If approved, WELIREG would be the first and
only oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor
available for these patients in the European Union
Positive opinion granted based on data from
the Phase 2 LITESPARK-004 trial and the Phase 3 LITESPARK-005
trial
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced that the European Medicines Agency’s
Committee for Medicinal Products for Human Use (CHMP) adopted a
positive opinion recommending the conditional approval of WELIREG®
(belzutifan), Merck’s oral hypoxia-inducible factor-2 alpha
(HIF-2α) inhibitor, as monotherapy for:
- The treatment of adult patients with von Hippel-Lindau (VHL)
disease who require therapy for associated, localized renal cell
carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or
pancreatic neuroendocrine tumors (pNET), and for whom localized
procedures are unsuitable;
- The treatment of adult patients with advanced clear cell renal
cell carcinoma (RCC) that progressed following two or more lines of
therapy that included a programmed death receptor-1 (PD-1) or
programmed death-ligand 1 (PD-L1) inhibitor and at least two
vascular endothelial growth factor (VEGF) targeted therapies.
The CHMP’s recommendation will now be reviewed by the European
Commission for marketing authorization in the European Union (EU),
and a final decision is expected in the first quarter of 2025.
“Today’s positive CHMP opinion brings us closer to offering
WELIREG, a first-in-class HIF-2α inhibitor, to certain patients in
the European Union, in order to help address critical gaps in care
for these patients,” said Dr. Marjorie Green, senior vice president
and head of oncology, global clinical development, Merck Research
Laboratories. “We are committed to providing innovative treatment
options that address serious unmet needs for patients globally and
look forward to the European Commission’s decision.”
The CHMP recommendation in VHL disease-associated tumors is
based on objective response rate (ORR) and duration of response
(DOR) results from the LITESPARK-004 trial. If approved, WELIREG
would be the first and only systemic treatment for patients with
VHL disease-associated tumors in the EU.
In August 2021, WELIREG was approved in the U.S. for the
treatment of adult patients with VHL disease who require therapy
for associated RCC, CNS hemangioblastomas or pNET not requiring
immediate surgery based on the results from LITESPARK-004, an
open-label clinical trial in 61 patients with VHL-associated RCC.
In the LITESPARK-004 trial, WELIREG showed an ORR of 49% (95% CI,
36-62) in patients with VHL-associated RCC (n=30/61); all responses
were partial responses (PR). Median DOR for these patients was not
reached, with ongoing responses ranging from 2.8+ to 22+ months;
among responders, 56% (n=17/30) maintained a response for at least
12 months.
Patients enrolled in LITESPARK-004 had other VHL-associated
tumors, including CNS hemangioblastomas and pNET. In patients with
VHL-associated CNS hemangioblastomas (n=24) in this trial, WELIREG
showed an ORR of 63% (95% CI, 41-81) (n=15/24), with a complete
response (CR) rate of 4% (n=1/24) and a PR rate of 58% (n=14/24).
Median DOR for these patients was not reached, with ongoing
responses ranging from 3.7+ to 22+ months; among responders, 73%
(n=11/15) maintained a response for at least 12 months. In patients
with VHL-associated pNET (n=12) in this trial, WELIREG showed an
ORR of 83% (95% CI, 52-98) (n=10/12), with a CR rate of 17%
(n=2/12) and a PR rate of 67% (n=8/12). Median DOR for these
patients was not reached, with ongoing responses ranging from 11+
to 19+ months; among responders, 50% (n=5/10) maintained a response
for at least 12 months.
The CHMP recommendation in advanced clear cell RCC that
progressed following two or more lines of therapy that included a
PD-(L)1 inhibitor and at least two VEGF targeted therapies, is
based on PFS and ORR results from the LITESPARK-005 trial, the
first positive Phase 3 trial in these patients.
In December 2023, WELIREG was approved in the U.S. for the
treatment of adult patients with advanced RCC following a PD-1 or
PD-L1 inhibitor and a VEGF-TKI based on the results from
LITESPARK-005, an open-label clinical trial in 746 patients with
unresectable, locally advanced or metastatic clear cell RCC that
progressed following PD-1 or PD-L1 checkpoint inhibitor and VEGF
receptor targeted therapies either in sequence or in combination.
In the trial, WELIREG reduced the risk of disease progression or
death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) versus
everolimus in these patients. Median PFS was 5.6 months (95% CI,
3.9-7.0) for WELIREG versus 5.6 months (95% CI, 4.8-5.8) for
everolimus. The ORR for WELIREG was 22% (n=82) (95% CI, 18-27),
with a CR rate of 3% (n=10) and a PR rate of 19% (n=72), and the
ORR for everolimus was 4% (n=13) (95% CI, 2-6), with no patients
achieving a CR and a PR rate of 4% (n=13).
