Rhythm Pharmaceuticals Announces Topline Results from Phase 3 EMANATE Trial

Rhea-AI Summary

Rhythm Pharmaceuticals (Nasdaq: RYTM) reported topline Phase 3 EMANATE results: the four genetic substudies did not meet prespecified primary endpoints for placebo-adjusted BMI change at Week 52.

Post hoc LOCF analyses showed statistically significant BMI reductions in POMC/PCSK1 Hets (−5.5%, p=0.0010) and SRC1 (NCOA1) (−6.2%, p<0.0001). No new safety signals were observed. A conference call was scheduled for 4:30 p.m. ET on March 16, 2026.

Positive

• Post hoc BMI −5.5% in POMC/PCSK1 Hets (LOCF, p=0.0010)
• Post hoc BMI −6.2% in SRC1 (NCOA1) (LOCF, p<0.0001)
• No new safety signals observed versus prior studies

Negative

• All four EMANATE substudies failed prespecified primary endpoints at Week 52
• Primary endpoint placebo-adjusted BMI reductions were not statistically significant

  0.05)

News Market Reaction – RYTM

-3.13%

2 alerts

-3.13% News Effect

-4.5% Trough Tracked

-$200M Valuation Impact

$6.18B Market Cap

2K Volume

On the day this news was published, RYTM declined 3.13%, reflecting a moderate negative market reaction. Argus tracked a trough of -4.5% from its starting point during tracking. Our momentum scanner triggered 2 alerts that day, indicating moderate trading interest and price volatility. This price movement removed approximately $200M from the company's valuation, bringing the market cap to $6.18B at that time.

Data tracked by StockTitan Argus on the day of publication.

Key Figures

POMC/PCSK1 Hets cohort size: 78 patients LEPR Hets cohort size: 23 patients SRC1 cohort size: 73 patients +5 more

8 metrics

POMC/PCSK1 Hets cohort size 78 patients EMANATE Phase 3 POMC/PCSK1 heterozygous substudy

LEPR Hets cohort size 23 patients EMANATE Phase 3 LEPR heterozygous substudy

SRC1 cohort size 73 patients EMANATE Phase 3 SRC1 (NCOA1) substudy

SH2B1 cohort size 121 patients EMANATE Phase 3 SH2B1 substudy

POMC/PCSK1 BMI change (LOCF) -5.5% BMI difference (p=0.0010) Post hoc LOCF analysis at Week 52, modified ITT

SRC1 BMI change (LOCF) -6.2% BMI difference (p<0.0001) Post hoc LOCF analysis at Week 52, modified ITT

POMC/PCSK1 completer BMI change -9.7% BMI reduction (p=0.0002) Post hoc analysis, genetically confirmed Week 52 completers

SRC1 completer BMI change -8.0% BMI reduction (p=0.0158) Post hoc analysis, genetically confirmed Week 52 completers

Market Reality Check

Price: $87.68 Vol: Volume 189,359 is well be...

low vol

$87.68 Last Close

Volume Volume 189,359 is well below the 20-day average of 795,763 (relative volume 0.24). low

Technical Price 87.38 is trading below the 200-day MA at 95.68 and 28.49% under the 52-week high.

Peers on Argus

RYTM is up 2.13% while key biotech peers ABVX, LEGN, AXSM, CYTK and NUVL show de...

RYTM is up 2.13% while key biotech peers ABVX, LEGN, AXSM, CYTK and NUVL show declines between -0.64% and -3.73%, indicating stock-specific dynamics rather than a sector-wide move.

Previous Clinical trial Reports

5 past events · Latest: Dec 11 (Positive)

Same Type Pattern 5 events

Date	Event	Sentiment	Move	Catalyst
Dec 11	Phase 2 PWS data	Positive	+12.3%	Positive exploratory Phase 2 efficacy and safety data in Prader-Willi syndrome.
Dec 10	PWS data preview	Positive	+12.3%	Announcement of upcoming preliminary Phase 2 PWS data and conference call details.
Mar 19	Orphan designation Japan	Positive	-1.8%	Orphan drug designation for hypothalamic obesity in Japan with sizable rare population.
Nov 13	Phase 3 pediatric data	Positive	-0.5%	Published Phase 3 VENTURE results showing strong BMI and hunger improvements in children.
Jul 23	Phase 2 HO start	Neutral	+0.0%	First patients dosed in Phase 2 trial of oral MC4R agonist LB54640 in hypothalamic obesity.

