WELIREG is the first and only oral
hypoxia-inducible factor-2 alpha inhibitor approved in the European
Union
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced that the European Commission (EC) has
conditionally approved 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 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 EC approval of these two indications is based on results
from the LITESPARK-004 and LITESPARK-005 trials, respectively, and
follows the positive recommendation from the Committee for
Medicinal Products for Human Use adopted in December 2024. This
marks the first approval for WELIREG in the European Union (EU).
WELIREG is now approved in over 30 countries for certain adult
patients with previously treated advanced RCC and in more than 40
countries for adult patients with certain eligible VHL
disease-associated tumors.
“The approval of WELIREG in the EU introduces the first and only
systemic treatment option for adult patients with certain VHL
disease-associated tumors for whom localized procedures are
unsuitable, and offers a new option for adult patients with
advanced clear cell renal cell carcinoma that progressed following
a PD-1 or PD-L1 inhibitor and at least two VEGF targeted
therapies,” said Dr. Marjorie Green, senior vice president and head
of oncology, global clinical development, Merck Research
Laboratories. “This is an important moment, and we are pleased that
WELIREG, a first-in-class HIF-2α inhibitor, can now potentially
help these patients in need.”
This approval allows marketing of WELIREG for these indications
in all 27 EU member states, as well as Iceland, Liechtenstein and
Norway. The conditional approval of WELIREG will be valid for one
year, subject to yearly renewal, pending additional clinical data
from LITESPARK-004 and another ongoing Phase 2 trial of WELIREG in
patients with certain VHL disease-associated tumors. Timing for
commercial availability of WELIREG in individual EU countries will
depend on multiple factors, including the completion of national
reimbursement procedures.
Results in Patients With Certain Eligible VHL
Disease-associated Tumors (LITESPARK-004)
WELIREG is now the first and only systemic therapy for the
treatment of VHL disease-associated tumors in the EU. The approval
in adult patients with certain eligible VHL disease-associated
tumors is based on objective response rate (ORR) and duration of
response (DOR) results from the LITESPARK-004 trial.
WELIREG was approved in the U.S. in August 2021 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. In
patients with VHL disease-associated RCC (n=61), WELIREG showed an
ORR of 49% (95% CI, 36-62) (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. Among these 61 patients, the study also evaluated response
rates in other common disease-associated tumors including CNS
hemangioblastomas and pNET. In patients with VHL disease-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
disease-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.
Results in Certain Patients With Previously Treated Advanced
RCC (LITESPARK-005)
The approval in adult patients with advanced clear cell RCC that
progressed following two or more lines of therapy, including a PD-1
or PD-L1 inhibitor and at least two VEGF targeted therapies, is
based on progression-free survival (PFS) and ORR results from the
LITESPARK-005 trial, which was the first trial in advanced RCC to
specifically evaluate patients who progressed following these
treatments.
WELIREG was approved in the U.S. in December 2023 for the
treatment of adult patients with advanced RCC following both a PD-1
or PD-L1 inhibitor and a VEGF-tyrosine kinase inhibitor based on
the results from LITESPARK-005. 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. 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 LITESPARK-004
LITESPARK-004 is an open-label Phase 2 trial
(ClinicalTrials.gov, NCT03401788) evaluating WELIREG for the
treatment of patients with VHL disease who had at least one
measurable solid tumor localized to the kidney and who did not
require immediate surgery. The study enrolled 61 patients who
received WELIREG (120 mg orally once daily) until disease
progression or unacceptable toxicity. The primary endpoint is ORR
in VHL disease-associated RCC. Secondary endpoints include, DOR,
time to response, PFS, time to surgery and safety. Additionally,
this study evaluated response rates in other common VHL
disease-associated tumors including pNET and CNS
hemangioblastomas.
About LITESPARK-005
LITESPARK-005 is an open-label, randomized, active-controlled
Phase 3 trial (ClinicalTrials.gov, NCT04195750) evaluating WELIREG
compared to everolimus for the treatment of 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.
The trial enrolled 746 patients who were randomized to receive
WELIREG (120 mg orally once daily) or everolimus (10 mg orally once
daily). The dual primary endpoints are PFS and overall survival.
Secondary endpoints include ORR, DOR and safety.
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 disease are at
risk for recurrent, benign blood vessel tumors as well as some
cancerous ones. One of the most commonly occurring tumors 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. Clear cell RCC is considered the most common form of RCC,
representing about 70% of all cases. 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
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N.J., USA
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(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
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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
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Risks and uncertainties include but are not limited to, general
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including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and health care
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The company undertakes no obligation to publicly update any
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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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