who reached Month 3 of setmelanotide therapy achieved meaningful reduction in Hyperphagia Questionnaire for Clinical Trials1 (HQ-CT) scores; one patient’s baseline and Month 3 HQ-CT score was 0, therefore not evaluable; and

•Safety and tolerability results have been consistent with setmelanotide’s well-established clinical profile.

The 52-week trial remains ongoing. Seventeen (17) of the 18 patients enrolled remain on active setmelanotide therapy. We anticipate announcing six-month results from 18 patients from the ongoing Phase 2 trial in the first half of 2026 and potentially advancing setmelanotide to a registrational trial for PWS. In addition, we have initiated a Part D arm in the Phase 1 trial of MC4R agonist RM-718 that will enroll up to 20 patients with PWS. We began screening patients with PWS for enrollment in December 2025, and we anticipate completing enrollment in the second half of 2026.

Clinical Development to Address Additional Genetically-caused MC4R Pathway Diseases

We also are advancing a broad clinical development program evaluating setmelanotide, and we are leveraging the largest known DNA database focused on obesity—with approximately 120,000 sequencing samples as of December 2025—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, and we believe setmelanotide has the potential to address the hyperphagia and severe obesity associated with these rare genetic 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. We anticipate reading out topline data from this trial in March 2026.

POMC, PCSK1 and LEPR are core genes of the MC4R pathway. Heterozygous variants in POMC, PCSK1 and LEPR have been associated with clinical obesity that may be due to MC4R pathway dysfunction. Obesity due to rare variants in the SRC1 gene is an autosomal dominant disorder that is characterized by early-onset severe obesity and hyperphagia, as SRC1 variants found in individuals with severe obesity significantly impaired leptin-induced POMC expression (Yang et al 2019, Nat Comm. 10, Article 1718). Specifically, SRC1 is a transcriptional coactivator that has links to both the leptin receptor and to POMC. When the leptin receptor is activated, SRC1 is activated through a cascade of events that then drives the expression of POMC. Individuals who have heterozygous loss-of-function variants in their SRC1 genes can have insufficient leptin receptor activation of the MC4R pathway as a result of decreased POMC expression. This decreases the amount of available MSH to activate the MC4R, consequently resulting in hyperphagia and obesity in these individuals. Obesity due to variants in the SH2B1 gene is a rare genetic disease that is characterized by early-onset severe obesity, hyperphagia, hyperinsulinemia, and reduced final height. SH2B1 variants can arise through either DNA variants in the SH2B1 gene or through chromosomal deletions (chromosome 16) that encompass the SH2B1 gene. In both cases, dysfunction/loss of only one copy of the SH2B1 gene is sufficient to give rise to obesity and hyperphagia. The SH2B1 protein has been shown to have direct links to the MC4R-pathway. Specifically, SH2B1 is an adapter protein that amplifies the signal coming through the leptin receptor. In individuals who carry heterozygote loss of function mutations in SH2B1 or a chromosomal deletion that removes the SH2B1 from the chromosome, individuals may have insufficient leptin receptor activity activation of their MC4R pathway. This gives rise to a well-documented form of severe early-onset obesity and hyperphagia.

Based on enrollment and our understanding of the variant classification associated with each of these four genes, we consider the two most encouraging substudies to be POMC and/or PCSK1 (n=79) and SH2B1 (n=121). 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), suggest 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 we would need to complete additional studies in order to seek regulatory approval for these genetic indications. We believe the SH2B1 and POMC/PCSK1 substudies are sufficiently enrolled and powered to seek registration, pending success. The primary endpoint for each substudy is the difference in mean percent change in BMI from baseline to 52 weeks in setmelanotide arm compared to placebo arm. We anticipate reporting topline data in the first quarter of 2026.

Proof of Concept Achieved in Exploratory Phase 2 Basket Study

In January 2021, we announced proof-of-concept data from our 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. We 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).

PPL HET Obesity (POMC, LEPR, PCSK1) highlights included:

•Overall, 12 of 35 patients (34.3%) achieved the primary endpoint. This full analysis includes six patients who withdrew early;

•Mean reduction from baseline in body weight over three months across all 35 patients was -3.7%, which includes both clinical responders and non-responders; and

•Among the 12 patients who achieved the primary endpoint (responder group), the mean reduction from baseline in body weight over three months was -10.1%.