Pattern Detected

Clinical and regulatory updates for setmelanotide have often been positive, but price reactions have been mixed, with several strong rallies on favorable data and some instances where upbeat announcements were followed by modest declines.

Recent Company History

Over recent years, Rhythm has repeatedly highlighted progress for setmelanotide in rare obesity indications. Prior clinical-trial news includes positive Phase 3 results in young children, exploratory efficacy signals in Prader-Willi syndrome, and orphan drug designation in Japan with estimated patient populations in the low thousands. Earlier-stage pipeline work, such as first dosing in a Phase 2 MC4R agonist trial, underscores a broad MC4R strategy. Today’s EMANATE topline results add another key data point within this ongoing clinical-development arc.

Historical Comparison

+4.5% avg move · Past clinical-trial headlines for RYTM moved the stock by an average of 4.46%. Today’s Phase 3 EMANA...

clinical trial

+4.5%

Average Historical Move clinical trial

Past clinical-trial headlines for RYTM moved the stock by an average of 4.46%. Today’s Phase 3 EMANATE topline, with missed primary endpoints but post hoc BMI signals, fits into a history of nuanced clinical readouts.

Clinical updates trace a path from initial Phase 2 and Phase 3 successes in rare genetic obesities and hypothalamic obesity through orphan designations and pediatric data, now extending to EMANATE’s multi-gene Phase 3 results and informing next-generation MC4R agonist development.

Regulatory & Risk Context

Active S-3 Shelf · $200,000,000

Shelf Active

Active S-3 Shelf Registration 2026-02-26

$200,000,000 registered capacity

An effective S-3ASR shelf filed on 2026-02-26 registers resale of 2,395,831 common shares issuable upon preferred conversion and allows the company to sell up to $200,000,000 of common stock via an at-the-market agreement with TD Securities (USA) LLC from time to time.

Market Pulse Summary

This announcement details topline Phase 3 EMANATE results, where four substudies did not meet primar...

Analysis

This announcement details topline Phase 3 EMANATE results, where four substudies did not meet primary endpoints but post hoc analyses showed meaningful BMI reductions in specific genetic groups. Prior clinical news for setmelanotide has often moved the stock by around 4.46%, underscoring how pivotal such data can be. Investors may focus on how these findings guide next‑generation MC4R agonist development, future trial designs, and any subsequent regulatory or pipeline updates.

Key Terms

phase 3, randomized, double‑blind, placebo‑controlled, +4 more

8 terms

phase 3 medical

"The four substudies of this global, Phase 3 trial evaluating setmelanotide"

Phase 3 is the late-stage clinical testing step for a new drug or medical treatment, where the product is given to large groups of patients to confirm effectiveness, monitor side effects, and compare it to standard care. Successful Phase 3 results are often the final scientific hurdle before regulators decide on approval and market launch—like passing a final exam before graduation—and can sharply change a company's valuation and future revenue prospects.

randomized medical

"EMANATE was a global, randomized, double‑blind, placebo‑controlled Phase 3 trial"

Randomized means participants or units in a study are assigned to different groups by chance rather than by choice, like flipping a coin to decide who gets a new treatment and who gets a comparison. For investors, randomized designs matter because they reduce bias and make results more trustworthy, so outcomes from randomized studies carry more weight when assessing regulatory approval, commercial prospects, and the risk that trial results will change a company’s valuation.

double‑blind medical

"global, randomized, double‑blind, placebo‑controlled Phase 3 trial"

A double‑blind trial is a medical study setup in which neither the participants nor the people administering the treatment know who is receiving the active therapy and who is getting a placebo or alternative. Think of it like a blind taste test where both tasters and servers are kept in the dark to prevent bias. For investors, double‑blind results are more reliable because they reduce the chance that expectations or behavior influenced the outcome, making efficacy and safety claims more credible.

placebo‑controlled medical

"global, randomized, double‑blind, placebo‑controlled Phase 3 trial"

A placebo-controlled study compares a real treatment to an inactive substitute (a placebo) so researchers can tell if the treatment actually works beyond the power of expectation or chance. For investors, placebo-controlled results matter because they provide a clearer signal about a drug or therapy’s true effectiveness and safety—think of it as A/B testing for medicine, where reliable A/B results reduce uncertainty about future regulatory approval and commercial value.

modified intent-to-treat medical

"analyzed in the modified intent-to-treat (ITT) population using prespecified"

