Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a
biopharmaceutical company aimed at developing and commercializing
therapies for the treatment of rare genetic diseases of obesity,
today announced a significant expansion of its clinical development
program for setmelanotide with five new planned Phase 2 and 3
clinical trials. Rhythm will review these updates on its second
quarter 2021 financial results and business update conference call
today at 8 a.m. ET.
New trials include the pivotal EMANATE Phase 3
trial and the DAYBREAK Phase 2 trial, which together will evaluate
setmelanotide in people with variants in one of 36 genes in the
melanocortin-4 receptor (MC4R) pathway. Based on genetic sequencing
data and setmelanotide response rates achieved in a phase 2 trial,
Rhythm estimates that the five genetic indications being studied in
the EMANATE trial represent a potential addressable patient
population of approximately 100,000-200,000 people in the United
States.
In addition, Rhythm plans to initiate a Phase 3
trial in pediatric patients ages 2 to 6 years old, as these genetic
diseases often present with severe obesity very early in life. The
weekly formulation of setmelanotide, which is designed to improve
compliance and adherence, will be studied in two phase 3 trials,
including a switch study of patients currently on setmelanotide
therapy and a de novo trial in patients with BBS.
The company expects to initiate all five studies
in the second half of 2021.
“We are excited to announce the significant
expansion of our development program for setmelanotide. With these
five clinical trials, we will explore opportunities to extend the
reach of our precision medicine to address the needs of many more
patients suffering from a rare genetic disease of obesity, as well
as the potential to improve convenience for patients and caregivers
with a weekly formulation,” said Murray Stewart, M.D., Chief
Medical Officer of Rhythm Pharmaceuticals. “We are grateful to the
FDA and EMA for their responsiveness throughout this process. These
rare genetic diseases of obesity are serious, life-threatening
diseases that affect children with early-onset, severe obesity.
This expansion of our development programs reflects our goal to
deliver new options to these patients who otherwise have no
approved therapies that specifically address the underlying cause
of their obesities. We look forward to continuing this productive
dialogue as we initiate these studies and, ultimately, seek to
advance setmelanotide toward potential additional
registrations.”
Pivotal EMANATE Phase 3 Trial and
DAYBREAK Phase 2 Trial
Rhythm has reached agreement with the U.S. Food
and Drug Administration (FDA) and European Medicines Agency (EMA)
on the clinical design and primary endpoint of its pivotal Phase 3
EMANATE trial of setmelanotide. The trial will be a randomized,
double-blind, placebo-controlled study with five independent
sub-studies evaluating setmelanotide in patients with: a variant in
one of two alleles in the proopiomelanocortin (POMC) or proprotein
convertase subtilisin/kexin type 1 (PCSK1) genes; leptin receptor
(LEPR) genes (or heterozygous POMC/PCSK1 or LEPR obesity); certain
variants of the SRC1; certain variants of SH2B1 genes; or PCSK1
N221D deletions within the MC4R pathway. Each sub-study will be
entirely independent of the others and, if successful, is designed
to allow Rhythm to submit separate regulatory submissions to the
FDA and EMA.
The company plans to enroll 110 patients in each
sub-study, randomized one to one to daily setmelanotide or placebo.
The trial will enroll patients from six to 65 years old with a body
mass index (BMI) of greater than 30 or above the 95th percentile.
The primary efficacy endpoint in each sub-study will be the mean
percent change in BMI in response to setmelanotide at 52 weeks as
compared to placebo. Secondary endpoints will include responder
analyses, assessment of the change in hunger scores, and changes in
quality-of-life measures.
Rhythm also announced the final design of its
Phase 2 DAYBREAK trial of setmelanotide. The trial will be a
two-stage, placebo-controlled study in patients with specific
variants within one of 31 genes which the Company believes have
“strong” or “very strong” relevance to the MC4R pathway.
