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
presented new data and analyses from phase 2 and 3 trials
evaluating setmelanotide at the 59th Annual European Society for
Paediatric Endocrinology (ESPE) Meeting, which is being held
virtually this week.
The Company and its collaborators delivered three oral
presentations and four poster presentations, including:
- a new subgroup analysis of data from the 52-week, Phase 3 trial
evaluating setmelanotide in Bardet-Biedl syndrome (BBS) that showed
setmelanotide achieved statistically significant weight loss and
hunger reduction compared to minimal effect observed with placebo
during a 14-week, double-blind treatment period;
- complete topline analyses from the exploratory Phase 2 Basket
Trial that showed setmelanotide achieved clinically meaningful
weight loss or BMI-Z reduction in 30% (9 of 30) of study
participants with obesity due to variants of the SRC1 gene;
and
- complete topline analyses from the exploratory Phase 2 Basket
Trial that showed setmelanotide achieved clinically meaningful
weight loss or BMI-Z reduction in 43% (15 of 35) of study
participants with obesity due to variants of the SH2B1 gene,
including 16p11.2 chromosomal deletions.
“We know from decades of study that reduced activation of the
central melanocortin-4 receptor (MC4R) pathway can lead to
early-onset, severe obesity and a pathological hunger known as
hyperphagia, which characterize rare genetic diseases of obesity,”
said Dr. Jesús Argente, who is an author on all three oral
presentations and Professor in the Department of Pediatrics and
Pediatric Endocrinology, Universidad Autónoma de Madrid in Spain.
“In these trials, treatment with setmelanotide, an MC4R agonist,
provided patients across three distinct diseases – BBS, as well as
obesity due to SRC1 or SH2B1 deficiency – with clinically
meaningful reductions in weight loss and hunger. Together, these
data support the potential for further development of setmelanotide
for patients with rare genetic diseases of obesity driven by a
range of variants in the MC4R pathway.”
“In addition to presenting data from our Phase 2 and 3 trials of
setmelanotide, we also presented posters at ESPE describing the
gene selection process and the design of our Phase 2 DAYBREAK
trial,” said Linda Shapiro, M.D., Ph.D., Chief Medical Officer of
Rhythm. “We are excited to share these presentations, which provide
further rationale for our planned clinical development strategy.
Collectively, these presentations depict setmelanotide’s potential
to deliver meaningful benefit – even without change in exercise or
diet -- to people with obesity and variants in the SRC1 or SH2B1
gene, both of which are included in our Phase 3 EMANATE trial, and
they support our decision to enroll people with obesity and
variants in at least one of 31 other genes, all of which have
‘strong’ or ‘very strong’ MC4R pathway relevance, in our Phase 2
DAYBREAK trial. We look forward to initiating both EMANATE and
DAYBREAK in the fourth quarter, which will evaluate setmelanotide
on top of standard of care dietary and physical activity guidance,
as we work to broaden setmelanotide’s reach to many more patients
with rare genetic diseases of obesity caused by variants in the
MC4R pathway.”
New Subgroup Analysis of Data from Phase 3 Trial in
BBSIn a presentation entitled, “Phase 3 Trial of
Setmelanotide in Participants with Bardet-Biedl Syndrome:
Placebo-Controlled Results,” Dr. Argente presented data from a
14-week double-blind treatment period, which preceded an open-label
period that totaled 52 weeks on therapy. Highlights of the data
include:
- Patients 12 years old or older treated with setmelanotide
(n=14) compared to placebo (n=15) at 14 weeks demonstrated an
average:
- Greater weight loss of 3.8 kg, or 3%, of their baseline body
weight (p<0.05);
- Greater reduction in ‘most hunger score’ of 20.4% from baseline
(p<0.05).
- All patients, including those younger than 12 years, treated
with setmelanotide (n=16) achieved an average BMI reduction from
baseline of 1.5 kg/m2, or 3.8%, greater than patients treated with
placebo (n=16) (p<0.05).