About von Hippel-Lindau disease Von Hippel-Lindau disease
is a rare genetic disease, which impacts an estimated 200,000
people worldwide and an estimated 10,000 to 15,000 people in
Europe. Patients with VHL are at risk for recurrent, benign blood
vessel tumors as well as some cancerous ones. The most commonly
occurring tumor is RCC, a form of kidney cancer, which occurs in
about 70% of patients with VHL disease.
About renal cell carcinoma Renal cell carcinoma is by far
the most common type of kidney cancer. In 2020, more than 130,000
new cases of RCC were diagnosed in Europe. Renal cell carcinoma is
about twice as common in men than in women. Approximately 30% of
patients with kidney cancer are diagnosed at an advanced stage.
About WELIREG® (belzutifan) 40 mg tablets, for oral use
Indications in the U.S. Certain von Hippel-Lindau (VHL)
disease-associated tumors WELIREG (belzutifan) is indicated for the
treatment of adult patients with von Hippel-Lindau (VHL) disease
who require therapy for associated renal cell carcinoma (RCC),
central nervous system (CNS) hemangioblastomas, or pancreatic
neuroendocrine tumors (pNET), not requiring immediate surgery.
Advanced Renal Cell Carcinoma (RCC) WELIREG is indicated for the
treatment of adult patients with advanced renal cell carcinoma
(RCC) following a programmed death receptor-1 (PD-1) or programmed
death ligand 1 (PD-L1) inhibitor and a vascular endothelial growth
factor tyrosine kinase inhibitor (VEGF-TKI).
Selected Safety Information for WELIREG Warning:
Embryo-Fetal Toxicity Exposure to WELIREG during pregnancy can
cause embryo-fetal harm. Verify pregnancy status prior to the
initiation of WELIREG. Advise patients of these risks and the need
for effective non-hormonal contraception as WELIREG can render some
hormonal contraceptives ineffective.
Anemia WELIREG can cause severe anemia that can require
blood transfusion. Monitor for anemia before initiation of, and
periodically throughout, treatment. Transfuse patients as
clinically indicated. For patients with hemoglobin <8 g/dL,
withhold WELIREG until ≥8 g/dL, then resume at the same or reduced
dose or permanently discontinue WELIREG, depending on the severity
of anemia. For life-threatening anemia or when urgent intervention
is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then
resume at a reduced dose or permanently discontinue WELIREG.
In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of
patients with VHL disease and 7% had Grade 3 events. Median time to
onset of anemia was 31 days (range: 1 day to 8.4 months).
The safety of erythropoiesis-stimulating agents (ESAs) for
treatment of anemia in patients with VHL disease treated with
WELIREG has not been established.
In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88%
of patients with advanced RCC and 29% had Grade 3 events. Median
time to onset of anemia was 29 days (range: 1 day to 16.6 months).
Of the patients with anemia, 22% received transfusions only, 20%
received ESAs only, and 12% received both transfusion and ESAs.
Hypoxia WELIREG can cause severe hypoxia that may require
discontinuation, supplemental oxygen, or hospitalization.
Monitor oxygen saturation before initiation of, and periodically
throughout, treatment. For decreased oxygen saturation with
exercise (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg), consider
withholding WELIREG until pulse oximetry with exercise is greater
than 88%, then resume at the same or a reduced dose. For decreased
oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55
mm Hg) or when urgent intervention is indicated, withhold WELIREG
until resolved and resume at a reduced dose or discontinue. For
life-threatening or recurrent symptomatic hypoxia, permanently
discontinue WELIREG. Advise patients to report signs and symptoms
of hypoxia immediately to a healthcare provider.
In LITESPARK-004, hypoxia occurred in 1.6% of patients.
In LITESPARK-005, hypoxia occurred in 15% of patients and 10%
had Grade 3 events. Of the patients with hypoxia, 69% were treated
with oxygen therapy. Median time to onset of hypoxia was 30.5 days
(range: 1 day to 21.1 months).
Embryo-Fetal Toxicity Based on findings in animals,
WELIREG can cause fetal harm when administered to a pregnant
woman.
Advise pregnant women and females of reproductive potential of
the potential risk to the fetus. Advise females of reproductive
potential to use effective non-hormonal contraception during
treatment with WELIREG and for 1 week after the last dose. WELIREG
can render some hormonal contraceptives ineffective. Advise male
patients with female partners of reproductive potential to use
effective contraception during treatment with WELIREG and for 1
week after the last dose.
Adverse Reactions In LITESPARK-004, serious adverse
reactions occurred in 15% of patients, including anemia, hypoxia,
anaphylaxis reaction, retinal detachment, and central retinal vein
occlusion (1 patient each).
WELIREG was permanently discontinued due to adverse reactions in
3.3% of patients for dizziness and opioid overdose (1.6% each).
