RYTM 8-K
Rhythm Pharmaceuticals, Inc. (RYTM)
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
CURRENT REPORT
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Item 2.02. Results of Operations and Financial Condition.
On January 10, 2025, Rhythm Pharmaceuticals, Inc. (the “Company”) issued a press release announcing, among other things, the Company’s preliminary unaudited net product revenues for the fourth quarter of 2024 and the fiscal year ended December 31, 2024. The full text of the press release issued by the Company is furnished as Exhibit 99.1 to this Current Report on Form 8-K.
The information contained in Item 2.02 of this Current Report on Form 8-K (including Exhibit 99.1 ) shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended (the “Securities Act”), or the Exchange Act, except as expressly provided by specific reference in such a filing.
Item 7.01. Regulation FD Disclosure.
On January 10, 2025, in connection with its participation in the J.P. Morgan Healthcare Conference, the Company posted a corporate slide presentation in the “Investors” portion of its website at www.rhythmtx.com. A copy of the presentation is furnished as Exhibit 99.2 to this Current Report on Form 8-K. The Company undertakes no obligation to update, supplement or amend the materials attached hereto as Exhibit 99.2.
The information contained in Item 7.01 of this Current Report on Form 8-K (including Exhibit 99.2) shall not be deemed “filed” for purposes of Section 18 of the Exchange Act, or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act, or the Exchange Act, except as expressly provided by specific reference in such a filing.
Item 8.01. Other Events.
On January 10, 2025, the Company announced preliminary unaudited net revenues from global sales of IMCIVREE® (setmelanotide) of approximately $42 million for the fourth quarter of 2024, an increase of 26% on a sequential basis from the third quarter of 2024, and approximately $130 million for the full year of 2024. The sequential quarter-over-quarter increase was due to growth in reimbursed patients on therapy and inventory growth in the United States. U.S. sales of IMCIVREE contributed approximately 74% of the fourth quarter preliminary unaudited net product revenues and approximately 73% of the full year 2024 preliminary unaudited net product revenues.
The Company also provided the following clinical development updates:
| • | The Company is on track to report topline data from its Phase 3 trial evaluating setmelanotide in acquired hypothalamic obesity (the “Phase 3 acquired HO trial”) in the first half of 2025. |
| • | The Company completed enrollment in the supplemental, 12-patient Japanese cohort of the Phase 3 acquired HO trial. Data from this supplemental cohort will serve as the basis for a regulatory submission in Japan. |
| • | The Company anticipates enrolling the first patients with congenital HO in a 34-week substudy of the Phase 3 acquired HO trial in the first quarter of 2025. This substudy is independent from the Phase 3 acquired HO trial. |
| • | The Company completed enrollment in the Phase 3 EMANATE trial, which is comprised of four substudies: SH2B1 (n=121); POMC and/or PCSK1 (n=79); SRC1 (n=73); and LEPR (n=23). The four-substudy design of this trial allows for independent data readouts and potential registration for each genetic cohort. The primary endpoint for each substudy is the difference in mean percent change in BMI from baseline to 52 weeks in the setmelanotide arm compared to the placebo arm. The Company anticipates reporting topline data from the Phase 3 EMANATE trial in the first half of 2026. |
| • | The Company plans to initiate a new, 26-week, open-label Phase 2 trial evaluating setmelanotide for treatment of Prader-Willi Syndrom (“PWS”) in the first quarter of 2025. The Company plans to enroll up to 20 patients with PWS and obesity aged 6 to 65 years old. Patients will be dose escalated to 5 mg/day, as tolerated. The primary |
| endpoints are safety and tolerability. Key secondary endpoints will assess weight, hyperphagia, behavior and pharmacokinetics. This trial will be conducted at a single site in the United States. |
| • | PWS is 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 at about 2 years of age. PWS is estimated to affect approximately 400,000 people worldwide and approximately 20,000 people in in the United States. Currently, there are no approved therapies for the treatment of PWS that effectively reduce extreme hyperphagia or address low energy expenditure. |
| • | The Company is on track to complete enrollment in the Phase 2 trial evaluating bivamelagon, an oral MC4R agonist, in acquired HO in the first quarter of 2025. |
| • | Following acceptance of a protocol amendment, the Company expects to begin dosing patients with acquired HO in Part C of the Phase 1 trial evaluating RM-718, a weekly MC4R agonist, in the first quarter of 2025. The Company plans to enroll up to 30 patients with acquired HO for 16 weeks in Part C of this Phase 1 trial. |
Financial Disclosure Advisory
This Current Report on Form 8-K contains certain estimated preliminary financial results for the fourth quarter and fiscal year ended December 31, 2024. These estimates are based on the information available to the Company at this time. The Company’s financial closing procedures for the fourth quarter and full year 2024 are not yet complete and, as a result, actual results may vary from the estimated preliminary results presented here due to the completion of the Company’s financial closing and audit procedures. 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.
Forward-Looking Statements
This Current Report on Form 8-K 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 Company’s anticipated financial performance for any period of time, including preliminary unaudited revenues, for the fourth quarter and full year ending December 31, 2024; the potential, safety, efficacy, and regulatory and clinical progress, potential regulatory submissions, approvals and timing thereof of setmelanotide and other product candidates, including bivamelagon (LB54640) and RM-718; the announcement of data from our clinical trials, including our global Phase 3 trial evaluating setmelanotide in patients with acquired hypothalamic obesity; the ongoing enrollment of patients in our clinical trials; 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”, “aim” and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including, but not limited to, our actual financial results for the fourth quarter and full year 2024 may differ from our preliminary estimates; our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the ability to achieve necessary regulatory approvals, risks associated with data analysis and reporting, failure to identify and develop additional product candidates, 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, the impact of competition, risks relating to product liability lawsuits, inability to maintain collaborations, or the failure of these collaborations, our reliance on third parties, risks relating to intellectual property, our ability to hire and retain necessary personnel, general economic conditions, risks related to internal control over financial reporting, and the other important factors discussed under the caption “Risk Factors” in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2024 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.
Item 9.01. Financial Statements and Exhibits.
