Bardet-Biedl Syndrome

— Patients with acquired hypothalamic obesity on setmelanotide therapy (n=81) achieved mean BMI change of -16.5% compared with +3.3% for placebo (n=39) at 52 weeks (p<0.0001) — — -19.2% placebo-adjusted BMI reduction achieved in adult patients 18 years old and older (n=49) at 52 weeks — — -20.2% placebo-adjusted BMI reduction achieved in patients younger than 18 years old (n=71) at 52 weeks — — Regulatory submissions in the U.S. and EU anticipated to be completed in the third quarter of 2025 — — Company to host conference call today at 8 a.m. ET — BOSTON, MA, USA I April 07, 2025 I 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 positive topline results from the pivotal Phase 3 TRANSCEND trial evaluating setmelanotide, a melanocortin-4 receptor (MC4R) agonist, for the treatment of acquired hypothalamic obesity. The global trial met its primary endpoint with a statistically significant and highly clinically meaningful reduction in body mass index (BMI) with setmelanotide in both adult and pediatric patients versus placebo. Highlights from the topline data include: “Acquired hypothalamic obesity is a serious disease resulting from damage to the hypothalamus, often due to brain tumors or their treatment or certain other injuries resulting in accelerated weight gain, hyperphagia and reduction in energy expenditure. There is an urgent need for effective treatments as current approaches, including lifestyle interventions and pharmacotherapy intended for general obesity, have shown limited effectiveness in achieving long-term, durable weight loss,” said Susan Phillips, MD, pediatric endocrinologist at Rady Children’s Hospital-San Diego and professor of pediatrics at UC San Diego School of Medicine. “These data are highly clinically meaningful, offering hope that a new targeted therapy may become available for patients – both adults and children – living with acquired hypothalamic obesity.” The global Phase 3 TRANSCEND trial is believed to be the largest and longest placebo-controlled trial to evaluate a therapy for patients with acquired hypothalamic obesity. The double-blinded, 52-week trial enrolled 120 patients, randomized 2:1. In addition to the primary endpoint and other data points above, clinically meaningful improvements were observed across key secondary endpoints at week 52, including: No new safety signals with setmelanotide were observed, in line with setmelanotide’s well-established and well-understood safety profile. Consistent with prior clinical experience, setmelanotide was generally well tolerated in the TRANSCEND study. The most common treatment-emergent adverse events (affecting >20% of participants) were nausea, vomiting, diarrhea, injection site reaction, skin hyperpigmentation and headache. No serious adverse events leading to study discontinuation were reported. “This 12-month placebo-controlled trial required an incredible commitment from patients, their families and clinical staff for which we are extremely grateful. The highly clinically meaningful results from the TRANSCEND study potentially represent a transformational milestone for Rhythm,” said David Meeker, M.D., Chairman, President and Chief Executive Officer of Rhythm. “Given these compelling new efficacy data with setmelanotide in a broader patient population than in our Phase 2 trial, we are preparing to submit a supplemental New Drug Application to the FDA and a Type II variation request to the European Medicines Agency in the third quarter of 2025. These planned submissions could pave the way for setmelanotide to become the first-ever approved therapy for these patients. In addition, these strong results with an MC4R agonist increase our confidence in the development of our next-generation MC4R agonists, currently in ongoing Phase 1/2 clinical trials in acquired hypothalamic obesity.” Rhythm anticipates presenting full data from the TRANSCEND study at an upcoming medical meeting. Conference Call Information Rhythm Pharmaceuticals will host a live conference call and webcast at 8:00 a.m. ET today to discuss these clinical data. Participants may register for the conference call here . A webcast of the call will also be available under “Events and Presentations” in the Investor Relations section of the Rhythm Pharmaceuticals website at https://ir.rhythmtx.com/ . The archived webcast will be available on Rhythm Pharmaceuticals’ website approximately two hours after the conference call and will be available for at least 30 days following the call. About the Phase 3 TRANSCEND Trial The global, randomized, double-blind, placebo-controlled Phase 3 TRANSCEND trial evaluated the efficacy and safety of setmelanotide in patients with acquired hypothalamic obesity. A total of 120 patients age 4 years and older were randomized 2:1 to either a daily subcutaneous injection of setmelanotide (80 patients) or placebo (40 patients). The primary endpoint was mean percent change in body mass index (BMI) from baseline after 52 weeks of treatment. Secondary endpoints assess daily hunger, hyperphagia (extreme unsatisfied drive to consume food), weight, quality of life and safety and tolerability. A supplemental cohort of 12 Japanese patients remains ongoing with completion and topline data anticipated in the first quarter of 2026. About Acquired Hypothalamic Obesity Acquired hypothalamic obesity is a rare form of obesity that occurs following damage to the hypothalamic region of the brain, which includes the melanocortin-4 receptor (MC4R) pathway and is responsible for controlling physiological functions such as hunger and weight regulation. Acquired hypothalamic obesity most frequently follows the growth or surgical removal of craniopharyngioma, astrocytoma or other rare brain tumors. Additional causes of injury may include traumatic brain injury, stroke, or inflammation due to infection. Patients experience accelerated weight gain, a reduction in energy expenditure, and hyperphagia (a chronic pathological condition characterized by insatiable hunger, impaired satiety, and persistent abnormal food-seeking behaviors) leading to severe obesity within six to 12 months following tumor resection or other injury. Rhythm estimates there are 5,000 to 10,000 people living with hypothalamic obesity in the U.S., 5,000 to 8,000 people living with hypothalamic obesity in Japan, and 3,500 to 10,000 people living with hypothalamic obesity in the E.U. 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. Please see the full Prescribing Information for additional Important Safety Information. 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. SOURCE : Rhythm Pharmaceuticals

