Setmelanotide Acetate

iStock, Golden Sikorka After greenlighting 56 novel therapeutics in 2025, four notable applications continue to await the agency’s action after being delayed from the fourth quarter last year. After a 2025 campaign that saw the FDA approve 56 novel therapeutics for cancer, neurological, rare diseases and more, the agency faces six major catalysts in the first quarter of 2026—four of which are carryovers from the fourth quarter of last year. FDA approval and rejection rates were within historical norms, Jefferies analysts said in an investor note on Jan. 3, with the 46 Center for Drug Evaluation and Research nods trending down from 49 in 2024 and 10 Center for Biologics Evaluation and Research approvals remaining flat. The regulator issued 19 rejections in 2025, with 15 of those coming from CDER, according to Jefferies. While CDER’s total is par for the course, the 4 complete response letters from CBER are “higher than historical standards,” the analysts wrote. The PDUFA holdovers from Q4 2025 aren’t surprising given the FDA’s ontime approval rate has slipped recently. According to RBC Capital Markets’ 2026 RBC Global Biotech Outlook report, the FDA met its deadline around 75% of the time in the third and fourth quarters of 2025.” Here, BioSpace looks at the major regulatory deadlines to watch for as 2026 kicks off. Travere Seeks Filspari Expansion Into Rare Kidney Disease After securing full approval in IgA nephropathy (IgAN) in August 2024, Travere Therapeutics is looking to expand its endothelin blocker Filspari into the rare kidney disease focal segmental glomerulosclerosis (FSGS). The FDA’s decision is expected on Jan. 13. Affecting approximately seven people out of 1 million , FSGS is characterized by scarring at the kidney’s small blood vessel networks called glomeruli, in turn compromising the organ’s ability to filter waste out of the bloodstream. FSGS manifests as sudden weight gain, hypertension, swelling and, in severe cases, kidney failure. When left unchecked, FSGS can require emergency medical attention or become fatal. Travere’s answer to FSGS is Filspari, a small-molecule dual-blocker of the endothelin type A receptor and the angiotensin II type 1 receptor, both of which play a role in glomerular injury . The company initially pursued FSGS approval for Filspari in 2023, using data from the Phase III DUPLEX study , a double-blinded, parallel and active-controlled study with more than 370 participants. However, Filspari failed to significantly outperform Sanofi’s Avapro in terms of kidney function improvement, according to data published in November that year in The New England Journal of Medicine . The FDA in a Type C meeting said these data “are not sufficient to support an sNDA submission,” according to a December 2023 press release from Travere. In its updated filing, accepted by the regulator in May 2025 , Travere included findings from the Phase II DUET study, which found a more than twofold reduction in proteinuria—a key marker of liver damage—versus Avapro. If approved, Filspari would be the first drug in the U.S. specifically indicated for FSGS. REGENXBIO Gears Up for Hunter Syndrome Verdict After Delay The FDA was initially scheduled to render a decision on REGENXBIO’s biologics license application for Hunter syndrome gene therapy RGX-121 by Nov. 9, 2025. However, after the biotech filed additional information to support the BLA, the FDA in August last year pushed back the target action date to Feb. 8, 2026. At the time of the delay, the agency did not raise any issues with RGX-121’s data package nor identify any safety issues. RGX-121 is an adeno-associated virus vector–based therapy designed to deliver a functioning copy of the human iduronate-2-sulfatase gene into the central nervous system. In patients with Hunter syndrome, also known as mucopolysaccharidosis II , this gene is mutated, leading to a defect in the enzyme of the same name that under healthy conditions helps breakdown certain cellular waste molecules. As a result, patients with the disease develop its hallmark symptoms, such as developmental delays, growth abnormalities and abnormal accumulation of cerebrospinal fluid (CSF). RGX-121 is backed by data from the Phase I/II/III CAMPSIITE study, which in February 2024 demonstrated an 86% median decrease in a key disease biomarker, called DS26, in the CSF. DS26 concentrations in CAMPSIITE approached normal levels, REGENXBIO said at the time. Moreover, 80% of patients were able to stay off enzyme replacement therapy at the time of readout. If approved, RGX-121 would be the first one-time therapy that directly addresses the