(d) Exhibits
The following Exhibits 99.1 and 99.2 relate to Items 2.02 and 7.01, respectively, and shall each be deemed to be furnished, and not filed:
Exhibit |
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99.1 |
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99.2 | ||
104 |
| Cover Page Interactive Data File (embedded within the inline XBRL document) |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| RHYTHM PHARMACEUTICALS, INC. | |
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Date: January 10, 2025 | By: | /s/ Hunter Smith |
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| Hunter Smith |
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| Chief Financial Officer |
Exhibit 99.1
Rhythm Pharmaceuticals Announces Preliminary Fourth Quarter and Full Year 2024 Net Product Revenues, Pipeline Advancements and Upcoming Milestones
-- Preliminary unaudited net revenues from global sales of IMCIVREE® (setmelanotide) of approximately $42 million for the fourth quarter of 2024 and approximately $130 million for the full year of 2024 --
-- On track to report topline data from global Phase 3 trial evaluating setmelanotide in acquired hypothalamic obesity in the first half of 2025 --
-- Completed enrollment in supplemental Japanese cohort of Phase 3 trial of setmelanotide in acquired hypothalamic obesity --
-- Completed enrollment in two substudies in Phase 3 EMANATE trial of setmelanotide in genetically-caused MC4R pathway diseases --
-- Plan to initiate new Phase 2 trial exploring setmelanotide in Prader-Willi syndrome--
BOSTON, January 10, 2025 – Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a commercial-stage biopharmaceutical company focused on transforming the lives of patients living with rare neuroendocrine diseases, today announced preliminary unaudited net revenues from global sales of IMCIVREE® (setmelanotide) for the fourth quarter and full year of 2024, pipeline advancement updates and upcoming milestones.
“Rhythm enters 2025 poised for the next level of growth. Over the past two years, we have established the commercial viability of our rare MC4R pathway diseases franchise by demonstrating steady continued growth in an increasing number of countries, and this year we are looking forward to a series of readouts from our robust clinical development pipeline,” said David Meeker, M.D., Chairman, Chief Executive Officer and President of Rhythm. “Our Phase 3 trial in acquired hypothalamic obesity (HO) remains on track, and we completed enrollment in the supplemental 12-patient Japanese cohort which will form the basis for a Japanese regulatory filing and the significant opportunity to treat hypothalamic obesity there. We are set to begin our congenital HO substudy with the potential to further expand the opportunity related to injury to and or failure of the hypothalamus to develop. These indications represent significant unmet medical needs and potentially transformative opportunities for Rhythm.”
Dr. Meeker continued, “We have completed enrollment of what we believe to be the two most promising substudies in the Phase 3 EMANATE trial. Based on the unmet need and severity of Prader-Willi syndrome (PWS) and learnings from our initial study, we plan to initiate an exploratory Phase 2 study with higher doses of setmelanotide over a longer duration of 6 months. As we previously indicated, 2024 was a year of execution and we expect 2025 will be a year of readouts.”
Preliminary Unaudited Fourth Quarter and Full Year 2024 Net Product Revenues
Based on preliminary unaudited financial information, Rhythm expects net revenues from global sales of IMCIVREE to be approximately $42 million for the fourth quarter of 2024, an increase of 26% percent on a sequential basis from the third quarter of 2024. Net revenues for the full year of 2024 are expected to be approximately $130 million, compared to $77.4 million for the full year of 2023. The sequential quarter over quarter increase was due to growth in reimbursed patients on therapy and inventory growth in the United States. U.S. sales of IMCIVREE contributed approximately 74% of fourth quarter preliminary unaudited net product revenues and approximately 73% of full-year 2024 revenues. The Company plans to report its fourth quarter and full year 2024 financial results in late February 2025.
Pipeline Advancement and Upcoming Milestones
Setmelanotide
Acquired Hypothalamic Obesity (HO)
| ● | The Company is on track to report topline data from the pivotal, 120-patient cohorts of its global, Phase 3 trial evaluating setmelanotide in acquired HO in the first half of 2025. |
| ● | Rhythm has completed enrollment in its supplemental, 12-patient Japanese cohort of the global Phase 3 trial evaluating setmelanotide in acquired HO. Data from this supplemental cohort will serve as the basis for a regulatory submission in Japan. |
Congenital HO
| ● | Rhythm anticipates enrolling the first patients with congenital HO in a 34-week substudy of the ongoing global Phase 3 trial in the first quarter of 2025. This substudy is independent from the pivotal Phase 3 trial in acquired hypothalamic obesity. |
Genetically Caused MC4R Pathway Diseases
| ● | Rhythm completed enrollment in the Phase 3 EMANATE trial, which is comprised of four substudies: SH2B1 (n=121); POMC and/or PCSK1 (n=79); SRC1 (n=73); and LEPR (n=23). The four-substudy design of this trial allows for independent data readouts and potential registration for each genetic cohort. 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. The Company anticipates reporting topline data from the Phase 3 EMANATE trial in the first half of 2026. |
Prader-Willi Syndrome (PWS)
| ● | Today, Rhythm announced it plans to initiate a new, 26-week, open-label Phase 2 trial evaluating setmelanotide for treatment of PWS in the first quarter of 2025. Rhythm plans to enroll up to 20 patients with PWS and obesity aged 6 to 65 years old. Patients will be dose escalated to 5 mg/day, as tolerated. The primary endpoints are safety and tolerability. Key secondary endpoints will assess weight, hyperphagia, behavior and pharmacokinetics. This trial will be conducted at a single site in the United States. |
