Robust evidence of the clinical benefit of
WINREVAIR demonstrated in the STELLAR and ZENITH studies resulted
in a loss of clinical equipoise in the HYPERION study
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, announced today the Phase 3 HYPERION study evaluating
WINREVAIR (sotatercept-csrk) versus placebo (both in combination
with background therapy) in recently diagnosed adults with
pulmonary arterial hypertension (PAH, WHO* Group 1) functional
class (FC) II or III at intermediate or high risk of disease
progression will be stopped early. The decision to stop the
HYPERION study prior to its scheduled completion was based on the
positive results from the interim analysis of the ZENITH trial and
a review of the totality of data from the WINREVAIR clinical
program to date. The program’s external steering committee and
Merck made this decision in light of these data, which will enable
all study participants to have the opportunity to access WINREVAIR.
Merck discussed this decision to stop the HYPERION study early with
the U.S. Food and Drug Administration (FDA) and has informed
HYPERION study investigators.
"After closely reviewing the robust efficacy data across a broad
spectrum of patients evaluated in the WINREVAIR clinical
development program, the steering committee has unanimously
concluded that the HYPERION study, evaluating WINREVAIR versus
placebo on top of background therapy, has lost clinical equipoise
and should be stopped early,” said Dr. Vallerie McLaughlin**, Kim A
Eagle MD Endowed Professor of Cardiovascular Medicine and Director,
Pulmonary Hypertension Program, University of Michigan in Ann
Arbor. “PAH is a progressive and debilitating disease with a high
incidence of morbidity and mortality, and we look forward to
continuing to evaluate these patients and any potential impact to
the treatment landscape as a result of these data.”
“Based on the strong, positive interim efficacy data from the
ZENITH trial, as well as the totality of available WINREVAIR data,
we concluded that it would not be ethical to continue the HYPERION
study,” said Dr. Eliav Barr, senior vice president and head of
global clinical development, chief medical officer, Merck Research
Laboratories. “We are grateful to the dedicated community of
patients who participated in these studies and are pleased to offer
the option of receiving WINREVAIR through the Phase 3 SOTERIA
open-label extension study.”
Findings from the HYPERION study will be available later this
year and presented at a future medical congress.
WINREVAIR is currently approved in the U.S. and 38 countries
based on the results from the Phase 3 STELLAR trial.
*World Health Organization
**Dr. McLaughlin is a member of the adult sotatercept steering
committee, an investigator in the ZENITH and HYPERION trials and a
paid consultant to Merck.
About HYPERION
The HYPERION study (NCT04811092) is a global, double-blind,
placebo-controlled clinical trial to evaluate WINREVAIR when added
to background PAH therapy in newly diagnosed intermediate or
high-risk PAH patients. Participants enrolled in the study had a
diagnosis within 12 months of study screening of symptomatic PAH
(WHO Group 1, classified as FC II or III) and presentation of
idiopathic or heritable PAH, PAH associated with connective tissue
diseases (CTD), drug- or toxin-induced PAH, post shunt correction
PAH, or PAH presenting at least one year following the correction
of congenital heart defects.
The study enrolled approximately 300 study participants, who
were randomized in a 1:1 ratio to either WINREVAIR plus background
PAH therapy or placebo plus background PAH therapy. The primary
composite outcome measure is time to clinical worsening (TTCW) as
measured by first confirmed morbidity or mortality event. Clinical
worsening events are defined as all-cause death, non-planned PAH
worsening-related hospitalization of ≥ 24 hours, atrial septostomy,
lung transplantation, and deterioration in six-minute walk test
from baseline combined with at least one of the following changes
including worsening of WHO FC from baseline, signs/symptoms of
increased right heart failure, addition of a background PAH therapy
or change in the background PAH therapy delivery route to
parenteral.
Secondary outcome measures include improvement of six-minute
walk distance (6MWD), improvement and maintenance or achievement of
N-terminal pro-B-type natriuretic peptide (NT-proBNP) and
improvement in WHO FC or maintenance of WHO FC II as well as
additional measures. Participants in the HYPERION trial will have
the opportunity to receive WINREVAIR as part of the open-label,
long-term extension study, SOTERIA (NCT04796337), consistent with
that study’s eligibility criteria.