underlying genetic cause of Hunter syndrome, REGENXBIO said in its August 2025 news release. Ascendis Awaits Achondroplasia Decision for TransCon CNP Also hit with a delay late last year was Ascendis Pharma, which announced on Nov. 26 that the FDA had extended its review for achondroplasia drug TransCon CNP, also known as navepegritide, following a major amendment to the company’s application. A decision was originally scheduled for Nov. 30, 2025, but was pushed back to Feb. 28 this year. Affecting one in 15,000 to 40,000 newborns , achondroplasia qualifies as a rare disease but is also the most common cause of dwarfism. Achondroplasia is caused by a gain-of-function mutation in the FGFR3 gene, which weakens the activity of certain cells that are important for bone development. Lying along this pathway is a hormone called C-type natriuretic peptide (CNP), which promotes bone growth by countering the effect of FGFR3. Ascendis is looking to leverage this interaction with TransCon CNP, which helps bolster the level of this hormone in patients. Data from the Phase II ACcomplisH study, published in November 2023 in The Lancet , showed that TransCon CNP significantly improved annualized growth velocity by more than 1 cm per year on average as compared with placebo. If approved, TransCon CNP will go toe-to-toe with BioMarin’s Voxzogo, which in November 2021 became the first-ever drug approved for achondroplasia. TransCon CNP is expected to be a strong challenger to Voxzogo, prompting BioMarin in its Q3 earnings call last year to withdraw its earnings target of $4 billion by 2027—a decision driven mainly by competitive threats to the drug. Rare Diseases Ascendis Readies BioMarin Challenge in Achondroplasia While Others Search for Root Cause Therapies from industry leaders BioMarin and Ascendis Pharma supply a key hormone that promotes bone growth. In order to move the field forward, challengers are looking to address the underlying cause of the rare, genetic disease. October 13, 2025 · 7 min read · Tristan Manalac Rocket Sets for Launch of Kresladi in Rare Genetic Disorder On or before March 28, the FDA will render its decision on Rocket Pharmaceuticals’ Kresladi for the treatment of leukocyte adhesion deficiency-I (LAD-I). With at least 300 cases reported worldwide , LAD-I is a rare, genetic disorder that primarily affects children. It is characterized by a dysfunctional immune system, manifesting as recurrent and severe infections. The disease is often fatal. Kresladi addresses LAD-I by delivering a functional copy of the ITGB2 gene, which encodes a crucial surface protein found on immune cells. Pivotal Phase I/II data released in Oct. 2023 showed a 100% overall response rate 12 months after infusion. Rocket filed an application for FDA approval soon after but was rebuffed in June 2024 due to manufacturing concerns. The regulator accepted the company’s resubmission in October 2025. A LAD-I expansion for Kresladi would give Rocket a much-needed win after a series of stumbles and reorganizations last year. In May, the FDA placed a hold on the biotech’s Danon disease gene therapy RP-A501 after a patient died due to acute systemic infection. The hold was released a few months later. Then, in October, Rocket pulled its BLA for mozafancogene autotemcel, a gene therapy it was proposing for Fanconi anemia. The withdrawal was due to “business and strategic considerations,” the biotech said at the time, pointing to a prior restructuring initiative . Rhythm Looks To Retain Groove After Delayed Decision in Rare Obesity Rhythm Pharmaceuticals is looking to expand the label of its MC4 receptor agonist Imcivree to include acquired hypothalamic obesity, a severe and rare type of excessive weight gain tied to brain damage. The application is currently under extended FDA review, with a decision expected on March 20. The hypothalamus, found at the base of the brain, is responsible for regulating hormones, including those involved in appetite and metabolism. Injuries to the hypothalamus can dysregulate these activities, which in some cases can lead to obesity. Patients with this type of hypothalamic obesity often suffer from type 2 diabetes, fatty liver disease and sleep problems. Imcivree , administered via a subcutaneous injection, works by activating the MC4 receptor, which helps regulate hunger, satiety and energy expenditure. Data from the Phase III TRANSCEND study released in April last year showed Imcivree lowered body mass index by 16.5% at 52 weeks, versus a 3.3% gain in comparators taking placebo. This benefit, Stifel analysts said in an April 7 note to investors, “is outstanding in a highly difficult-to-treat