| ● | PWS is 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 at about 2 years of age. PWS is estimated to affect approximately 400,000 people worldwide and approximately 20,000 people in in the United States. Currently, there are no approved therapies for the treatment of PWS that effectively reduce extreme hyperphagia or address low energy expenditure. |
Bivamelagon (LB54640)
| ● | Rhythm is on track to complete enrollment in the Phase 2 trial evaluating bivamelagon, an oral MC4R agonist, in acquired HO in the first quarter of 2025. |
RM-718
| ● | Following acceptance of a protocol amendment, Rhythm expects to begin dosing patients with acquired HO in Part C of the Phase 1 trial evaluating RM-718, a weekly MC4R agonist, in the first quarter of 2025.The Company plans to enroll up to 30 patients with acquired hypothalamic obesity for 16 weeks in Part C of this Phase 1 trial. |
Financial Disclosure Advisory
This release contains certain estimated preliminary financial results for the fourth quarter and fiscal year ended December 31, 2024. These estimates are based on the information available to the Company at this time. The Company’s financial closing procedures for the fourth quarter and full year 2024 are not yet complete and, as a result, actual results may vary from the estimated preliminary results presented here due to the completion of the Company’s financial closing and audit procedures. 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 LB54640 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, and regulatory and clinical progress, potential regulatory submissions, approvals and timing thereof of setmelanotide and other product candidates, including bivamelagon (LB54640) and RM-718; the announcement of data from our clinical trials, including our global Phase 3 trial evaluating setmelanotide in patients with acquired hypothalamic obesity; the ongoing enrollment of patients in our clinical trials; the potential benefits of any of the Company’s products or product candidates for any specific disease indication or at any dosage; expectations surrounding potential clinical trial results, regulatory submissions and approvals our business strategy and plans, including regarding the ongoing commercialization of setmelanotide, expectations surrounding net revenues and sales and reimbursement of IMCIVREE, our anticipated financial performance for any period of time, including preliminary unaudited net product revenues, for the fourth quarter and full year ending December 31, 2024, 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, risks relating to our net revenues and anticipated financial results for the fiscal year ended December 31, 2024, 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 Quarterly Report on Form 10-Q for the three months ended September 30, 2024 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
Media Contact:
Sheryl Seapy
Real Chemistry
(949) 903-4750
| © Rhythm® Pharmaceuticals, Inc. All rights reserved. ® January 2025 Rhythm Pharmaceuticals |
| ® 2 This presentation contains certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, and that involve risks and uncertainties, including without limitation statements regarding the potential, safety, efficacy, and regulatory and clinical progress of setmelanotide, Bivamelagon (formerly LB54640), and RM718, including the anticipated timing for initiation of clinical trials and release of clinical trial data and our expectations surrounding potential regulatory submissions, approvals and timing thereof, our business strategy and plans, including regarding commercialization of setmelanotide and our other product candidates, the announcement of data from our clinical trials, including our global Phase 3 trial evaluating setmelanotide in patients with acquired hypothalamic obesity, the ongoing enrollment of patients in our clinical trials, the potential benefits of any of the Company's products or product candidates for any specific disease indication or at any dosage, the application of genetic testing and related growth potential, expectations surrounding the potential market opportunity for our product candidates, anticipated milestones, our future financial performance and the sufficiency of our cash, cash equivalents and short-term investments to fund our operations, and strategy, prospects and plans, including regarding the commercialization of setmelanotide, our anticipated financial performance for any period of time, including preliminary unaudited net revenues, for the fourth quarter and full year ending December 31, 2024, and the timing of any of the foregoing. Statements using words such as "expect", "anticipate", "believe", "may" 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 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 liquidity and expenses, the impact of global events on our business and operations, including our preclinical studies, clinical trials and commercialization prospects, and general economic conditions, and other risks as may be detailed from time to time in our Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q and other reports we file 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 presentation or to update them to reflect events or circumstances occurring after the date of this presentation, whether as a result of new information, future developments or otherwise. Financial Disclosure Advisory This presentation contains certain estimated preliminary financial results for the fourth quarter and fiscal year ended December 31, 2024. These estimates are based on the information available to the Company at this time. The Company's financial closing procedures for the fourth quarter and full year 2024 are not yet complete and, as a result, actual results may vary from the estimated preliminary results presented here due to the completion of the Company's financial closing and audit procedures. 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. Forward Looking Statements |