Dosage interruptions due to an adverse reaction occurred in 39%
of patients. Those which required dosage interruption in >2% of
patients were fatigue, decreased hemoglobin, anemia, nausea,
abdominal pain, headache, and influenza-like illness.
Dose reductions due to an adverse reaction occurred in 13% of
patients. The most frequently reported adverse reaction which
required dose reduction was fatigue (7%).
The most common adverse reactions (≥25%), including laboratory
abnormalities, that occurred in patients who received WELIREG were
decreased hemoglobin (93%), fatigue (64%), increased creatinine
(64%), headache (39%), dizziness (38%), increased glucose (34%),
and nausea (31%).
In LITESPARK-005, serious adverse reactions occurred in 38% of
patients. The most frequently reported serious adverse reactions
were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%),
and pleural effusion (2.2%). Fatal adverse reactions occurred in
3.2% of patients who received WELIREG, including sepsis (0.5%) and
hemorrhage (0.5%).
WELIREG was permanently discontinued due to adverse reactions in
6% of patients. Adverse reactions which resulted in permanent
discontinuation (≥0.5%) were hypoxia (1.1%) and hemorrhage
(0.5%).
Dosage interruptions due to an adverse reaction occurred in 39%
of patients. Of the patients who received WELIREG, 28% were 65 to
74 years, and 10% were 75 years and over. Dose interruptions
occurred in 48% of patients ≥65 years of age and in 34% of younger
patients. Adverse reactions which required dosage interruption in
≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%),
fatigue (3.2%), and hemorrhage (2.2%).
Dose reductions due to an adverse reaction occurred in 13% of
patients. Dose reductions occurred in 18% of patients ≥65 years of
age and in 10% of younger patients. The most frequently reported
adverse reactions which required dose reduction (≥1.0%) were
hypoxia (5%) and anemia (3.2%).
The most common (≥25%) adverse reactions, including laboratory
abnormalities, were decreased hemoglobin (88%), fatigue (43%),
musculoskeletal pain (33%), increased creatinine (34%), decreased
lymphocytes (34%), increased alanine aminotransferase (32%),
decreased sodium (31%), increased potassium (29%), and increased
aspartate aminotransferase (27%).
Drug Interactions Coadministration of WELIREG with
inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of
belzutifan, which may increase the incidence and severity of
adverse reactions. Monitor for anemia and hypoxia and reduce the
dosage of WELIREG as recommended.
Coadministration of WELIREG with CYP3A4 substrates decreases
concentrations of CYP3A4 substrates, which may reduce the efficacy
of these substrates or lead to therapeutic failures. Avoid
coadministration with sensitive CYP3A4 substrates. If
coadministration cannot be avoided, increase the sensitive CYP3A4
substrate dosage in accordance with its Prescribing Information.
Coadministration of WELIREG with hormonal contraceptives may lead
to contraceptive failure or an increase in breakthrough
bleeding.
Lactation Because of the potential for serious adverse
reactions in breastfed children, advise women not to breastfeed
during treatment with WELIREG and for 1 week after the last
dose.
Females and Males of Reproductive Potential WELIREG can
cause fetal harm when administered to a pregnant woman. Verify the
pregnancy status of females of reproductive potential prior to
initiating treatment with WELIREG.
Use of WELIREG may reduce the efficacy of hormonal
contraceptives. Advise females of reproductive potential to use
effective non-hormonal contraception during treatment with WELIREG
and for 1 week after the last dose. Advise males with female
partners of reproductive potential to use effective contraception
during treatment with WELIREG and for 1 week after the last
dose.
Based on findings in animals, WELIREG may impair fertility in
males and females of reproductive potential and the reversibility
of this effect is unknown.
Pediatric Use Safety and effectiveness of WELIREG in
pediatric patients under 18 years of age have not been
established.
Merck’s focus on cancer Every day, we follow the science
as we work to discover innovations that can help patients, no
matter what stage of cancer they have. As a leading oncology
company, we are pursuing research where scientific opportunity and
medical need converge, underpinned by our diverse pipeline of more
than 25 novel mechanisms. With one of the largest clinical
development programs across more than 30 tumor types, we strive to
advance breakthrough science that will shape the future of
oncology. By addressing barriers to clinical trial participation,
screening and treatment, we work with urgency to reduce disparities
and help ensure patients have access to high-quality cancer care.
Our unwavering commitment is what will bring us closer to our goal
of bringing life to more patients with cancer. For more
information, visit https://www.merck.com/research/oncology/.
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
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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;
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protections for innovation products; and the exposure to
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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, including information for
the Boxed Warning about embryo-fetal toxicity, for WELIREG
(belzutifan) at
https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf
and Medication Guide for WELIREG at
https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_mg.pdf.
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Merck (NYSE:MRK)
過去 株価チャート
から 11 2024 まで 12 2024
Merck (NYSE:MRK)
過去 株価チャート
から 12 2023 まで 12 2024