The company plans to enroll 500 patients in the
first stage of the study and to advance approximately 130 patients
into the second stage of the study. The first stage of the study
will consist of a 16-week open-label run-in; patients 18 years or
older who achieve 5 percent weight loss from baseline, or patients
under 18 years who achieve a BMI-Z score decrease of at least 0.1
from baseline during this period will be eligible for enrollment in
the second stage of the study. Stage 2 will be a 24-week,
double-blind, placebo-controlled, randomized, withdrawal study, in
which patients will be randomized 2:1 to receive setmelanotide or
placebo. For the more prevalent genes, patients will be stratified
by variant classification. The primary efficacy endpoint is a
responder analysis by gene, based on the proportion of patients who
enter Stage 2 who are responders compared to placebo.
Rhythm expects to conduct EMANATE and DAYBREAK
at approximately 75 sites across North America, Europe and the
Middle East.
Updated Uncovering Rare Obesity Genetic
Test Launched
In order to facilitate patient enrollment,
Rhythm launched in July 2021 an improved Uncovering Rare Obesity®
(URO) genetic test with an expanded panel. This no-charge genetic
testing program now includes 80 genes with ties to obesity,
including the 36 genes with documented ties to the MC4R pathway
that are being evaluated in EMANATE and DAYBREAK. To date, URO has
processed approximately 10,000 patient samples and the yield has
been consistent with prior reports. As of August 2021 and since URO
was first launched, Rhythm has identified approximately 650
patients who would be eligible for EMANATE or DAYBREAK and who live
within a reasonable distance of a target trial site. In addition to
an expanded gene panel, Rhythm recently enhanced the program to
facilitate test ordering and results reporting, with support for
interpretation of results.
Phase 3 Pediatric Trial
Rhythm’s Phase 3 trial in pediatric patients
ages 2 to 6 years old will be a multi-center, one-year, open-label
trial. The company plans to enroll 10 patients, including five with
obesity due to biallelic POMC, PCSK1 or LEPR deficiency and five
patients with the clinical diagnosis of Bardet-Biedl syndrome (BBS)
and genetic confirmation. All patients enrolled in the trial will
have a BMI greater than the 97th percentile and will weigh more
than 20 kg at baseline. The primary efficacy endpoint will be a
responder analysis, based on the proportion of patients who
experience a decrease from baseline in BMI-Z of ≥0.2.
Phase 3 Switch and Phase 3
De Novo Trials of Weekly
Formulation
Rhythm will evaluate its weekly formulation of setmelanotide in
two simultaneous Phase 3 trials, including a switch study and a de
novo trial.
The switch study will be a randomized, double-blind clinical
trial in patients with BBS, biallelic or heterozygous POMC, PCSK1
or LEPR deficiency. Rhythm expects to enroll 30 patients,
randomized 1:1 to receive once weekly setmelanotide and once daily
placebo, or once daily setmelanotide and once weekly placebo for 13
weeks. Following the 13-week randomized treatment period, the trial
will crossover to an open-label, 13-week study in which all
patients will receive once-weekly setmelanotide. The primary
efficacy endpoint will be a responder analysis, based on the
proportion of patients with no weight gain defined as a change of 5
percent or less from baseline to week 13.
The de novo trial will be a randomized, double-blind clinical
trial in patients with BBS. The company expects to enroll 20
patients, randomized 1:1 to receive 30 mg of setmelanotide or
placebo once weekly for 18 weeks. Following the 18-week treatment
period, patients will continue on treatment, or crossover from
placebo to active therapy, for an additional 14 weeks. The primary
efficacy endpoint will be the mean change from baseline in body
weight after approximately 18 weeks of once weekly dosing.
Conference Call Information
Rhythm Pharmaceuticals will host a live conference call and
webcast at 8:00 a.m. ET today to discuss this update, as well as
review its second quarter 2021 financial results and recent
business activities. The conference call may be accessed by dialing
(844) 498-0570 (domestic) or (409) 983-9726 (international), and
referring to conference ID 6776764. A webcast of the call will be
available under "Events and Presentations" in the Investor
Relations section of the Rhythm Pharmaceuticals website
at http://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 PharmaceuticalsRhythm is a
commercial-stage biopharmaceutical company committed to
transforming the treatment paradigm for people living with rare
genetic diseases of obesity. The Company’s precision medicine,
IMCIVREE (setmelanotide), was approved in November 2020 by the U.S.