| ® 3 Rhythm’s Value Drivers Significant expansion opportunity in hypothalamic obesity (both acquired and congenital) Advancing setmelanotide clinical development in Prader-Willi syndrome and genetically-defined MC4R pathway diseases Continued BBS global commercial execution 1 2 3 Driving life-cycle management with bivamelagon and RM-718 4 |
| ® 4 What’s New? Completed enrollment in supplemental Japanese cohort of Ph 3 trial of setmelanotide in acquired hypothalamic obesity Completed enrollment in two substudies in Phase 3 EMANATE trial in genetically-caused MC4R pathway diseases Plans to initiate new Phase 2 trial exploring setmelanotide in Prader-Willi syndrome in Q1 25 On track to report topline data from pivotal, Ph3 trial in acquired hypothalamic obesity in H1 25 ~$42 million for Q4 25 Announced preliminary unaudited net revenues from global sales of IMCIVREE $130 million for FY2024 |
| ® 5 Continued Growth in IMCIVREE Global Sales Increase in number of patients on reimbursed therapy +26% Preliminary unaudited net revenues from global sales of IMCIVREE® (setmelanotide) QoQ increase from Q3 2024 74% of 4Q revenues from U.S. 73% of FY ‘24 revenues from U.S. Drivers of QoQ growth evenly split among two factors: Inventory growth: Excess of vials shipped to specialty pharma over vials dispensed to patients 1 $42M Q4 2024 ~ $130M FY 2024 ~ 2 The Company plans to report fourth quarter and full year 2024 financial results in late February |
| ® 6 Adipose tissue Leptin Blood-brain barrier MC4R neuron POMC neuron AgRP neuron AgRP LEPR Upstream Downstream Hypothalamus PCSK1 POMC LEPR MC4R Downstream MC4R activity Low Normal α-MSH β-MSH α-MSH β-MSH MC4R Pathway Biology is Clear and Strong: Regulates Hunger, Caloric Intake, Energy Expenditure and, Consequently, Body Weight1-4 AgRP, agouti-related peptide; LEPR, leptin receptor; MC4R, melanocortin-4 receptor; MSH, melanocyte-stimulating hormone; PCSK1, proprotein convertase subtilisin/kexin type 1; POMC, proopiomelanocortin. 1. Abuzzahab et al. Horm Res Paediatr. 2019;91:128-136. 2. Erfurth. Neuroendocrinology. 2020;110:767-779. 3. Rose et al. Obesity (Silver Spring). 2018;26:1727-1732. 4. Roth. Front Endocrinol (Lausanne). 2011;2:49. Hyperphagia Energy Expenditure Obesity |
| ® 7 Hyperphagia and Early-onset Obesity Have a Significant Impact on Patients and their Families “I was hungry all day long. I even started sneaking food in the middle of the night because my mind was constantly on my hunger.” “Prior to IMCIVREE, I didn’t realize how much of my mental energy was consumed by my hunger. I’m able to free up my mind and do more enjoyable things with my life.” Kathryn, Diagnosed with BBS at 6 years old BORN WITH: Autosomal recessive polycystic kidney disease (diagnosed in utero), polydactyly 2 YEARS OLD: Visual impairment and developmental delays emerge 6 YEARS OLD: Pronounced hyperphagia; clinical presentation prompted BBS diagnosis via genetic testing TEEN YEARS: Hyperphagia, obesity, and visual deficits worsen 28 YEARS OLD: IMCIVREE prescribed by PCP IMCIVREE Patient Ambassador program launched with 8 patient/caregiver speakers |
| ® 8 Clinical Development Programs Designed to Expand Opportunity in Hyperphagia and Severe Obesity 600 – 2,500* POMC, PCSK1 and LEPR deficiencies 4,000 - 5,000* Bardet-Biedl syndrome In ongoing Phase 3 trials ~29,000** EMANATE Lead indications 5,000 - 10,000* Hypothalamic obesity Positive signals observed in six new genes and gene families Phase 2 DAYBREAK trial *Estimated prevalence of U.S. patients based on company estimates; does not include ex-U.S. prevalence estimates. Estimated U.S. patients based on population with early-onset, severe obesity who may benefit from setmelanotide based on sequencing results that factor in variant classifcations, as applicable, current estimated responder rates and that 1.7% of the U.S. population (328M; 2019 US census) presents with severe early onset obesity (Hales et al 2018Ɨ); ~95% of individualswith severe early onset obesity remain obese into adulthood (Ward et al 2017). **Estimated prevalence in United States of SH2B1 and POMC and/or PCSK1 cohorts. Approved in U.S., EU,+ |
| ® 9 Well Capitalized: Cash Sufficient to Fund Planned Operations into 2026 Guidance Cash on hand expected to be sufficient to fund operations into 2026 61.2 Million Common shares outstanding as of Sept. 30, 2024 1Analyst coverage includes all brokerage firms known by the company as of March 2024 to have analysts covering the company. This list may not be complete and is subject to change. Analyst opinions, estimates or forecasts are their own and may not represent the opinions, estimates or forecasts of the company. Goldman Sachs temporarily suspended coverage. Analyst coverage1 BofA Securities; Canaccord Genuity; Guggenheim; HC Wainwright; Jefferies; JMP Securities; Morgan Stanley; Needham; Oppenheimer; Stifel; TD Cowen; Wells Fargo $298.4M cash, cash equivalents and short-term investments as of Sept. 30, 2024 |
| ® 10 Multiple Anticipated Milestones Q1 2025 Begin dosing patients in Ph3 congenital hypothalamic obesity substudy evaluating setmelanotide Q1 2025 Complete enrollment in Ph2 trial evaluating bivamelagon (LB54640) in acquired hypothalamic obesity Q1 2025 Begin dosing patients with acquired hypothalamic obesity in Part C of Ph1 trial evaluating RM-718 Q1 2025 Begin dosing patients in exploratory Ph2 Prader-Willi trial evaluating setmelanotide H1 2025 Topline data from Ph3 acquired hypothalamic obesity trial H1 2026 Topline data from Ph3 EMANATE trial evaluating setmelanotide in four genetically-defined, rare MC4R pathway diseases |
| ® 11 David Meeker, MD Chair, President and Chief Executive Officer Hunter Smith Chief Financial Officer Jennifer Lee Executive Vice President, Head of North America Yann Mazabraud Executive Vice President, Head of International Joe Shulman Chief Technology Officer Alastair Garfield, PhD Chief Scientific Officer 25-plus years; focus on rare genetic disease treatments, including Aldurazyme®, Fabrazyme® and Myozyme® 20-plus years in finance, M&A, capital markets; financial leadership for Otezla® 20-plus years leading global commercial strategy in rare diseases 20-plus years leading global commercial strategy in rare diseases 20-plus years experience leading CMC, supply chain planning and quality assurance and control 20 years experience in neurobiology of appetite /body weight regulation; rare disease drug discovery Rhythm Leadership – Strong Team with Broad Biopharma Experience |