In our analyses, we are 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 genetics of obesity remains an emerging field, the vast majority of variants in genes associated with the MC4R pathway are classified as VUS. Our 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.

•Patients with PPL HET obesity were stratified into three pre-specified cohorts by classification of their genetic variants according to ACMG guidelines;

•Four of eight patients (50.0%) with a pathogenic or likely pathogenic variant achieved greater than 5% weight loss over three months;

•Four of eight patients (50.0%) with the N221D variant of the PCSK1 gene achieved greater than 5% weight loss over three months; and

•Four of 19 patients (21.1%) with a variant of unknown significance (VUS) achieved greater than 5% weight loss over three months.

In September 2021, we presented updated interim data from the SRC1 and SH2B1 cohorts at the at the 59th Annual European Society for Paediatric Endocrinology (ESPE) Meeting. The data presented were based on an interim analysis of patients who completed 12 weeks of therapy. These presentations included analyses that showed setmelanotide

achieved clinically meaningful weight loss or BMI Z reduction in 30% (9 of 30) of study participants with obesity due to variants of the SRC1 gene and clinically meaningful weight loss or BMI Z reduction in 43% (15 of 35) of study participants with obesity due to variants of the SH2B1 gene, including 16p11.2 chromosomal deletions.

Specifically, in the SRC1 cohort, a total of 30 patients with obesity and deficiency in the SRC1 gene were enrolled in the full analysis set of this study. These patients had a mean BMI of 45.4 kg/m2 or BMI Z of 3.0 at baseline. Highlights of these data, as of a cut-off date of March 16, 2021, include:

•Nine of 30 (or 30%) of patients achieved a clinically meaningful response to setmelanotide at three months, as defined by weight loss of 5% or greater from baseline, or for patients under 18 years old, a reduction of at least 0.15 in BMI Z score:

◦In adult patients 18 years or older, six of 20 (or 30%) achieved 5% or greater weight loss at three months;

◦In patients younger than 18 years, three of 10 (or 30%) achieved a BMI Z reduction of 0.15% or more at three months.

•Across all enrolled patients, the mean overall weight loss from baseline to three months among patients 18 years and older (a sample of 20) was -4.0% (a standard deviation of 3.3%), and the mean overall BMI Z score reduction from baseline to three months among patients younger than 18 years (n=10) was -0.21 (a standard deviation of 0.23).

In addition, these interim data showed a clear separation between patients who responded to setmelanotide treatment at three months and those who did not:

•The mean body weight reduction for adult patients who responded (n= 6) was 7.9% (90% confidence interval (CI), −9.7 to −6.0), as compared to 2.3% (90% CI, −3.2 to −1.4) for adult patients who did not respond (a sample of 14);

•The mean BMI Z reduction for patients younger than 18 years who responded (n= 3) was 0.48 (90% CI, −0.95 to −0.01), as compared to 0.09 (90% CI, −0.11 to −0.07) for those who did not respond (n= 7).

In the SH2B1 cohort, a total of 35 patients with obesity and 16p11.2 deletions that include the SH2B1 gene or deficiency in the SH2B1 gene were enrolled in the full analysis set of this study. These patients had a mean BMI of 47.2 kg/m2 or BMI Z of 3.6 at baseline. Highlights of these interim data, as of a cut-off date of March 16, 2021, include:

•Fifteen of 35 (or 42.9%) of patients achieved a clinically meaningful response to setmelanotide at three months, as defined by weight loss of 5% or greater from baseline, or for patients under 18 years old, a reduction of at least 0.15 in BMI Z score:

◦In patients 18 or older, eight of 22 (or 36.4%) achieved 5% or greater weight loss at three months;

◦In patients younger than 18 years, seven of 13 (or 53.8%) achieved a BMI Z reduction of 0.15% or more at three months.

Across all enrolled patients, the mean overall weight loss from baseline to three months among patients 18 years and older (n= 22) was -3.1% (a standard deviation of 3.9%), and the mean overall BMI Z score reduction from baseline to three months among patients younger than 18 years (n= 13) was -0.15 (a standard deviation of 0.13). In addition, the interim data showed a clear separation between patients who responded to setmelanotide treatment at three months and those who did not:

•The mean body weight reduction for adult patients who responded (n= 8) was 7.2% (90% CI, −8.6 to −5.8), as compared to 0.8% (90% CI, −1.9 to 0.3) for adult patients who did not respond (n= 14);

•The mean BMI Z reduction for patients younger than 18 years who responded (n= 7) was 0.25 (90% CI, −0.29 to −0.21), as compared to 0.03 (90% CI, −0.08 to 0.02) patients younger than 18 years who did not respond (n= 7).