In December 2020, Rhythm announced that its Phase 3 trial
evaluating setmelanotide in patients with BBS and Alström syndrome
met its primary endpoint and all key secondary endpoints, with
statistically significant and clinically meaningful reductions in
weight and hunger at 52 weeks on therapy. All primary endpoint
responders were patients with BBS; no patients with Alström
syndrome met the primary endpoint.
Rhythm recently submitted a supplemental New Drug Application to
the U.S. Food and Drug Administration (FDA) and remains on track to
submit a type II amendment to the European Medicines Agency (EMA)
in the fourth quarter of 2021 for both BBS and Alström
syndrome.
Complete Topline Analyses from Phase 2 Exploratory
Basket Trial SRC1 and SH2B1 CohortsRhythm also presented
complete topline data from two genetic cohorts in its exploratory
Phase 2 Basket Trial. These proof-of-concept data support the
Company’s pivotal EMANATE Phase 3 trial, a randomized,
double-blind, placebo-controlled study with five independent
sub-studies evaluating setmelanotide in patients with five distinct
rare genetic diseases of obesity, including patients whose obesity
is linked to certain variants of the SRC1 or SH2B1 genes. Based on
genetic sequencing data and setmelanotide response rates achieved
in the Basket 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.
Phase 2 Data in Obesity Due to SRC1 Deficiency Dr. Sadaf Farooqi
of Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge
Biomedical Research Centre, University of Cambridge, Cambridge, UK,
presented, “A Phase 2 Trial of the Melanocortin-4 Receptor Agonist
Setmelanotide in Obesity Due to SRC1 Insufficiency: Body Weight,
Body Mass Index Z Score, and Safety Results.” A total of 30
patients with obesity and deficiency in the SRC1 gene were enrolled
in the full analysis set of this study. The SRC1 gene is a key
transcription modulator of POMC, certain variants of which are
associated with early-onset, severe obesity. These patients had a
mean BMI of 45.4 kg/m2 or BMI-Z of 3.0 at baseline. BMI-Z, or BMI
standard deviation score, represents the number of standard
deviations from the median BMI for a child’s age and sex.
Highlights of the data include:
- Nine of 30 (30%) of patients achieved a clinically meaningful
response to setmelanotide at three months, as defined by weight
loss of 5% or greater from baseline, or for patients under 18 years
old, a reduction of at least 0.15 in BMI-Z score:
- In adult patients 18 years or older, six of 20 (30%) achieved
5% or greater weight loss at three months;
- In patients younger than 18 years, three of 10 (30%) achieved a
BMI-Z reduction of 0.15% or more at three months.
- Across all enrolled patients, the mean overall weight loss from
baseline to three months among patients 18 years and older (n=20)
was -4.0% (SD: 3.3%), and the mean overall BMI-Z score reduction
from baseline to three months among patients younger than 18 years
(n=10) was -0.21 (SD: 0.23).
In addition, the data show a clear separation between patients
who responded to setmelanotide treatment at three months and those
who did not:
- The mean body weight reduction for adult patients who responded
(n=6) was 7.9% (90% CI, −9.7 to −6.0), as compared to 2.3% (90% CI,
−3.2 to −1.4) for adult patients who did not respond (n=14);
- The mean BMI-Z reduction for patients younger than 18 years who
responded (n=3) was 0.48 (90% CI, −0.95 to −0.01), as compared to
0.09 (90% CI, −0.11 to −0.07) for those who did not respond
(n=7).
Phase 2 Data in Obesity Due to SH2B1 Deficiency Cecilia Scimia,
M.D., Ph.D., Medical Director at Rhythm, presented, “Efficacy and
Safety Results of a Phase 2 Trial of Setmelanotide in Obesity Due
to SH2B1 Variants and 16p11.2 Deletion Syndrome.” A total of 35
patients with obesity and 16p11.2 deletions that include the
SH2B1gene or deficiency in the SH2B1 gene, which is a promotor of
leptin signaling in the MC4R pathway and can be associated with
early-onset, severe obesity, were enrolled in the full analysis set
of this study. These patients had a mean BMI of 47.2 kg/m2 or BMI-Z
of 3.6 at baseline. Highlights of the data include:
- Fifteen of 35 (42.9%) of patients achieved a clinically
meaningful response to setmelanotide at three months, as defined by
weight loss of 5% or greater from baseline, or for patients under
18 years old, a reduction of at least 0.15 in BMI-Z score:
- In patients 18 or older, eight of 22 (36.4%) achieved 5% or
greater weight loss at three months;
- In patients younger than 18 years, seven of 13 (53.8%) achieved
a BMI-Z reduction of 0.15% or more at three months.
