Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a commercial-stage
biopharmaceutical company committed to transforming the care of
people living with rare genetic diseases of obesity, today
announced the first patient has been dosed with setmelanotide, the
company’s melanocortin-4 receptor (MC4R) agonist, in the Phase 2
DAYBREAK clinical trial to treat the severe obesity and hyperphagia
potentially caused by a genetic variant that impairs function of
the MC4R pathway. The company also announced the dosing of the
first patient in the Phase 3 trial evaluating a switch from the
daily to a novel weekly formulation of setmelanotide.
The DAYBREAK trial [NCT04963231] is designed to evaluate
setmelanotide in patients who carry a confirmed variant in one or
more of 31 genes with strong or very strong relevance to the MC4R
pathway, which regulates the body’s energy balance, including
appetite, energy expenditure and body weight. Results from the
DAYBREAK clinical trial have the potential to identify future
patient populations and to inform the design of future
registrational studies to support setmelanotide label
expansion.
“With significant advances in gene sequencing and analysis, we
have deepened our understanding of the relationship between
genetics and severe obesity. However, there remains a significant
unmet need with no effective therapeutic options for most patients
with rare genetic diseases of obesity,” said Sadaf Farooqi, M.D.,
Ph.D., of the Wellcome-MRC Institute of Metabolic Science at the
University of Cambridge, a principal investigator for the DAYBREAK
trial and world-renowned expert on genetic obesity. “The DAYBREAK
trial is a comprehensive and robust trial designed to evaluate
setmelanotide in patients with early-onset, severe obesity and
hyperphagia, which may be caused by a genetic impairment of the
MC4R pathway.”
DAYBREAK is a two-stage, double-blind, placebo-controlled trial
that will be conducted at more than 75 trial sites across 12
countries. Rhythm plans to enroll approximately 500 patients (6 to
65 years old) with severe obesity and a variant in one of 31 genes
relevant to the MC4R pathway. Any patients who demonstrate a
clinically meaningful response to setmelanotide at the end of a
16-week, open-label run-in period will be eligible to enter the
second stage of the study. Stage 2 will be a 24-week, double-blind,
placebo-controlled withdrawal study, in which patients will be
stratified into genetically defined cohorts and randomized 2:1 to
receive setmelanotide or placebo.
The primary efficacy endpoint is a responder analysis based on
the proportion of patients treated with setmelanotide who achieve a
clinically meaningful weight reduction threshold at the end of
treatment compared to patients treated with placebo. Each
genetically defined cohort can read out results independently.
“DAYBREAK is designed to enable rapid and robust
proof-of-concept in multiple genetic cohorts, potentially
demonstrating setmelanotide treatment effects on obesity and
hunger,” said Linda Shapiro, M.D., Ph.D., Chief Medical Officer of
Rhythm. “The initiation of DAYBREAK is an exciting milestone in our
journey to transform the care and lives of many more people living
with rare genetic disorders of obesity.”
Rhythm estimates that approximately 35 percent of people living
with early-onset, severe obesity may test positive for a genetic
variant that would make them eligible to enroll in DAYBREAK. The
Company offers Uncovering Rare Obesity® a no-charge, comprehensive
genetic testing program for rare genetic diseases of obesity, which
can be ordered by physicians in the United States. Rhythm’s
European program, which is designed to complement existing genetic
testing programs, is expected to be available in the first half of
2022.
Phase 3 Weekly Switch Trial Underway
Rhythm also announced today that it has dosed the first patients
in the Phase 3 switch trial evaluating a weekly formulation of
setmelanotide in patients 6 years of age and older with a rare
genetic disease of obesity who are currently taking the daily
formulation of setmelanotide.