Consistent with prior clinical experience, setmelanotide was generally well tolerated in each of these rare genetic diseases of obesity as of the cutoff date. The most common treatment-emergent adverse events, or TEAEs, included mild injection site reactions, hyperpigmentation, and nausea and vomiting, which occurred early in the treatment course. There were no SAEs related to treatment with setmelanotide.

Phase 2 DAYBREAK trial

In 2024, we completed our Phase 2 DAYBREAK trial, a signal- finding study with a two-stage design, that successfully identified six cohorts of interest for further study. We believe the DAYBREAK trial was the most comprehensive Phase 2 trial ever initiated in rare MC4R pathway diseases. 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. We 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, we deemed the following genes or gene families to merit further study with MC4R agonism: SEMA3 family, PHIP, and TBX3 or PLXNA family.

On November 4, 2024, we presented topline data from the DAYBREAK trial at ObesityWeek® 2024 in San Antonio, Texas. Results from Stage 2 showed:

•A significantly higher proportion of patients in the setmelanotide arm achieved or maintained 5% BMI reduction from baseline through the end of Stage 2 compared with the placebo arm (84.4% vs. 29.4%, p=0.001); a -12.4% mean percent BMI reduction was observed for all patients (n=29) on continuous setmelanotide therapy of 40 weeks;

•Change in BMI between baseline and the end of stage 2 was variable between gene cohorts, with the most consistent pattern of response seen in patients with PHIP variants.

•Other encouraging responses were observed from the SIM1, MAGEL2, PLXNA(1-4), and SEMA3(A-G) genes; and

•Setmelanotide was well tolerated with no new safety concerns.

During our “Update on MC4R Pathway Program” event on December 6, 2023, we announced data from the Stage 1 open-label part of DAYBREAK, which demonstrated potential efficacy in patients in multiple genetically-defined cohorts. We presented data from the full analysis set for DAYBREAK, which included 164 patients. A total of 112 patients completed the 16-week Stage 1 of the Phase 2 trial, with 52 patients who discontinued. The rates of response from Stage 1 of the trial were:

•30% of patients (12 of 40) with variants in the SEMA3 gene cohort;

•35.6% of patients (16 of 45) with variants in the PLXNAs gene cohort;

•56.3% of patients (9 of 16) with variants in the PHIP gene cohort;

•40% of patients (2 of 5) with variants in the TBX3 gene cohort;

•30% of patients (3 of 10) with variants in the MAGEL2 gene cohort; and

•25% of patients (5 of 20) with variants in the SIM1 gene cohort.

For those who completed Stage 1, the rates of response of patients who achieved a BMI reduction of greater than 5% from a post-hoc analysis were:

•44.4% of patients (12 of 27) with variants in the PLXNs gene cohort;

•61.5% of patients (16 of 26) with variants in the SEMA3 gene cohort; and

•69.2% of patients (9 of 13) with variants in the PHIP gene cohort.

We believe these data and analyses from DAYBREAK provide valuable insight into the MCR4 pathway, and we will continue our work to better understand which gene variants have loss of function and maybe disease causing as opposed to those variants which are benign. We believe this work will allow us to identify more accurately patients who may respond to MC4R agonism. We may continue clinical development in these genetic indications with bivamelagon and/or RM-718.

Weekly Formulation of Setmelanotide

In collaboration with Camurus AB, or Camurus, we have 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. While we believe that this formulation may be more convenient and less burdensome than setmelanotide, which is a once-daily administration, for patients and their families, we have paused development in favor of advancing RM-718. In the event RM-718 shows positive efficacy and safety results, we will discontinue development of the weekly formulation of setmelanotide. Concurrently, we are engaging with applicable regulatory authorities to address the impact of our discontinuing development of the weekly formulation of setmelanotide, which was a component of our pediatric investigation plan, or PIP, in the EU (and the United Kingdom). In Q1 2025 we submitted a request to modify the PIP to remove elements related to the weekly formulation with agreement received in Q2 2025.