A modified intent-to-treat (mITT) population is a version of a clinical trial analysis that includes most but not all people who were originally randomized, typically excluding those who never received the study treatment or lacked key baseline data. For investors, mITT matters because it can change how effective or safe a drug appears compared with a strict all-randomized analysis; thinking of it like judging a recipe only from cooks who actually made the dish helps explain how the choice of who is counted can shift results and influence regulatory and market reactions.

treatment-emergent adverse events medical

"The most common treatment-emergent adverse events included skin hyperpigmentation"

Events or symptoms that either appear for the first time or get worse after a patient starts a treatment; think of new or intensified side effects that show up once medicine or a medical device is used. Investors watch these closely because they affect whether a therapy can gain regulatory approval, be prescribed widely, or face legal and commercial setbacks—similar to how early customer complaints can sink a new product’s prospects.

post hoc analyses medical

"According to post hoc analyses based on last observation carried forward"

Analyses performed after the main study results are known to explore patterns or generate new ideas rather than to test a predefined hypothesis. Like looking back over a travel route to spot interesting detours, these checks can suggest additional benefits or risks but are more likely to be misleading and need confirmation in new, planned studies. Investors should treat post hoc findings as tentative signals that can influence expectations but carry higher uncertainty and regulatory scrutiny.

last observation carried forward medical

"post hoc analyses based on last observation carried forward (LOCF) for missing values"

Last observation carried forward is a method used in clinical studies to fill in missing follow-up measurements by repeating a patient’s most recent recorded value for later time points. For investors, it matters because this way of handling missing data can make a drug or treatment look more or less effective depending on who drops out, so understanding its use helps assess how reliable reported trial results and related financial claims are—like trusting a map that holds your last GPS point when the signal drops.

AI-generated analysis. Not financial advice.

-- Four substudies did not meet pre-specified primary endpoints -- 

-- Post hoc analyses show setmelanotide achieved statistically significant BMI reductions in patients with obesity due to a heterozygous variant of the POMC/PCSK1 and SRC1 (NCOA1) genes at 52 weeks –

-- Conference call planned for 4:30 p.m. ET today –

BOSTON, March 16, 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 the topline results from its EMANATE trial. The four substudies of this global, Phase 3 trial evaluating setmelanotide did not meet primary endpoints.

“We are grateful to the patients with rare, genetically-driven MC4R pathway diseases and investigators who participated in this trial,” said David Meeker, MD, Chair, President and Chief Executive Officer of Rhythm Pharmaceuticals. “While we are disappointed the EMANATE substudies did not meet their primary endpoint, we are encouraged by compelling signals from additional analyses of the heterozygous POMC/PCSK1 and SRC1 substudies and learnings that sharpen our ability to identify true loss-of-function variants and inform the development of our next-generation MC4R agonists in rare genetically driven obesity indications.”

Dr. Meeker continued, “These patients continue to face a profound unmet medical need, with no approved treatment options that target the underlying biology of their disease. These results provide important insights that support our commitment to advancing targeted therapies for patients with rare genetic obesities.”

EMANATE was a global, randomized, double‑blind, placebo‑controlled Phase 3 trial designed to evaluate the efficacy and safety of setmelanotide in patients with rare, genetically-driven obesities of the MC4R pathway. The study comprised four independent genetic substudies in patients with obesity due to a heterozygous (Hets) variant of the POMC/PCSK1 gene, the LEPR gene, the SRC1 (NCOA1) gene, and the SH2B1 gene with patients randomized 1:1 to receive setmelanotide or placebo for 52 weeks.

EMANATE Topline Results

The primary endpoint was the difference in mean percent change in BMI from baseline to Week 52 versus placebo, analyzed in the modified intent-to-treat (ITT) population using prespecified multiple imputation to account for missing values and discontinuations. Topline results include:

• POMC / PCSK1 Hets (N=78): –4.3% placebo-adjusted reduction in BMI (p=0.15);
• LEPR Hets (N=23): –3.6% placebo-adjusted reduction in BMI (p=0.94);
• SRC1 (NCOA1) (N=73): –4.0% placebo-adjusted reduction in BMI (p=0.12); and
• SH2B1 (N=121): –1.7% placebo-adjusted reduction in BMI (p=0.43).