- Across all enrolled patients, the mean overall weight loss from
baseline to three months among patients 18 years and older (n=22)
was -3.1% (SD: 3.9%), and the mean overall BMI-Z score reduction
from baseline to three months among patients younger than 18 years
(n=13) was -0.15 (SD: 0.13).
In addition, the data show a clear separation between patients
who responded to setmelanotide treatment at three months and those
who did not:
- The mean body weight reduction for adult patients who responded
(n=8) was 7.2% (90% CI, −8.6 to −5.8), as compared to 0.8% (90% CI,
−1.9 to 0.3) for adult patients who did not respond (n=14);
- The mean BMI-Z reduction for patients younger than 18 years who
responded (n=7) was 0.25 (90% CI, −0.29 to −0.21), as compared to
0.03 (90% CI, −0.08 to 0.02) patients younger than 18 years who did
not respond (n=7).
As previously reported, setmelanotide was generally well
tolerated, with a consistent safety profile across these
trials.
Additional Poster PresentationsFour additional
abstracts were presented as posters:
Bhavik Shah, Ph.D., Senior Director Translational Research and
Nonclinical Development, Rhythm Pharmaceuticals, presented, “An
Evidence-based Framework to Evaluate Melanocortin-4 Receptor (MC4R)
Pathway Relevance for Obesity-associated Genes.” In this poster,
Dr. Shah outlined Rhythm’s evidence-based framework for gene
selection criteria, which was used to identify MC4R
pathway-relevant genes for inclusion in the Phase 2 DAYBREAK trial.
The DAYBREAK trial is designed to evaluate setmelanotide in
patients with specific variants in 31 genes classified under this
framework as having “strong” or “very strong” relevance to the MC4R
pathway.
Cecilia Scimia, M.D., Ph.D., Medical Director, Rhythm
Pharmaceuticals, presented additional detail on the design of
Rhythm’s Phase 2 DAYBREAK trial in a separate poster, “Design of a
Phase 2, Double-Blind, Placebo-Controlled Trial of Setmelanotide in
Patients with Genetic Variants in the Melanocortin-4 Receptor
Pathway.”
Ida Moeller, ScD, ScM, MMSc, Director of Biomedical Informatics,
Rhythm Pharmaceuticals, presented “Frequency of MC4R Pathway
Variants in a Large US Cohort of Pediatric and Adult Patients with
Severe Obesity.” In this poster, Dr. Moeller reviewed updated data
from individuals sequenced as part of Rhythm’s Uncovering Rare
Obesity® (URO) genetic testing program. As of May 2021, Rhythm had
sequenced genetic samples from 7,826 individuals in the United
States with severe obesity, of which approximately 25% were found
to be carrying a variant in one of 11 select MC4R pathway related
genes. In July, Rhythm launched an updated URO genetic test with an
expanded gene panel.
Jennifer Miller, M.D., Division of Pediatric Endocrinology,
University of Florida, presented, “Efficacy and Safety of
Setmelanotide in Individuals with Obesity Due to POMC or LEPR
Deficiency: Phase 3 Results from Pivotal and Supplemental Cohorts.”
Highlights from this presentation include:
- A total of 85.7% of patients in the POMC trial (12/14;
p<0.0001) and 53.3% of patients in the LEPR trial (8/15;
p<0.0001) achieved ≥10% weight loss from baseline at 52
weeks;
- The mean percent change in body weight from baseline to 52
weeks was −25.8% (SD: 9.7%; p<0.0001) and −12.3% (SD: 7.5%;
p<0.0001) in the POMC and LEPR trials, respectively.
All Rhythm’s presentations from ESPE 2021 will be available
following the meeting on the Publication and Presentations section
of its website: https://www.rhythmtx.com/publications/ .
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 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
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 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 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, 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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