We have 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 our 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

Historically, clinical data with other MC4R therapies suggested that MC4R-mediated side effects may include changes in blood pressure and heart rate, increased erections in males, changes in libido and sexual function in females, and nausea and vomiting. It is noteworthy that the pattern of effects differed among each of the other MC4R therapies, underscoring the complex physiology of MC4R. With setmelanotide, there has been little, if any, evidence of blood pressure or heart rate changes, preliminarily supporting an important differentiation of setmelanotide from previous MC4R therapies. Monitoring for blood pressure and heart rate changes, as well as other potential adverse events, or AEs, is included in all setmelanotide clinical trials.

Because of these first generation MC4R therapy failures, the setmelanotide program employed an intensive preclinical screening program to assess clinical candidates for blood pressure and heart rate effects, along with efficacy. The cornerstone of this preclinical screening program was a significant investment in obese primate studies which validated setmelanotide as a promising compound for clinical development. Research supporting a unique mechanism of action of setmelanotide, compared to earlier MC4R agonists and the endogenous ligand MSH, was published in May 2018 in Nature Medicine.

Setmelanotide was generally well-tolerated in our 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.

Over the course of our clinical development program, a total of 1,073 patients who participated in our trials have received the daily or weekly formulation of setmelanotide, including 31 patients who had been on setmelanotide therapy for more than five years, as of November 24, 2025 (excluding commercial therapy):

Duration of Setmelanotide Therapy

Number of patients

<1 year

709

>1 year

364

>2 years

218

>3 years

126

>4 years

66

>5 years

31

Total

1,073

In the majority of our trials, we 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.

We 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.

Overall, the most common AEs reported among setmelanotide treated patients in our clinical trials have been skin hyperpigmentation, injection site reactions, nausea, headache, vomiting, diarrhea and decreased appetite.

Life Cycle Management and Pipeline Expansion

In addition to setmelanotide, we have two earlier-stage investigational MC4R agonists in clinical development, RM-718, formulated for weekly administration, and bivamelagon (formerly LB54640), an oral small molecule. These investigational assets were designed to be selective for the MC4R and MC1R functionally sparing (in order to not cause hyperpigmentation). In 2025, we made significant progress in each program, with bivamelagon achieving proof-of concept in a Phase 2 trial in hypothalamic obesity and RM-718 now being evaluated in a Phase 1/2 trial for both hypothalamic obesity and PWS. In addition, we are advancing potential candidates for CHI, a rare genetic disease.

Bivamelagon, an oral MC4R agonist

On January 4, 2024, we announced that we 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, and we believe the data generated to date suggests bivamelagon has the potential to address MC4R pathway diseases without hyperpigmentation or cardiovascular side effects. We believe our deep developmental experience and global commercial presence uniquely position us to develop this molecule with the goal of offering a portfolio of treatment options to patients struggling with hyperphagia and severe obesity enabling the treatment that is right for them.

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.

In July 2025, we announced that bivamelagon achieved statistically significant, clinically meaningful BMI reductions in patients with hypothalamic obesity in a placebo-controlled, Phase 2 trial. These results were consistent with BMI reductions achieved with setmelanotide therapy in similar patient populations in past trials. In the 14-week, double-blind, four-arm, placebo-controlled portion of the trial, bivamelagon achieved:

•-9.3% BMI reduction from baseline in the 600mg cohort (n=8) (p-value=0.0004);

•-7.7% BMI reduction from baseline in the 400mg cohort (n=7) (p-value=0.0002);

•-2.7% BMI reduction from baseline in the 200mg cohort (n=6) (p-value = 0.0180); and

•BMI for patients in the placebo cohort (n=7) increased by 2.2% over 14 weeks.

In a post-hoc analysis comparing the randomized Phase 2 results to results from prior setmelanotide trials, bivamelagon demonstrated BMI reductions consistent with BMI reductions achieved with setmelanotide therapy as observed in similar patient populations at comparable dosing durations. In this post-hoc comparison of the subset of setmelanotide patients who demonstrated study compliance and were not on concomitant glucagon-like peptide-1 (GLP-1) therapy (no patients who enrolled in the Phase 2 bivamelagon trial were on concomitant GLP-1 therapy), setmelanotide and bivamelagon achieved:

•-9.7% and -10.5% mean BMI reductions achieved in a pooled patient population (n=59; n=64) from Phase 2 and Phase 3 trials of setmelanotide therapy at 12 weeks and 16 weeks, respectively; as compared to:

•-8.8% and -10.1% mean BMI reductions achieved in patients (400mg n=6; 600mg n=7) at 14 weeks of bivamelagon therapy.