Rhythm’s weekly formulation of setmelanotide is designed to
offer patients a more convenient dosing regimen. It is being
evaluated in a Phase 3 randomized, double-blind switch trial in
patients with obesity due to biallelic or heterozygous POMC, PCSK1
or LEPR genetic variants or a clinical diagnosis of BBS with
genetic confirmation, who were previously enrolled in Rhythm’s
long-term, open-label daily setmelanotide extension trial. 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, patients will crossover to an
open-label, 13-week study in which all patients will receive
once-weekly setmelanotide. The primary efficacy endpoint is 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.
Additional Phase 3 Clinical Trials on Track to Initiate
in 2022
Rhythm expects to initiate three additional Phase 3 trials of
setmelanotide in 2022, including:
- The pivotal Phase 3 EMANATE clinical trial, which is expected
to initiate in the first quarter of 2022. EMANATE, a randomized,
double-blind, placebo-controlled trial, will evaluate setmelanotide
in five independent sub-studies in patients with obesity due to: a
heterozygous variant of the POMC/PCSK1 genes or LEPR gene, certain
variants of the SRC1 gene or the SH2B1 gene, or PCSK1 N221D
deletions within the MC4R pathway. The company estimates these
populations represent approximately 100,000-200,000 people in the
United States.
- The Phase 3 pediatric trial evaluating daily setmelanotide in
patients between the ages of 2 and less than 6 years of age with
rare genetic diseases of obesity, which is expected to initiate in
the first quarter of 2022. Rare genetic diseases of obesity often
present early in life, and Rhythm’s genetic testing programs have
identified many patients with these diseases who are younger than 6
years old. If successful, VENTURE could enable earlier therapeutic
intervention, with the potential to change the overall trajectory
of disease and transform the lives of these patients and their
families. This trial [NCT04966741] is a multi-center, one-year,
open-label trial in pediatric patients with obesity due to
biallelic POMC, PCSK1 or LEPR deficiency or a clinical diagnosis of
BBS with genetic confirmation. The primary efficacy endpoint is a
responder analysis, based on the proportion of patients who
experience a decrease from baseline in BMI Z of ≥0.2.
- A second Phase 3 trial to evaluate the weekly formulation of
setmelanotide, which is expected to initiate in the second half of
2022. This de novo trial will be a randomized, double-blind
clinical trial in patients with BBS who live outside the United
States. The company expects to enroll 40 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 is the
mean change from baseline in body weight after approximately 18
weeks of once weekly dosing.
About Rhythm PharmaceuticalsRhythm is a
commercial-stage biopharmaceutical company committed to
transforming the treatment paradigm for people living with rare
genetic diseases of obesity. Rhythm’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 in July and September 2021,
respectively, by the European Commission (EC) and Great
Britain’s Medicines & Healthcare Products Regulatory
Agency (MHRA) 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- and MHRA-authorized
therapy for patients with these rare genetic diseases of obesity.
The Company submitted a supplemental New Drug Application (sNDA) to
the FDA, which was accepted for filing in September November 2021
and assigned a Prescription Drug User Fee Act (PDUFA) goal date of
March 16, 2022, and submitted a Type II variation application to
the European Medicines Agency in October 2021 seeking regulatory
approval and authorization for setmelanotide to treat obesity and
control of hunger in adult and pediatric patients 6 years of age
and older with BBS or Alström syndrome in both the United States
and European Union. Additionally, Rhythm is advancing a broad
clinical development program for setmelanotide in other rare
genetic diseases of obesity and is leveraging the Rhythm Engine and
the largest known obesity DNA database -- now with approximately
45,000 sequencing samples -- to improve the understanding,
diagnosis and care of people living with severe obesity due to
certain genetic deficiencies. Rhythm’s headquarters is
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, 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 and Great Britain, IMCIVREE is indicated 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 should be prescribed
and supervised by a physician with expertise in obesity with
underlying genetic etiology.
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 POPULATIONSDiscontinue 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, EU SmPC
and MHRA SmPC for IMCIVREE.
Forward-Looking
StatementsThis 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 with
respect to our ongoing DAYBREAK and Phase 3 weekly switch trials
and planned EMANATE, VENTURE and Phase 3 de novo trials, 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, 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 September 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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