| ® 12 Patient Population Pre-clinical Phase 1/2 Phase 3 Regulatory Approval Bardet-Biedl syndrome or biallelic POMC, PCSK1 or LEPR deficiency (2 years of age and older)* Setmelanotide daily formulation Acquired hypothalamic obesity Congenital hypothalamic obesity Prader Willi syndrome Bivamelagon Acquired hypothalamic obesity RM-718 Acquired hypothalamic obesity Pre-clinical Congenital hyperinsulinism (CHI) Expanding Pipeline in Rare Neuroendocrine Diseases US, EU, UK Complete Ongoing *IMCIVREE approved in Israel & Canada (6 years of age and older). LEPR, leptin receptor; MC4R, melanocortin-4 receptor; PCSK1, proprotein convertase subtilisin/kexin type 1; POMC, proopiomelanocortin. Enrollment complete Enrollment complete Pivotal data H1 2025 |
| ® 13 Hypothalamic Obesity Acquired and Congenital Setmelanotide, bivamelagon and RM-718 |
| ® 14 Hypothalamic Obesity: A Rare, Acquired Form of Obesity Following Injury to the Hypothalamic Region Craniopharyngioma and other suprasellar brain tumors and treatment – tumor resection surgery and radiation – is most common cause MC4R pathway deficiency following injury to hypothalamic region causes reduced energy, hyperphagia and rapid-onset, severe obesity No approved treatments available are released or inhibited when peripheral signals, such as PYY, GLP-, ghrelin, leptin, or insulin, reach the hypothalamus (). AgRP-expressing neurons exhibit orexigenic effects when activated by hunger hormones such as ghrelin (). In contrast, satiety hormones, such as PYY, GLP- , leptin, insulin, and CCK, inhibit the activity of AgRP-expressing neurons. AgRP-expressing neurons are highly active after a period of starvation, leading to increased food intake. Optogenetic and chemogenetic activation of AgRP-expressing neurons strongly stimulates the search for food and initiation of food intake (, ). Damage to these neurons may result in loss of appetite, with extreme starvation and cachexia. Clinically, this phenomenon, also known as diencephalic syndrome, is an atypical presenting symptom of CP (). Conversely, activation of AgRP-expressing neurons in animals stimulates food-seeking behav-ior, even when obesity is present. From an evolu-tionary standpoint, ensuring sufficient energy intake Figure 1. Schematic overview of the human hypothalamus. CPs most likely arise from epithelial remnants of the craniopharyngeal duct or the Rathke pouch (light yellow bar). Remnants of the Rathke pouch may be located in infrasellar, sellar, or suprasellar regions and may give rise to a CP in these locations. Purely sellar or infrasellar CP is very rare. CP expansion frequently occurs, with destruction of the optic chiasm or midbrain, resulting in obstructive hydrocephalus. The hypothalamus consists of many hypothalamic nuclei, which are all highly connected through neural pathways. The connection between the arcuate nucleus and paraventricular nucleus is emphasized. Afferent and efferent blood vessels provide a pipeline for pituitary hormones, as well as hunger and satiety hormones that stimulate hypothalamic neuron orexigenic and anorexigenic responses, respectively. ARC, arcuate nucleus; CRH, corticotropin-releasing hormone; DM, dorsomedial hypothalamic nucleus; OC, optic chiasm; PA, preoptic area; PH, posterior hypothalamic nucleus; SC, suprachiasmatic nucleus; SO, supraoptic nucleus; VMN, ventromedial hypothalamus. [© 2019 Illustration Presentation ENDOCRINE SOCIETY]. Optic chiasm PA GnRH TRH CRH POMC ADH Oxytocin GH LH/FSH Sphenoid ACTH TSH AgRP NPY GH RH SO SC ARC DM PVN PH LHA VMH GLP-1 Ghrelin Leptin Insulin PYY CCK Internal carotid artery/portal system Pathway remnants Rathke’s pouch 196 van Iersel et al Interventions Against Hypothalamic Obesity Endocrine Reviews, February 2019, 40(1):193–235 REVIEW Downloaded from https://academic.oup.com/edrv/article-abstract/40/1/193/5103298 by University of Pennsylvania Library user on 18 August 2019 van Iersel et al. Endo Rev. 2020 (PMID: 30247642) |
| ® 15 Hypothalamic Obesity: A Transformative Opportunity for Rhythm *U.S. estimates 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.); **European estimates limited to the EU4 (Germany, France, Spain, Italy), UK and the Netherlands and prevalence of 0.1-0.3 in 10,000 patients; £ Rhythm estimates 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; Prevalence is 2-3 times higher than in the USA & Europe due to a higher frequency of craniopharyngioma been reported. 5,000 – 10,000* estimated U.S. prevalence ~500* Estimated U.S. incidence 3,500 – 10,000** estimated European prevalence ~500** additional cases diagnosed in U.S. each year 5,000 – 8,000£ estimated Japanese prevalence ü Unmet medical need is high ü Patients are identified ü Patients engaged with system |
| ® 16 HO: Aggressive, Rapid Weight Gain follows Therapy for CP Setmelanotide GLP1 therapy therapy Patient Case Study: Setmelanotide therapy achieved rapid, significant weight loss Patient case of M. Jennifer Abuzzahab, MD, Pediatric Endocrinologist, at Children's Minnesota |
| ® 17 Setmelanotide Achieved Progressive, Deepening BMI Reduction at 16 Weeks, 6 and 12 Months in Patients with Hypothalamic Obesity Error bars are the standard deviation. *Includes all patients who received 16 weeks of setmelanotide in the index trial and ≥12 months of treatment in the long-term extension. †One patient did not complete a Month-6 visit. ‡One sample t-test with 2-tailed P-values. §Paired t-test with 2-tailed P-values. BMI, body mass index; %BMI95, percent of the 95th percentile for BMI. |