In addition, patients reported meaningful reductions in their ‘most’ hunger scores at 14 weeks on therapy compared to placebo, consistent with past setmelanotide trials and MC4R agonism. Patients in the 600mg (n=8) and 400mg (n=6) cohorts achieved a mean reduction greater than 2.8 points in their ‘most’ hunger scores measured on a 10-point scale at 14 weeks of bivamelagon therapy. Six patients in the 200mg arm achieved a mean reduction of 2.1 points in their ‘most’ hunger score, while patients on placebo therapy reported a mean increase of 0.8 points in their mean ‘worst’ hunger score.

Bivamelagon demonstrated safety and tolerability results consistent with MC4R agonism and mechanism of action during the placebo-controlled portion of the trial. During the placebo-controlled portion of the trial, one patient discontinued therapy due to a serious adverse event. The most common reported adverse events were episodes of diarrhea and nausea, the vast majority of which were mild or grade 1. There were reports of mild, localized hyperpigmentation from four patients, including one patient on placebo. A total of 27 patients completed the 14-week, placebo-controlled portion of the trial, and 26 of them transitioned into the open-label extension of the trial and remained in that portion of the trial, as of July 7, 2025.

With these results in hand, we plan to seek input from U.S. and EU regulatory authorities on a Phase 3 trial design to advance bivamelagon in acquired hypothalamic obesity. In addition, we are refining the formulation of bivamelagon potentially to improve tolerability ahead of initiating a Phase 3 trial. We anticipate initiating this Phase 3 trial to evaluate bivamelagon for the treatment of hypothalamic obesity in 2026.

RM-718, a next generation MC4R peptide agonist

Our 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 MC4R selective and MC1R functionally 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. We 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.

Our Phase 1/2 clinical trial of RM-718 remains ongoing. This 1 trial is a four-part study to evaluate safety, tolerability and PK. The study consists of Part A: single ascending doses (SAD) of RM-718 in healthy participants 18 to 55 years old with obesity; Part B: multiple ascending doses (MAD) of RM-718 in healthy participants 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.

In Parts C and D of this Phase 1/2 trial, we are evaluating RM-718 in patients with hypothalamic obesity and PWS, respectively. In Part C, we plan to enroll up to 30 patients with acquired hypothalamic obesity for 16 weeks, and patients may continue on therapy for up to 52 weeks. We anticipate completing enrollment in Part C of this trial in the first quarter of 2026. For Part D, we plan to enroll up to 20 patients with PWS. We began screening patients with PWS for enrollment in December 2025, and we anticipate completing enrollment in the second half of 2026.

Nonclinical studies of RM-718 demonstrated significant and stable reduction of body weight (-12.9%) and body weight gain, reduced food, and water consumption (~ -25%) and improvement in insulin sensitivity without any pharmacological effects on the cardiovascular and respiratory systems. Studies in rodents (diet induced obese rats and mice including obese Zucker rats and Sprague Dawley rats) also demonstrated that RM-718 suppressed food intake and weight gain.

Nonclinical toxicology studies of RM-718 administered for 28 days were conducted in rats and cynomolgus monkeys with doses up to 30 mg/kg. RM-718 was well tolerated in rats and monkeys, with no evidence of systemic toxicity. RM-718-related clinical observations of hyperpigmentation of skin on the muzzle in monkeys were rare (observed in only one monkey at the 30 mg/kg dose). Microscopic analysis showed minimal to moderate increased pigment of the epidermis of the skin of the muzzle at ≥10 mg/kg/doses, and we believe this result is probably species-specific and the result of MC1R stimulation. We believe completed chronic toxicology studies in non-human primates (NHP) and rats (39 and 26 weeks, respectively) support long-term dosing in patients.