Food and Drug Administration (FDA) for chronic weight management in
adult and pediatric patients 6 years of age and older with obesity
due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing
and by the European Commission (EC) in July 2021 for the treatment
of obesity and the control of hunger associated with genetically
confirmed loss-of-function biallelic POMC, including PCSK1,
deficiency or biallelic LEPR deficiency in adults and children 6
years of age and above. IMCIVREE is the first-ever FDA-approved and
EC-authorized therapy for patients with these rare genetic diseases
of obesity. Rhythm is advancing a broad clinical development
program for setmelanotide in other rare genetic diseases of
obesity. The Company is leveraging the Rhythm Engine and the
largest known obesity DNA database - now with approximately 37,500
sequencing samples - to improve the understanding, diagnosis and
care of people living with severe obesity due to certain genetic
deficiencies. The company is based in Boston, MA.
IMCIVREE®
(setmelanotide) IndicationIn the United States,
IMCIVREE is indicated for chronic weight management in adult and
pediatric patients 6 years of age and older with obesity due to
proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin
type 1 (PCSK1), or leptin receptor (LEPR) deficiency. The condition
must be confirmed by genetic testing demonstrating variants
in POMC, PCSK1, or LEPR genes that are
interpreted as pathogenic, likely pathogenic, or of uncertain
significance (VUS).
In the EU, IMCIVREE is indicated for the treatment of obesity
and the control of hunger associated with genetically confirmed
loss-of-function biallelic pro-opiomelanocortin (POMC), including
PCSK1, deficiency or biallelic leptin receptor (LEPR) deficiency in
adults and children 6 years of age and above.
Limitations of UseIMCIVREE is not indicated for
the treatment of patients with the following conditions as IMCIVREE
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 POMC, PCSK1 or LEPR
deficiency, including obesity associated with other genetic
syndromes and general (polygenic) obesity.
Important Safety Information
WARNINGS AND PRECAUTIONS
Disturbance in Sexual Arousal: Sexual
adverse reactions may occur in patients treated with IMCIVREE.
Spontaneous penile erections in males and sexual adverse reactions
in females occurred in clinical studies with IMCIVREE. Instruct
patients who have an erection lasting longer than 4 hours to seek
emergency medical attention.
Depression and Suicidal Ideation: Some
drugs that target the central nervous system, such as IMCIVREE, may
cause depression or suicidal ideation. Monitor patients for new
onset or worsening of depression. Consider discontinuing IMCIVREE
if patients experience suicidal thoughts or behaviors.
Skin Pigmentation and Darkening of Pre-Existing
Nevi: IMCIVREE may cause generalized increased skin
pigmentation and darkening of pre-existing nevi due to its
pharmacologic effect. This effect is reversible upon
discontinuation of the drug. Perform a full body skin examination
prior to initiation and periodically during treatment with IMCIVREE
to monitor pre-existing and new skin pigmentary
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.
ADVERSE REACTIONS
- The most common adverse reactions (incidence ≥23%) were
injection site reactions, skin hyperpigmentation, nausea, headache,
diarrhea, abdominal pain, back pain, fatigue, vomiting, depression,
upper respiratory tract infection, and spontaneous penile
erection.
USE IN SPECIFIC POPULATIONS
Discontinue IMCIVREE when pregnancy is recognized unless the
benefits of therapy outweigh the potential risks to the fetus.
Treatment with IMCIVREE is not recommended for use while
breastfeeding.
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 Full Prescribing Information for IMCIVREE.
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 of setmelanotide, 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 participation in upcoming events and presentations.
Statements using word 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, the impact of our
management transition, 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
liquidity and expenses, the impact of the COVID-19 pandemic on our
business and operations, including our preclinical studies,
clinical trials and commercialization prospects, and general
economic conditions, and the other important factors discussed
under the caption “Risk Factors” in our Quarterly Report on Form
10-Q for the quarterly period ended June 30, 2021 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
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 ConnollyHead of
Investor Relations and Corporate CommunicationsRhythm
Pharmaceuticals, Inc.857-264-4280dconnolly@rhythmtx.com
Investor Contact:Hannah DeresiewiczStern
Investor Relations,
Inc.212-362-1200hannah.deresiewicz@sternir.com
Media Contact:Adam DaleyBerry & Company
Public Relations212-253-8881adaley@berrypr.com
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