| ® 18 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 Setmelanotide Achieved Sustained and Deepened BMI Reduction in Patients with Hypothalamic Obesity at One Year Adapted from data presented during The Obesity Society Annual Meeting (TOS 2023) on October 17, 2023, in Dallas. BMI % change from index trial baseline -25.5% mean percent reduction in BMI at Month 12 from baseline -17.7% mean percent reduction in BMI at Week 16 from baseline Week 16 Month 12 |
| ® 19 Body Composition Data Show Greater Decreases in Total Fat Mass vs. Lean Muscle Mass Patient number 1 2 3 4 5 6 7 8 9 10 11 12 Age at baseline 6 9 9 10 11 12 13 14 15 15 16 24 Percent change in BMI from baseline to Month 12 -35.8 -20.5 -39.1 -23.9 -7 -8.7 -21.6 -29.2 -14.6 -36.6 -42.4 -27.1 -57.8 -23.7 -36.5 -12.2 -5.0 -15.4 -24.2 3.1 -51.4 -53.9 -33.1 -5.1 -18.1 -28.1 -6.5 5.3 23.8 2.6 -4.2 -14.1 -38.2 -15.5 -80 -60 -40 -20 0 20 40 Change in mass, % Total fat mass Lean muscle mass -62.0 -15.7 -18.5 -15.7 -20.2 -9.9 -26.3 -22.3 -16.9 -28.2 -26.8 -8.5 -18.1 -6.8 -16.3 -11.5 -1.4 17.5 16.8 -5.6 -6.4 -15.7 -21.3 -12.3 -80 -60 -40 -20 0 20 40 Change in mass, % Week 16 ≥1 year |
| ® 20 Three of 11 pediatric patients achieved normal weight at one year based on NIH, WHO weight classifications All Patients Achieved a Decrease in Obesity Severity at One Year *Pediatric patients reported as %BMI95. †Or BMI ≥40 kg/m2 (whichever is lower). ‡Or BMI ≥35 to <40 kg/m2 (whichever is lower). §Or BMI ≥30 to <35 kg/m2 (whichever is lower). %BMI95, percent of the 95th percentile for BMI; BMI, body mass index; NIH, National Institutes of Health; WHO, World Health Organization. BMI, kg/m2 Adults (n=1) WHO Classification (NIH5) Pediatric patients (n=11)* BMI percentile6 ≥50 50 Obesity class III (extreme) 157 166 190 158 ≥140%† ≥95th percentile ≥45 to <50 149 ≥40 to <45 144 140 141 ≥35 to <40 37 Obesity class II (severe)5 139 124 131 126 120 138 ≥120% to <140%‡ ≥30 to <35 Obesity class I 96 109 109 ≥95% to <120%§ ≥25 to <30 Overweight 86 89 ≥85th to <95th percentile <25 Normal weight 83 73 79 ≥5th to <85th percentile |
| ® 21 Positive Real-world Setmelanotide Data Reported from French Early-access Program in Adult Patients with Acquired Hypothalamic Obesity *50% male; all aged ≥18 years, with a previous resection of craniopharyngioma (n=7) or of Rathke cleft cyst (n=1); Adapted from “3-Month Real-World Setmelanotide Hunger and Weight Outcomes in Patients with Hypothalamic Obesity” poster presented ObesityWeek®; November 3-6, 2024, in San Antonio, TX, USA. N=8* patients -5.6% Mean BMI reduction n Month 1 -12.8% Mean BMI reduction n Month 3 -21.3% Mean BMI reduction n Month 6 -5.3 -0.6 -6.9 -10.5 -2.3 -4.5 -4.6 - -9.6 -9.6 9.9 -19 -20.3 -5 -10.6 -9.9 -18.6 -14.9 -18.9 -27.8 -32.5 -12.5 -35 -30 -25 -20 -15 -10 -5 0 #1 #2 #3 #4 #5 #6 #7 #8 -5% change -10% change Change in BMI from baseline, % 19.3 years Mean age at resection 31.4 years Mean age at initiation of setmelanotide therapy 44.1 kg/m2 Mean BMI at baseline |
| ® 22 Positive Real-world Setmelanotide Data Reported from French Early-access Program in Adult Patients with Acquired Hypothalamic Obesity *50% male; all aged ≥18 years, with a previous resection of craniopharyngioma (n=7) or of Rathke cleft cyst (n=1); Adapted from “3-Month Real-World Setmelanotide Hunger and Weight Outcomes in Patients with Hypothalamic Obesity” poster presented ObesityWeek®; November 3-6, 2024, in San Antonio, TX, USA. N=8* patients -5.6% Mean BMI reduction n Month 1 -12.8% Mean BMI reduction n Month 3 -21.3% Mean BMI reduction n Month 6 -5.3 -0.6 -6.9 -10.5 -2.3 -4.5 -4.6 - -9.6 -9.6 9.9 -19 -20.3 -5 -10.6 -9.9 -18.6 -14.9 -18.9 -27.8 -32.5 -12.5 -35 -30 -25 -20 -15 -10 -5 0 #1 #2 #3 #4 #5 #6 #7 #8 -5% change -10% change Change in BMI from baseline, % 19.3 years Mean age at resection 31.4 years Mean age at initiation of setmelanotide therapy 44.1 kg/m2 Mean BMI at baseline |
| ® 23 Phase 3 Hypothalamic Obesity Trial: Enrollment Complete, Top-line Data Expected in H1 2025 Setmelanotide QD (n=80) Double-blind, placebo-control Placebo QD (n=40) Up to 8 weeks 52 weeks Dose titration Primary endpoint: Mean % change in BMI from baseline to after approximately 52 weeks on a therapeutic regimen of setmelanotide compared with placebo. Open-label extension patients randomized to setmelanotide: placebo 120 Pivotal cohort +12 Japanese patients enrolled supplemental cohort; Data from this supplemental cohort will serve as the basis for a regulatory submission in Japan. |
| ® 24 Congenital HO occurs due to dysfunction or damage to the hypothalamus from birth, with patients often experiencing hyperphagia and difficulty managing their weight The weight gain and appetite changes accompanying HO are often unresponsive to existing therapies for obesity No approved therapies for congenital HO Congenital HO Represents Additional Opportunity with Significant Unmet need >1,000 patients estimated prevalence in each the United States and Europe |
| ® 25 Case reports presented at 62nd annual meeting of the European Society for Paediatric Endocrinology (EPSE) Real-world Case Reports from French Early-access Program Suggest Setmelanotide may be Effective Treatment for Congenital HO Adapted from ‘3-Month real-world setmelanotide hunger and weight outcomes in four French paediatric patients with acquired or congenital hypothalamic obesity,’ presented at ESPE on November 18, 2024, by Dr. Ahlam Azar-Kolakez, et al. |
| ® 26 Independent substudy leverages existing Ph3 trial infrastructure; Enrollment expected to begin in Q1 2025 34-week Substudy in Congenital Hypothalamic Obesity Added to Pivotal, Ph3 HO Study ~90% power to detect a treatment difference (treatment - placebo) of -12% in percent change of BMI from baseline after 26 weeks on a therapeutic regimen (up to 34 weeks) at 2-sided alpha of 0.05 patients randomized 2:1 setmelanotide: placebo 39 Setmelanotide QD (n=26) Double-blind, placebo-control Placebo QD (n=13) Variable duration 34 weeks Dose titration Open-label extension |