About ZENITH
The ZENITH study (NCT04896008) is a global, double-blind,
placebo-controlled clinical trial to evaluate WINREVAIR when added
to maximum tolerated background PAH therapy on time to first event
of all-cause death, lung transplantation, or PAH worsening related
hospitalization of ≥24 hours, in participants with WHO FC III or IV
PAH at high risk of mortality. ZENITH study inclusion criteria
required Registry to Evaluate Early and Long-Term PAH Disease
Management (REVEAL) Lite 2.0 risk score of ≥9.
The study enrolled 172 participants, who were randomized in a
1:1 ratio to either WINREVAIR plus background PAH therapy or
placebo plus background PAH therapy. The primary composite outcome
measure is time to first confirmed morbidity or mortality event.
Events are defined as all-cause death, lung transplantation, or PAH
worsening-related hospitalization of ≥24 hours. Secondary outcome
measures include overall survival, transplant-free survival and
several additional measures. Participants who have completed the
ZENITH trial have the opportunity to receive sotatercept as part of
the open-label, long-term extension study, SOTERIA (NCT04796337),
consistent with that study’s eligibility criteria.
About STELLAR
STELLAR (NCT04576988) is a pivotal Phase 3, randomized,
double-blind, placebo-controlled, multicenter, parallel-group study
designed to evaluate the safety and efficacy of WINREVAIR compared
to placebo, as an add-on to background therapy for the treatment of
adults with PAH (WHO Group 1). The primary endpoint was exercise
capacity, as measured by 6MWD 24 weeks following initiation of
treatment. Nine secondary outcome measures were assessed:
proportion of participants achieving multicomponent improvement
(consisting of improvement in 6MWD, improvement in NT-proBNP level,
and either improvement in WHO FC or maintenance of WHO FC II);
change from baseline in pulmonary vascular resistance (PVR); change
from baseline in NT-proBNP levels; proportion of participants who
improved in WHO FC; time to death or the first occurrence of a TTCW
event; proportion of participants who maintained or achieved a low
risk score using the simplified French Risk score calculator;
change from baseline in the Physical Impacts domain score of
PAH-SYMPACT®; change from baseline in the Cardiopulmonary Symptoms
domain score of PAH-SYMPACT; and change from baseline in the
Cognitive/Emotional Impacts domain score of PAH-SYMPACT.
About SOTERIA
SOTERIA (NCT04796337) is an ongoing open-label extension study
evaluating the long-term safety, tolerability and efficacy of
WINREVAIR when added to background therapy for the treatment of PAH
in patients who have completed previous WINREVAIR studies without
early discontinuation. The primary objective of SOTERIA is to
evaluate long-term safety and tolerability. The secondary objective
is to assess the continued efficacy of WINREVAIR, as measured by
6MWD, NT-proBNP, WHO FC, pulmonary vascular resistance, overall
survival, and simplified French risk score. Results from the
SOTERIA study were presented at the European Respiratory Society
(ERS) International Congress in 2023.
About WINREVAIR™ (sotatercept-csrk) for injection, for
subcutaneous use, 45 mg, 60 mg
WINREVAIR is FDA-approved for the treatment of adults with
pulmonary arterial hypertension (PAH, WHO Group 1) to increase
exercise capacity, improve WHO functional class (FC) and reduce the
risk of clinical worsening events. WINREVAIR is the first activin
signaling inhibitor therapy approved to treat PAH. WINREVAIR
improves the balance between pro-proliferative and
anti-proliferative signaling to modulate vascular proliferation. In
preclinical models, WINREVAIR induced cellular changes that were
associated with thinner vessel walls, partial reversal of right
ventricular remodeling, and improved hemodynamics.
WINREVAIR is the subject of a licensing agreement with Bristol
Myers Squibb.
Selected Safety Information for WINREVAIR in the U.S.
WINREVAIR may increase hemoglobin (Hgb). Severe erythrocytosis
may increase the risk of thromboembolic events or hyperviscosity
syndrome. Monitor Hgb before each dose for the first 5 doses, or
longer if values are unstable, and periodically thereafter, to
determine if dose adjustments are required.