patient population.” Imcivree was first approved in November 2020 for weight management in patients 6 years and older with obesity due to POMC, PCSK1 or LEPR deficiency, as confirmed by genetic testing. An expansion came in 2024, widening the age of applicability down to 2 years of age. Third Time the Charm for Aldeyra’s Dry Eye Disease Drug? Closing out this list is a drug that’s had a difficult regulatory road thus far: Aldeyra Therapeutics’ reproxalap, being proposed for the treatment of dry eye disease. An FDA review is ongoing and is set to end in a decision on or before March 16. Aldeyra has been trying to get FDA clearance for reproxalap since 2023. In November of that year, the regulator rejected the drug, noting that Aldeyra had failed to sufficiently establish reproxalap’s benefits on key symptoms of dry eye disease. At the time, the agency requested “at least one additional adequate and well-controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye.” In its resubmission, Aldeyra provided data from a late-stage dry eye chamber study , showing that reproxalap significantly improved patients’ comfort levels. The FDA was again unimpressed, handing out a second rejection in April last year. Aldeyra had “failed to demonstrate efficacy in adequate and well-controlled studies,” the regulator said at the time and asked for another study. Aldeyra filed another application in July 2025, buffing it up with data from “a single clinical trial that achieved the primary endpoint of reducing ocular discomfort.” The FDA was supposed to have released its verdict on Dec. 16, but asked for data from a field study that did not meet its primary endpoint. Topline findings in May 2025 were “ numerically supportive ” of reproxalap’s efficacy in dry eye disease, but failed to reach statistical significance. To give the regulator time to evaluate the submission, reproxalap’s review was extended by three months.

-- Q4 2025 preliminary net product revenues from global sales of IMCIVREE® (setmelanotide) of approximately $57 million for the fourth quarter of 2025, an 11% increase over Q3 2025 -- -- FY 2025 preliminary net product revenue of approximately $194 million, approximately 50% increase from FY2024 -- -- March 20, 2026 PDUFA goal date for sNDA for setmelanotide in acquired hypothalamic obesity -- -- On track to report topline data from 12-patient Japanese cohort of setmelanotide Phase 3 trial in acquired hypothalamic obesity in first quarter of 2026 -- -- On track to report topline data from Phase 3 EMANATE trial evaluating setmelanotide in genetically caused MC4R pathway diseases in first quarter of 2026 -- BOSTON, Jan. 09, 2026 (GLOBE NEWSWIRE) -- Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a global commercial-stage biopharmaceutical company focused on transforming the lives of patients living with rare neuroendocrine diseases, today announced preliminary unaudited net product revenues from global sales of IMCIVREE® (setmelanotide) for the fourth quarter and full year of 2025 and upcoming milestones. “2025 was a year of strong execution and reflects significant progress toward our mission of transforming the lives of patients with rare neuroendocrine diseases,” said David Meeker, M.D., Chairman, Chief Executive Officer and President of Rhythm. “Our preliminary fourth quarter and full-year 2025 net product revenues reflect consistent growth in both the United States and international markets, driven by a steady increase in patients on reimbursed therapy and continued progress in securing access to IMCIVREE.” Dr. Meeker continued, “Looking ahead, we are focused on delivering sustainable, long‑term growth as we prepare to launch IMCIVREE for patients with acquired hypothalamic obesity (HO) in the United States, pending FDA approval. Additionally in 2026, we are excited about top-line data readouts from the Japanese cohort of our Phase 3 trial in acquired HO and the Phase 3 EMANATE trial, initiating a Phase 3 trial to evaluate our oral MC4R agonist, bivamelagon, in acquired HO and advancing setmelanotide and RM-718 for patients with Prader-Willi syndrome.” Preliminary Unaudited Fourth Quarter and Full Year 2025 Net Product Revenues Based on preliminary unaudited financial information, Rhythm expects net product revenues from global sales of IMCIVREE to be approximately $57 million for the fourth quarter of 2025, an increase of 11% percent on a sequential basis from the third quarter of 2025. Net product revenues for the full year of 2025 are expected to be approximately $194 million, compared to $130 million for the full year of 2024, an increase of approximately 50% year over