| ® 27 Bivamelagon (LB54640) • Global rights acquired from LG Chem in January 2024 • Daily oral, highly selective MC4R agonist • Compelling Phase 1 data in healthy, obese volunteers • No hyperpigmentation observed • IP protection out to 2045, assuming patent term extension RM-718 • Developed in-house based on setmelanotide • 7-amino acid peptide administered QW • In vivo results: supportive of no off-target cardiovascular effects, like setmelanotide; No hyperpigmentation observed • In vivo results suggest potential efficacy for body weight reduction, hyperphagia reduction • IP protection out to 2040, assuming patent term extension Advancing Next-generation MC4R Agonists in Acquired HO Clinical Trials Efficient signal finding possible due to sensitivity of acquired HO to MC4R agonism |
| ® 28 Bivamelagon Showed Dose-response Body Weight Loss Healthy Volunteers with General Obesity As presented by LG Chem at The Obesity Society’s ObesityWeek® 2022. Favorable safety profile • No serious adverse events • No skin pigmentation, adrenal, or genitourinary adverse events observed • Mild to moderate nausea, diarrhea, vomiting most common |
| ® 29 Enrollment to be complete in Q1 2025 SIGNAL Trial: 14-week, Phase 2 Open-label Trial Evaluating Bivamelagon in Patients with Hypothalamic Obesity Placebo Low dose Middle dose High dose Open-label extension N=28 patients with hypothalamic obesity Randomized 1:1:1:1 Inclusion criteria • ≥18yo BMI ≥30 kg/m2 for adults • 12-<18 yo >95th percentile for patients • Setmelanotide-naive 14 weeks Up to 52 weeks Efficacy endpoint • Mean % change in BMI from baseline at 14 weeks |
| ® 30 Part C dosing of patients with acquired HO expected to begin in Q1 2025 Three-part Phase 1 Study Evaluating RM-718 QW Ongoing Part A: SAD RM-718 QW Part B: MAD RM-718 QW 4 doses Part C: MAD Hypothalamic Obesity RM-718 QW 16 weeks Screening: 28 days 9 cohorts X 6 subjects >18yo n=54 Randomized 2:1 (RM-718: Placebo) Single ascending doses 3mg - 80mg* Safety follow up 28 days Screening: 28 days 6 cohorts X 6 subjects >18yo n=36 Randomized 2:1 (RM-718: Placebo) Multiple ascending doses 3mg - 50mg* Safety follow up 28 days Screening: 28 days 1 cohort X up to 30 patients >12yo Open-label, multiple doses ascending 10mg - 40mg* Safety follow up 28 days Transition to open-label extension *Doses may be adjusted upward or downward based on emerging data; 2 additional cohorts may be permitted in Parts A and Part B based on emerging data. Part C dosing will be based on safety, tolerability, and available PK data from Parts A and B. In Part C, Dosing will initiate in patients ≥18 years of age. Based on the ongoing evaluation of safety, tolerability, and available PK data (including 8-week dosing data from a minimum of 6 patients ≥18 years of age), dosing may proceed in patients <18 years of age. Planned starting dose in Part C is 10mg. Part C doses will not exceed the highest Part A or Part B dose for which safety and tolerability data are supportive. Patients in Part C may be eligible to participate in an open-label extension study. |
| ® 31 EMANATE and DAYBREAK Genetically-defined MC4R Pathway Diseases |
| ® 32 Phase 3 EMANATE Trial€ EMANATE and DAYBREAK Studies to Drive Significant Expansion of Setmelanotide’s Potential Addressable Market *† Estimated U.S. patients based on population* with early-onset, severe obesity who may benefit from setmelanotide based on sequencing results, current estimated responder rates and that 1.7% of the US population (328M; 2019 US census) presents with severe early onset obesity (Hales et al 2018Ɨ); ~95% of individualswith severe early onset obesity remain obese into adulthood (Ward et al 2017); £ U.S. and EU regulatory submissions for BBS and Alström syndrome filed in September and October 2021, respectively. € Planned EMANATE trial would include patients with variants classified as pathogenic, likely pathogenic or suspected pathogenic; 20,000† Heterozygous POMC/PCSK1 deficiency Heterozygous LEPR deficiency SRC1 deficiency SH2B1 deficiency Study completed in 2024 23,000† 4,000† Phase 2 DAYBREAK Trial 6,000† Four independent sub-studies |
| ® 33 Each sub-study: Patients randomized 1:1 Phase 3 EMANATE Trial Comprised of Four Independent Sub-studies Genetic substudy Enrolled patients ACMG Classification POMC/ PCSK1* n=79 • Pathogenic • Likely pathogenic • VUS*-Suspected pathogenic LEPR* n=23 • Pathogenic • Likely pathogenic • VUS-Suspected pathogenic SRC1 n=73 • All VUS SH2B1 n=121 • Pathogenic • Likely pathogenic • VUS Setmelanotide Placebo 52 weeks Open-label extension Endpoints • Primary: Difference in mean percent change in BMI from baseline to 52 weeks in setmelanotide arm compared to placebo arm • Key secondary: Additional measurements of effects on weight-related and hunger/hyperphagia endpoints * VUS = Variant of uncertain significance; Enrollment completed in 4Q 2024; Topline data anticipated in H1 2026 NOTE: The SRC1 and LEPR substudies are currently under-enrolled, so additional studies may be necessary in order to seek regulatory approval. We believe the SH2B1 and POMC/PCSK1 substudies are fully enrolled and powered and could enable Rhythm to seek registration, pending success. |
| ® 34 DAYBREAK 2-Stage Design: 16-Week Run-in Followed by 24-week Randomized Withdrawal and Double-blind, Placebo-controlled ≥12 years starting dose 2 mg 6 to <12 years starting dose 1 mg 6 to <12 years dose titration to 2 mg Open-label dose titration 2 weeks Screening 2-8 weeks 14 weeks Open-label treatment at therapeutic dose 3 mg Open-label run-in Week 0 (baseline) Screening Week 16 Visit 1a R 2:1 Placebo Randomized, double-blind Setmelanotide 3 mg 24 weeks End of study visita Visit 14 Week 40 (primary assessment) Final visit Stage 1: Open-label Run-in Completers Non-responders End of study visit Week 44 aVirtual visit. R, randomization. Stage 2: Double-blind, Placebo-controlled Eligibility Criteria: Genetic confirmation in patients 6-65 years; Obesity: BMI ≥40 kg/m2 (adults ≥18 years) or BMI ≥97th percentile for age and sex (children <18) Primary Endpoint: proportion of patients by genotype who achieve a BMI reduction of ≥5% from baseline in response to setmelanotide at the end of Stage 1 S2 Eligibility Criteria Reduction at end of S1, from baseline: Adult: Reduction of ≥3% BMI; Pediatric: reduction of ≥3% BMI OR of ≥0.05 BMI Z-score |