WINREVAIR may decrease platelet count. Severe thrombocytopenia
may increase the risk of bleeding. Thrombocytopenia occurred more
frequently in patients also receiving prostacyclin infusion. Do not
initiate treatment if platelet count is <50,000/mm3. Monitor
platelets before each dose for the first 5 doses, or longer if
values are unstable, and periodically thereafter to determine
whether dose adjustments are required.
In clinical studies, serious bleeding (e.g., gastrointestinal,
intracranial hemorrhage) was reported in 4% of patients taking
WINREVAIR and 1% of patients taking placebo. Patients with serious
bleeding were more likely to be on prostacyclin background therapy
and/or antithrombotic agents, or have low platelet counts. Advise
patients about signs and symptoms of blood loss. Do not administer
WINREVAIR if the patient is experiencing serious bleeding.
WINREVAIR may cause fetal harm when administered to a pregnant
woman. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use an effective method
of contraception during treatment with WINREVAIR and for at least 4
months after the final dose. Pregnancy testing is recommended for
females of reproductive potential before starting WINREVAIR
treatment.
Based on findings in animals, WINREVAIR may impair female and
male fertility. Advise patients on the potential effects on
fertility.
The most common adverse reactions occurring in the phase 3
clinical trial (≥10% for WINREVAIR and at least 5% more than
placebo) were headache (24.5% vs 17.5%), epistaxis (22.1% vs 1.9%),
rash (20.2% vs 8.1%), telangiectasia (16.6% vs 4.4%), diarrhea
(15.3% vs 10.0%), dizziness (14.7% vs 6.2%), and erythema (13.5% vs
3.1%).
Because of the potential for serious adverse reactions in the
breastfed child, advise patients that breastfeeding is not
recommended during treatment with WINREVAIR, and for 4 months after
the final dose.
About PAH
Pulmonary arterial hypertension (PAH) is a rare, progressive and
life-threatening blood vessel disorder characterized by the
constriction of small pulmonary arteries and elevated blood
pressure in the pulmonary circulation. Approximately 40,000 people
in the U.S. are living with PAH. The disease progresses rapidly for
many patients. PAH results in significant strain on the heart,
leading to limited physical activity, heart failure and reduced
life expectancy. The five-year mortality rate for patients with PAH
is approximately 43%.
About Merck
At Merck, known as MSD outside of the United States and Canada,
we are unified around our purpose: We use the power of leading-edge
science to save and improve lives around the world. For more than
130 years, we have brought hope to humanity through the development
of important medicines and vaccines. We aspire to be the premier
research-intensive biopharmaceutical company in the world – and
today, we are at the forefront of research to deliver innovative
health solutions that advance the prevention and treatment of
diseases in people and animals. We foster a diverse and inclusive
global workforce and operate responsibly every day to enable a
safe, sustainable and healthy future for all people and
communities. For more information, visit www.merck.com and connect
with us on X (formerly Twitter), Facebook, Instagram, YouTube and
LinkedIn.
Forward-Looking Statement of Merck & Co., Inc., Rahway,
N.J., USA
This news release of Merck & Co., Inc., Rahway, N.J., USA
(the “company”) includes “forward-looking statements” within the
meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline candidates that
the candidates will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and health care
legislation in the United States and internationally; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the company’s ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial
instability of international economies and sovereign risk;
dependence on the effectiveness of the company’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s Annual
Report on Form 10-K for the year ended December 31, 2023 and the
company’s other filings with the Securities and Exchange Commission
(SEC) available at the SEC’s Internet site (www.sec.gov).
Please see Prescribing Information for WINREVAIR
(sotatercept-csrk) at
http://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_pi.pdf,
Patient Information for WINREVAIR at
http://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_ppi.pdf,
and Instructions for Use for WINREVAIR (1-vial kit, 2-vial kit)
at
https://www.merck.com/product/usa/pi_circulars/w/winrevair/winrevair_ifu_1-vial_2-vial_kits.pdf.
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