Treatment with Imcivree was associated with improvements in all primary and secondary endpoints in its TRANSCEND trial, prompting Rhythm to plan regulatory filings in the third quarter of this year. While pharma giants Novo Nordisk and Eli Lilly may have a solid hold on the obesity arena, Rhythm Pharmaceuticals is looking to corner a subset of the market with its Imcivree.About 5,000 to 10,000 people in the U.S. live with acquired hypothalamic obesity, or obesity that stems from damage to the part of the brain that controls hunger and weight regulation. Drugs meant for those with general obesity have shown “limited effectiveness” in providing long-term, durable weight loss for those with the rarer condition, pediatric endocrinologist Susan Philips, M.D., explained in an April 7 press release issued by Rhythm.Enter Imcivree (setmelanotide), a melanocortin-4 receptor (MC4R) agonist that was first approved in 2020 for patients six years and older with obesity due to rare genetic diseases proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR). Rhythm tested the drug in what is “believed to be” the largest and longest placebo-controlled study in those with acquired hypothalamic obesity, finding that Imcivree treatment prompted a mean BMI reduction of 16.5% from baseline, compared to a 3.3% BMI increase for those on placebo by week 52. Four out of five patients who took Imcivree cut down on their BMI by 5% or more, Rhythm said.The “highly clinically meaningful results” from the trial could represent a “transformational milestone for Rhythm,” CEO David Meeker, M.D. said in the release. The company is now gearing up to submit a regulatory bid for a label expansion with the FDA and the European Medicines Agency in the third quarter of this year, which could “pave the way for setmelanotide to become the first-ever approved therapy for these patients.”Rhythm plans to present full data from the trial at an upcoming medical meeting and is continuing to run the study in a supplemental cohort of 12 Japanese patients, with topline data expected in the first quarter of 2026. The results also serve to boost the company’s confidence in its next-generation MC4R agonists, which are currently being evaluated in ongoing phase 1/ 2 trials in acquired hypothalamic obesity, Meeker added. Outside of the U.S., Rhythm estimates that there are some 5,000 to 8,000 people who have the condition in Japan and about 3,500 to 10,000 in Europe. Hypothalamic obesity typically follows brain tumors or other brain injuries and manifests in accelerated weight gain, a decline in energy expenditure and hyperphagia, a pathological condition defined by insatiable hunger and abnormal food-seeking behaviors. After its initial approval, Imcivree picked up another nod in 2022 for adult and pediatric patients with obesity linked to another rare genetic disease, Bardet-Biedl syndrome. Late last year, the FDA expanded the drug’s use in its current indications to children as young as two. In 2024, Imcivree racked up sales of $130.1 million, a boost from 2023’s $77.4 million haul. An approval for hypothalamic obesity would be the first non-genetic disease population the drug is cleared to cover, marking a significant new opportunity for the drug. 

Rhythm Pharmaceuticals is looking to expand the potential market for its rare obesity treatment Imcivree beyond genetic disorders. The company said Monday the medicine reduced body weight in a late-stage trial of people with obesity associated with brain damage, laying the groundwork for regulatory filings later this year. Imcivree produced an average 16.5% drop in BMI from baseline in patients with acquired hypothalamic obesity, compared with a 3.3% increase for placebo. The result is statistically significant, according to a company release. Acquired hypothalamic obesity occurs when damage to the brain’s hypothalamus causes extreme hunger, reduced energy consumption and rapid weight gain. The damage can occur as a result of a brain tumor or injury. Standard weight loss drugs like GLP-1 agonists have “limited effectiveness” in helping patients lose and maintain their weight, Rhythm said. The Phase 3 TRANSCEND trial enrolled 120 adults and children with acquired hypothalamic obesity and followed them for 52 weeks. By the end of the study, 83% of patients treated with Imcivree saw a 5% or greater reduction in their BMI, according to the release. Rhythm said it plans to share the full data at an upcoming medical meeting. The biotech is also preparing for label expansion filings with the FDA and EMA in the third quarter. If it’s successful, Imcivree could become the first approved treatment for people with acquired hypothalamic obesity. The company estimates that there are 5,000 to 10,000 patients in the US and 3,500 to 10,000 in Europe. Imcivree, an MC4R agonist, secured its first FDA thumbs-up for three ultra-rare genetic disorders associated with excess weight back in 2020. Two years later, the drug won a label expansion for Bardet-Biedl syndrome. In 2024, it was approved to treat children as young as two . That same year, Imcivree hit sales of $130.1 million , up from $77.4 million in 2023.