| ® 35 DAYBREAK Baseline Demographics N=49 n Mean (SD) Range % of S1 starters BMI, kg/m2 Adult Baseline 25 46.1 (7.2) 40.4 - 69.9 23% Adult Stage 2 start 25 42.6 (7.0) 36.2 - 66.3 - BMI-Z (CDC) Pediatric Baseline 24 2.5 (0.3) 1.83 - 2.97 44% Pediatric Stage 2 start 24 2.25 (0.4) 1.48 - 2.92 - Sex, N=49 All <18 yrs ≥18 yrs Male n (%) 22 (44.9) 10 (45.5) 12 (54.5) Female n (%) 27 (55.1) 14 (51.9) 13 (48.1) Assignments: *3 placebo, 1 setmelanotide †4 placebo, 2 setmelanotide ‡3 who were rescued under protocol version 1 (placebo -> setmelanotide) Randomized into DAYBREAK Stage 2, n=49 Discontinued from stage 2, n=4* Completed stage 2, n=39‡ Moved to early bridging due to weight regain, n=6† |
| ® 36 84% or 27 of 32 patients on setmelanotide Data Highlights from Stage 2 of DAYBREAK Phase 2 Trial * Analyses were limited by the small number of PBO-treated pts -12.4% Mean BMI change from baseline (SD: 8.0%; range 1.2%-35.0%) n=32 patients on continuous setmelanotide therapy* VS. 29% or 5 of 17 patients on placebo achieved or maintained >5% BMI reduction from baseline P=0.001 |
| ® 37 *One adult and one pediatric SEMA3G patient dropped out of S2 prior to having any data and are not shown Several genetically defined subgroups may merit further study with next-generation MC4R agonists Variable Responses Observed in DAYBREAK Stage 2 in Different Genetic Cohorts Early bridging to setmelanotide Week -7.5 -10.0 -12.5 -15.0 0 8 16 24 32 40 -5.0 -2.5 0.0 Week Percentage BMI change from baseline, % -7.5 -10.0 -12.5 -15.00 8 16 24 32 40 -5.0 -2.5 0.0 Rescue with setmelanotide PHIP Adult, n=5 Pediatric, n=4 SEMA3(A-G) Adult, n=7* Pediatric, n=8* Week Percentage BMI change from baseline, % -20.0 -30.0 0 8 16 24 32 40 -10.0 0.0 -15.0 -25.0 -5.0 Discontinued Week -20.0 -30.0 0 8 16 24 32 40 -10.0 0.0 -15.0 -25.0 -5.0 Early Bridging Week -20.0 0 8 16 24 32 40 -10.0 0.0 -15.0 -25.0 -5.0 Percentage BMI change from baseline, % SIM1 Adult, n=2 Pediatric, n=3 Week -20.0 0 8 16 24 32 40 -10.0 0.0 -15.0 -25.0 -5.0 40 Week -20.0 -30.0 0 8 16 24 32 -10.0 0.0 -15.0 -25.0 -5.0 40 Week -20.0 -30.0 0 8 16 24 32 -10.0 0.0 -15.0 -25.0 -5.0 Rescue with setmelanotid e PLXNA (1-4) Adult, n=8 Pediatric, n=5 Percentage BMI change from baseline, % Early Bridging X X X X X X X S1 S1 S1 S1 S1 S1 S1 S1 S2 S2 S2 S2 S2 S2 S2 S2 Placebo Setmelanotide |
| ® 38 Prader-Willi Syndrome |
| ® 39 PWS is a complex, multi-system disorder Constant sense of hunger usually begins at 2yo; if not managed by stringent food restrictions and environmental controls, often results in life-threatening obesity Currently no approved therapies that effectively reduce the extreme hyperphagia or address low resting energy expenditure Prior setmelanotide study evaluated low doses (up to 2.5mg daily) for only 4 weeks; results were not statistically significant Revisiting Prader-Willi Syndrome In 2016, Rhythm completed a Phase 2 trial (NCT02311673) that evaluated setmelanotide in patients with PWS 16-65 years of age. The study had co-primary endpoints of weight and hyperphagia after 4 weeks of placebo or setmelanotide (doses up to 2.5 mg). No statistically significant treatment differences were observed for the co-primary endpoints ~20,000 patients estimated U.S. prevalence ~400,000 Estimated world-wide prevalence |
| ® 40 Single, US-site Up to 20 patients with PWS and obesity aged 6 to 65 years old Daily dose of setmelanotide escalated to 5 mg/day as tolerated for 26 weeks Primary endpoints: safety and tolerability Key secondaries: assessments on weight, hyperphagia, behavior and pharmacokinetics Initiating Exploratory Phase 2, Open-label Trial of Setmelanotide in PWS in Q1 2025 |
| ® 41 IMCIVREE Global Commercial Execution |
| ® 42 First and Only FDA- and EMA-approved Therapy that Targets Early-onset, Severe Obesity and Hyperphagia Associated with BBS IMCIVREE is a melanocortin 4 (MC4) receptor agonist indicated for chronic weight management in patients with monogenic or syndromic obesity due to: • Bardet-Biedl syndrome (BBS) • 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) |
| ® 43 FDA approved IMCIVREE for BBS in June 2022 Steady Growth in Net Product Revenues since BBS Launch Global net sales in $M $- $5,000 $10,000 $15,000 $20,000 $25,000 $30,000 $35,000 $40,000 $45,000 3Q 22 4Q 22 1Q 23 2Q 23 3Q 23 4Q 23 1Q 24 2Q 24 3Q 24 4Q 24 US Ex US $4.3M $8.8M $26.0M $24.2M $22.5M $11.5M $19.2M $29.1M $33.3M ~$42M* * Q4 2024 revenues are preliminary and unaudited as of Jan. 10, 2024. The Company plans to report its fourth quarter and full year 2024 financial results in late February 2025. |
| ® 44 Bardet-Biedl Syndrome Opportunity in U.S. and Europe U.S. prevalence estimated to be 4,000 to 5,000* patients EU + UK prevalence estimated to be 4,000 to 5,000 * patients *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. Rhythm estimates 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) based on patient identification efforts and proprietary genetic sequencing data, as well as our belief that BBS, like most rare diseases, is underdiagnosed. |
| ® 45 Continued Progress in Securing Market Access for IMCIVREE EARLY ACCESS OR NAMED PATIENT SALES LAUNCHED IMCIVREE is available in >15 countries outside the United States |
| ® 46 Setmelanotide Benefiting Patients with Hypothalamic Obesity through Reimbursed Early-access Programs in France and Italy France • Steady uptake since first available in early 2024 • Access granted by joint federal multidisciplinary committee monthly • Positive responses reported in adult patients at 2024 ObesityWeek® in San Antonio, TX Italy • Eligibility: patients between 6-24 yo with HO caused by craniopharyngioma • Physician makes request for access directly to Italian MoH • First patients beginning therapy |
| ® 47 BBS Commercial Launch Underway in England and Wales in Q4 2024 England and Wales • NICE recommended NHS reimbursement for patients younger than 18yo with BBS • 4 NHS BBS specialized clinics: 2 for adult patients, 2 for pediatric patients • Patients to be trained in hospital setting with at-home nursing support |
| ® 48 Thank you |
