Rhythm Pharmaceuticals Announces Oral MC4R Agonist Bivamelagon Achieved Statistically Significant, Clinically Meaningful BMI Reductions in Placebo-controlled Phase 2 Trial in Acquired Hypothalamic Obesity -- Bivamelagon

Rhythm Pharmaceuticals Announces Oral MC4R Agonist

Bivamelagon Achieved Statistically Significant, Clinically Meaningful BMI Reductions in Placebo-controlled Phase 2 Trial in Acquired Hypothalamic

-- Bivamelagon achieved BMI reductions in patients

with acquired hypothalamic obesity of -9.3% and -7.7% in 600mg and 400mg cohorts, respectively, at 14 weeks --

-- Post-hoc analysis showed BMI reductions in

bivamelagon trial were consistent with BMI reductions achieved by setmelanotide in past trials in similar patient populations --

-- Patients in both 600mg and 400mg cohorts

achieved mean reduction of -2.8 points in most hunger scores --

-- Limited instances of localized hyperpigmentation

-- Rhythm to request End-of-Phase 2 meeting

with U.S. FDA in order to pursue registrational path for bivamelagon in acquired hypothalamic obesity --

-- Company to host conference call today at

BOSTON, July 9, 2025 -- 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 its Phase 2 trial evaluating bivamelagon (formerly LB54640), an investigational

oral melanocortin-4 receptor (MC4R) agonist, in patients with acquired hypothalamic obesity. Bivamelagon achieved statistically significant

and clinically meaningful reductions in body mass index (BMI) at 14 weeks of treatment, consistent with BMI reductions achieved with setmelanotide

therapy in similar patient populations in past trials. Rhythm in-licensed bivamelagon from LG Chem, Ltd in January 2024.

In the 14-week, double-blind, four-arm, placebo-controlled portion

of the trial, bivamelagon achieved:

"We are excited by these results, which suggest bivamelagon has

the potential to treat patients with acquired hypothalamic obesity, and has established an appropriate dose range for future clinical

evaluation. Unlike in studies evaluating general obesity, once again we observed no placebo effect in this study," said David Meeker,

M.D., Chair, Chief Executive Officer and President of Rhythm Pharmaceuticals. "We look forward to engaging with U.S. and European

regulatory authorities to seek alignment on a Phase 3 trial design as we continue advancing bivamelagon."

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 GLP1 therapy (no patients who enrolled in the Phase 2 bivamelagon

trial were on concomitant GLP1 therapy), setmelanotide and bivamelagon achieved:

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'

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 (rectal bleeding). 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,

With these results in hand, Rhythm plans to seek input from U.S. and

EU regulatory authorities on a Phase 3 trial design to advance bivamelagon in acquired hypothalamic obesity. The Company plans to request

an End-of-Phase 2 meeting with the U.S. Food and Drug Administration (FDA) and to seek scientific advice from the Committee for Medicinal

Products for Human Use (CHMP) of the European Medicines Agency (EMA). Rhythm also is refining the formulation of bivamelagon potentially

to improve tolerability ahead of initiating a Phase 3 trial.

As previously announced, Rhythm will present results from this trial

in a poster accepted as a late-breaking abstract and data from Rhythm's pivotal Phase 3 TRANSCEND trial evaluating setmelanotide

in both a live oral presentation and a poster at The Endocrine Society's Annual Meeting (ENDO 2025) on July 12, 2025 in San

About the Bivamelagon Phase 2 Trial

The Phase 2 trial is a randomized, placebo-controlled, double-blind

study to assess efficacy and safety of bivamelagon (formerly LB54640) on safety, weight reduction, hunger, and quality of life in patients

12 years of age and older (n=28) with acquired hypothalamic obesity. In the randomized portion of the trial, patients took an oral daily

dose of either bivamelagon, low (200 mg), middle (400 mg), or high (600 mg), or placebo for 14 weeks. Patients may continue on therapy

in the open-label portion for up to 52 weeks.

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 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

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.

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,

Setmelanotide Indication

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.

Setmelanotide is not indicated for the treatment of patients

with the following conditions as setmelanotide would not be expected to be effective:

Prior serious hypersensitivity to setmelanotide or any of the excipients