year. U.S. sales of IMCIVREE contributed approximately 68% of fourth quarter preliminary unaudited net product revenues and approximately 69% of full-year 2025 preliminary unaudited net product revenues. The Company plans to report its fourth quarter and full year 2025 financial results in late February 2026. Anticipated Upcoming Milestones Setmelanotide Acquired Hypothalamic Obesity (HO) Launch IMCIVREE in the United States for the treatment of acquired hypothalamic obesity pending FDA approval; the FDA’s assigned PDUFA goal date is March 20, 2026; Announce topline data in the 12-patient Japanese cohort of the setmelanotide Phase 3 trial in acquired HO in the first quarter of 2026. Congenital HO Complete enrollment in the setmelanotide Phase 3 trial substudy in congenital HO in the first half of 2026. Genetically Caused MC4R Pathway Diseases Announce topline data in the Phase 3 EMANATE trial evaluating setmelanotide in genetically caused MC4R pathway diseases in the first quarter of 2026. Prader-Willi Syndrome (PWS) In December 2025, Rhythm announced positive preliminary data for the exploratory phase 2 trial of setmelanotide in patients with PWS that showed BMI and hyperphagia reductions at month 3 and month 6, as well as safety and tolerability consistent with setmelanotide’s well-established clinical profile. Rhythm anticipates announcing six-month results from 18 patients from the ongoing Phase 2 trial in the first half of 2026. Bivamelagon Pending further feedback from U.S. and European regulatory agencies, initiate a pivotal Phase 3 trial evaluating bivamelagon in acquired HO in 2026. RM-718 Complete enrollment in the Phase 1, Part C trial evaluating the weekly, MC4R agonist RM-718 in patients with acquired HO in the first quarter of 2026. Financial Disclosure Advisory This release contains certain estimated preliminary financial results for the fourth quarter and fiscal year ended December 31, 2025. These estimates are based on the information available to the Company at this time. The Company’s financial close process for the fourth quarter and full year 2025 is not yet complete and, as a result, actual results may vary from the estimated preliminary results presented here. The estimated preliminary financial results have not been audited or reviewed by the Company’s independent registered public accounting firm. These estimates should not be viewed as a substitute for the Company’s full interim or annual financial statements. Accordingly, you should not place undue reliance on this preliminary data. About Rhythm Pharmaceuticals Rhythm is a commercial-stage biopharmaceutical company committed to transforming the lives of patients and their families living with rare neuroendocrine diseases. Rhythm’s lead asset, IMCIVREE® (setmelanotide), an MC4R agonist designed to treat hyperphagia and severe obesity, is approved by the U.S. Food and Drug Administration (FDA) to reduce excess body weight and maintain weight reduction long term in adult and pediatric patients 2 years of age and older with syndromic or monogenic obesity due to Bardet-Biedl syndrome (BBS) or genetically confirmed pro-opiomelanocortin (POMC), including proprotein convertase subtilisin/kexin type 1 (PCSK1), deficiency or leptin receptor (LEPR) deficiency. Both the European Commission (EC) and the UK’s Medicines & Healthcare Products Regulatory Agency (MHRA) have authorized setmelanotide for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 2 years of age and above. Additionally, Rhythm is advancing a broad clinical development program for setmelanotide in other rare diseases, as well as investigational MC4R agonists bivamelagon and RM-718, and a preclinical suite of small molecules for the treatment of congenital hyperinsulinism. Rhythm’s headquarters is in Boston, MA. Setmelanotide Indication In the United States, setmelanotide is indicated 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 Bardet-Biedl syndrome (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). In the European Union and the United Kingdom, setmelanotide is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed BBS or loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 2 years of age and above. In the European Union and the United Kingdom, setmelanotide should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology. Limitations of Use Setmelanotide is not indicated for the treatment of patients with the following conditions as setmelanotide would not be expected to be effective: Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign Other types of obesity not related to BBS or POMC, PCSK1, or LEPR deficiency, including obesity associated with other genetic syndromes and general (polygenic) obesity Contraindication Prior serious hypersensitivity to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. WARNINGS AND PRECAUTIONS Disturbance in Sexual Arousal: Spontaneous penile erections in males and sexual adverse reactions in females have occurred. Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention. Depression and Suicidal Ideation: Depression, suicidal ideation and depressed mood have occurred. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors, or clinically significant or persistent depression symptoms occur. Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have been reported. If suspected, advise patients to promptly seek medical attention and discontinue IMCIVREE. Skin Hyperpigmentation, Darkening of Pre-existing Nevi, and Development of New Melanocytic Nevi: Generalized or focal increases in skin pigmentation, darkening of pre-existing nevi, development of new melanocytic nevi and increase in size of existing melanocytic nevi have occurred. Perform a full body skin examination prior to initiation and periodically during treatment to monitor pre-existing and new pigmented lesions. Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants: IMCIVREE is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol preserved drugs. ADVERSE REACTIONS Most common adverse reactions (incidence ≥20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection. USE IN SPECIFIC POPULATIONS Treatment with IMCIVREE is not recommended when breastfeeding. Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus. To report SUSPECTED ADVERSE REACTIONS, contact Rhythm Pharmaceuticals at +1 (833) 789-6337 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. See section 4.8 of the Summary of Product Characteristics for information on reporting suspected adverse reactions in Europe. Please see the full Prescribing Information for additional Important Safety Information. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding our preliminary, unaudited revenues for the fourth quarter and full year 2025; the safety, efficacy, potential benefits of, and clinical design or progress of any of our products or product candidates at any dosage or in any indication, including, setmelanotide, bivamelagon, and RM-718; the potential use of setmelanotide in patients with acquired hypothalamic obesity; the commercial growth of IMCIVREE; our expectations surrounding potential regulatory submissions, progress, or approvals and timing thereof for any of our product candidates; the estimated market size and addressable population for our drug products, including setmelanotide for the treatment of hypothalamic obesity; the future announcement of data from our ongoing clinical trials, including the Japanese cohort of our Phase 3 trial evaluating setmelanotide for patients with acquired hypothalamic obesity, the substudy evaluating setmelanotide for patients with congenital hypothalamic obesity, the Phase 3 EMANATE trial evaluating setmelanotide in genetically caused MC4R pathway diseases; Part C of the Phase 1 trial evaluating RM-718, and the open-label Phase 2 trial evaluating setmelanotide in patients with Prader-Willi syndrome; the ongoing enrollment in our clinical trials; and the timing of any of the foregoing. Statements using words such as “expect”, “anticipate”, “believe”, “may”, “will” and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to, our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the impact of competition, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, risks associated with the laws and regulations governing our international operations and the costs of any related compliance programs, our ability to successfully commercialize setmelanotide, our liquidity and expenses, our ability to retain our key employees and consultants, and to attract, retain and motivate qualified personnel, and general economic conditions, and the other important factors, including those discussed under the caption “Risk Factors” in Rhythm’s Quarterly Report on Form 10-Q for the three months ended September 30, 2025 and our other filings with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this press release or to update them to reflect events or circumstances occurring after the date of this press release, whether as a result of new information, future developments or otherwise. Corporate Contact: David Connolly Head of Investor Relations and Corporate Communications Rhythm Pharmaceuticals, Inc. dconnolly@rhythmtx.com Media Contact: Layne Litsinger Real Chemistry llitsinger@realchemistry.com Source: Rhythm Pharmaceuticals, Inc.