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, we completed the acquisition of Xinvento B.V., or Xinvento, a Dutch private limited liability company based in the Netherlands, through our wholly-owned subsidiary Rhythm Pharmaceuticals Netherlands B.V., a Dutch private limited liability company. Xinvento was founded in 2021 to identify and develop novel investigational therapeutic candidates designed to improve the care of patients and families living with CHI.

CHI is a rare disease that we believe is well aligned with our corporate strategy and broadens our focus into an adjacent endocrine indication with a high unmet need. CHI is the most frequent cause of severe, random and persistent hypoglycemia in newborns and children. Hypoglycemia results from an over-secretion of insulin, which causes blood sugar levels to fall dangerously low. Without proper and immediate treatment, patients with CHI may suffer seizures, coma, or

even death and, longer term, children may experience developmental delays, epilepsy, cerebral palsy, and other neurological damage. Available treatments are suboptimal in terms of safety, tolerability and effectiveness. Patient and family surveys conducted by Congenital Hyperinsulinism International, a global patient advocacy organization, demonstrate that hypoglycemic (low blood sugar) levels are occurring one or more times per day in 48% of patients, and up to once a week in an additional 20% of patients, in each case, despite being on standard of care. In the United States, the estimated incidence rate for CHI is 1:29,000 to 1:31,000, according to the literature. With the acquisition, Rhythm acquired a suite of assets designed to treat patients with this disease. In our CHI Program, we are focused on identifying and nominating a development candidate to advance into IND-enabling studies. We anticipate nominating a development candidate in 2026.

Genetic Sequencing and Patient Finding

We continue to expand our 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. Our obesity DNA database contains sequencing data from approximately 120,000 individuals, as of December 31, 2025. Our 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.

More than 90% of our DNA sequencing database is derived from the U.S. population. Therefore, our estimates of patient populations in Canada and Europe are more preliminary, but we believe the prevalence of these genetic diseases in Canada and Europe are similar to those in United States. By bringing additional awareness to these rare genetic diseases of obesity, our sequencing efforts have the potential to help foster patient communities and drive medical action in these populations.

URO, our 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 we collect sequencing samples and identify patients in the North America region. As obesity has reached epidemic levels in the United States, we are focused on identifying people with early-onset obesity that may be caused by certain rare genetic variants.

This program complements several initiatives designed to advance the understanding of genetic causes of severe obesity, and URO broadens these efforts and brings access to genetic testing into the community setting. Currently available physician-ordered genetic testing panels are often cost prohibitive, while many consumer genetic tests are incomplete when it comes to genetic disorders of obesity. This makes it difficult to confirm an underlying genetic cause of severe obesity. We believe the program marks an important step in the understanding of these disorders that might help patients and their families find new diagnosis and treatment strategies in the years ahead.

Our 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. We collect samples from individuals with severe obesity from seven countries, including Spain, Italy, Ireland, Israel, Turkey and Germany. Our partner CGC Genetics Unilabs conducts genetic testing for ROAD. This program covers the cost of the test, the kit and shipment.

As of the end of 2025, we have collected samples from approximately 120,000 individuals with severe obesity, primarily through our URO and ROAD programs, which now are our primary source of sequencing samples.

Commercial Efforts for IMCIVREE

We are focused on developing our global commercial infrastructure to make IMCIVREE available in as many markets as possible.

IMCIVREE, an MC4R agonist for which we hold 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.

We have achieved market access or named patient sales for IMCIVREE for BBS or POMC and LEPR deficiencies, or both, in more than 25 countries outside the United States, and we continue to collaborate with authorities to achieve access in additional markets. To date, we have had named patient sales in Austria, Greece, Russia, Switzerland and Turkey, among other countries.

Pending regulatory approvals, we anticipate launching IMCIVREE for acquired hypothalamic obesity in the United States in 2026, based on our FDA-assigned Prescription Drug User Fee Act (PDUFA) goal date of March 20, 2026. Regulatory review for our Type II variation submission is also ongoing in Europe. We anticipate disclosing topline data from a 12-patient Japanese cohort of our Phase 3 trial evaluating setmelanotide for acquired hypothalamic obesity in March 2026, and pending positive data, completing a new drug application submission in Japan. Regulatory decisions in Europe and Japan are anticipated later in 2026 or 2027.

While we are focused on commercial access for IMCIVREE, we are 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 often lost in the health care system, with limited educational resources and no effective treatments for their condition. All our 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.

Competition

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