According to post hoc analyses based on last observation carried forward (LOCF) for missing values, setmelanotide achieved statistically significant and clinically meaningful BMI reductions at Week 52 in the modified intent-to-treat patient populations in the POMC/PCSK1 Hets and SRC1 substudies:

• –5.5% least-squares mean difference in BMI in POMC/PCSK1 Hets patients (n=78; p=0.0010); and
• –6.2% least-squares mean difference in BMI in SRC1 (NCOA1) patients (n=73; p<0.0001).

According to post hoc analyses of genetically confirmed patients who reached Week 52 of treatment, setmelanotide achieved statistically significant and clinically meaningful BMI reductions in patients who completed the 52-week trial in the POMC/PCSK1 Hets and SRC1 substudies:

• –9.7% placebo-adjusted reduction in BMI in POMC/PCSK1 Hets patients (n=41; p=0.0002); and
• –8.0% placebo-adjusted reduction in BMI in SRC1 (NCOA1) patients (n=29; p=0.0158).

No new safety signals were observed with setmelanotide in the EMANATE trial, and the safety profile was consistent with prior clinical studies and commercial experience. The most common treatment-emergent adverse events included skin hyperpigmentation, injection site reactions, nausea, vomiting, and headache.

Rhythm plans to continue the analysis of the EMANATE dataset and evaluate potential clinical development paths forward with SRC1 (NCOA1) and POMC with its next-generation MC4R agonists bivamelagon and RM-718. In addition, the Company will continue to evaluate the potential for MC4R agonism in the genes and gene families previously identified through the exploratory Phase 2 DAYBREAK trial, including the SEMA3 family, PHIP, TBX3 or PLXNA family.

Conference Call Information 
Rhythm Pharmaceuticals will host a live conference call and webcast at 4:30 p.m. ET today to discuss this update. Participants may register for the conference call here. It is recommended that participants join the call ten minutes prior to the scheduled start. 

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 30 days following the call. 

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 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 the potential 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; clinical design, enrollment, or progress, and preliminary, interim and final data readouts; potential benefits from our EMANATE topline results, including our ability to identify true loss-of-function variants and develop our next-generation MC4R agonists; potential regulatory submissions, approvals and timing thereof of setmelanotide, bivamelagon, or RM-718; the potential benefits of any of the Company’s products or product candidates for any specific disease indication or at any dosage, including the potential benefits of setmelanotide, bivamelagon or RM-718 for patients with MC4R pathway diseases; expectations surrounding pending and potential regulatory submissions and approvals, including within the United States, the EU and other regions; business strategy and plans, including regarding commercialization of setmelanotide in the United States, the EU and other regions; our participation in upcoming events and presentations; 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, 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 discussed under the caption “Risk Factors” in Rhythm’s Annual Report on Form 10-K for the year ended December 31, 2025 and 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 release or to update them to reflect events or circumstances occurring after the date of this 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. 
857-264-4280 
dconnolly@rhythmtx.com   

Media Contact: 
Layne Cosgrove 
Real Chemistry 
410-916-1035 
llitsinger@realchemistry.com 

FAQ

What did Rhythm Pharmaceuticals announce about the EMANATE Phase 3 trial (RYTM) on March 16, 2026?

They announced that the four genetic substudies did not meet prespecified primary endpoints at Week 52. According to the company, post hoc LOCF analyses showed significant BMI reductions in POMC/PCSK1 and SRC1 substudies while no new safety signals were observed.

How large were the placebo-adjusted BMI changes reported for POMC/PCSK1 and SRC1 in the EMANATE trial (RYTM)?

Post hoc LOCF analyses showed −5.5% BMI difference in POMC/PCSK1 and −6.2% in SRC1 at Week 52. According to the company, these results were statistically significant (p=0.0010 and p<0.0001 respectively).

Did the primary EMANATE endpoints reach statistical significance for RYTM across all substudies?

No, the four prespecified primary endpoints were not met at Week 52 in the modified ITT analysis. According to the company, primary placebo-adjusted BMI reductions had p-values above 0.05 in each substudy.

Were there any new safety concerns for setmelanotide reported in the EMANATE topline results (RYTM)?

No new safety signals were identified in EMANATE; safety remained consistent with prior experience. According to the company, common adverse events included skin hyperpigmentation, injection site reactions, nausea, vomiting, and headache.

What are Rhythm's next steps after the EMANATE topline results for RYTM?

Rhythm will continue dataset analyses and evaluate development paths for SRC1 and POMC with next-generation MC4R agonists. According to the company, programs include bivamelagon and RM-718 and further genetic analyses.