WELIREG Approved for Adult Patients With VHL
Disease Who Require Therapy for Associated Renal Cell Carcinoma,
Central Nervous System Hemangioblastomas, or Pancreatic
Neuroendocrine Tumors, Not Requiring Immediate Surgery
WELIREG Expands Merck’s Oncology Portfolio
as the First and Only Systemic Therapy Approved for These Patients
With VHL Disease
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced that the U.S. Food and Drug Administration
(FDA) has approved WELIREG, an oral hypoxia-inducible factor-2
alpha (HIF-2α) inhibitor, 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. The recommended dose of WELIREG (40 mg
tablets) is 120 mg once daily until disease progression or
unacceptance toxicity. The approval is based on results from the
open-label Study 004 trial (N=61), where the major efficacy
endpoint was overall response rate (ORR) in patients with
VHL-associated RCC.
WELIREG is the first HIF-2α inhibitor therapy approved in the
U.S. As an inhibitor of HIF-2α, WELIREG reduces transcription and
expression of HIF-2α target genes associated with cellular
proliferation, angiogenesis and tumor growth.
The WELIREG label contains a boxed warning that 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. WELIREG can render some hormonal contraceptives
ineffective. WELIREG can cause severe anemia that can require a
blood transfusion. Monitor for anemia before initiation of WELIREG
and periodically throughout treatment. WELIREG can cause severe
hypoxia that may require discontinuation, supplemental oxygen, or
hospitalization. Monitor oxygen saturation before initiation of and
periodically throughout treatment with WELIREG. For more
information, see "Selected Safety Information" below.
“VHL disease is a rare and serious condition. Until today, there
were no systemic therapies approved to help treat patients
diagnosed with certain types of VHL-associated tumors,” said Dr.
Eric Jonasch, principal investigator of Study 004 and professor,
Department of Genitourinary Medical Oncology, Division of Cancer
Medicine, The University of Texas MD Anderson Cancer Center. “The
approval of WELIREG, which is based on data showing an overall
response rate across three different types of VHL-associated
tumors, addresses this significant unmet need by introducing a new
option for physicians and their patients impacted by this
disease.”
“WELIREG is the first and only approved systemic therapy for
patients with certain types of VHL-associated tumors, representing
an important new treatment option for patients affected by this
rare condition,” said Dr. Scot Ebbinghaus, vice president, clinical
research, Merck Research Laboratories. “Today’s approval of WELIREG
is a significant milestone and is a testament to Merck’s commitment
to bring forward innovative new treatment options for more
patients.”
“The approval of a non-surgical treatment option is meaningful
for helping patients with certain types of VHL-associated tumors,”
said Dr. Ramaprasad Srinivasan, head, Molecular Cancer Therapeutics
Section, Urologic Oncology Branch, National Cancer Institute (NCI),
and principal investigator on the Cooperative Research and
Development Agreement (CRADA) under which the NCI served as a site
in Study 004. “In Study 004, nearly half of all patients with
VHL-associated renal cell carcinoma, as well as the majority of
patients with VHL-associated central nervous system
hemangioblastomas or pancreatic neuroendocrine tumors, who were
treated with WELIREG experienced a reduction of their respective
tumor size. The FDA’s approval of WELIREG marks an important step
forward by introducing a systemic therapy that has the potential to
improve the current treatment paradigm for patients with certain
types of VHL-associated tumors.”
Merck is working to optimize production of WELIREG to allow for
a sustainable supply to meet anticipated U.S. demand. Commercial
supply is expected to be available by early September.
Data Supporting the Approval
The approval was based on data
from Study 004 (ClinicalTrials.gov, NCT03401788), an open-label trial in 61 patients
with VHL-associated RCC diagnosed based on a VHL germline
alteration and with at least one measurable solid tumor (as defined
by Response Evaluation Criteria in Solid Tumors [RECIST] v1.1)
localized to the kidney. Enrolled patients had other VHL-associated
tumors, including CNS hemangioblastomas and pNET. CNS
hemangioblastomas and pNET in these patients were diagnosed based
on the presence of at least one measurable solid tumor in the
brain/spine or pancreas, respectively, as defined by RECIST v1.1
and identified by an independent review committee (IRC). The study
excluded patients with metastatic disease. Patients received
WELIREG at a dose of 120 mg once daily until progression of disease
or unacceptable toxicity. In
Study 004, the median duration of exposure to WELIREG was 68 weeks
(range, 8.4 to 104.7).
The study population characteristics were: median age of 41
years (range, 19 to 66), 3.3% age 65 or older; 53% male; 90% white,
3.3% Black or African American, 1.6% Asian, and 1.6% Native
Hawaiian or other Pacific Islander; 82% had an Eastern Cooperative
Oncology Group (ECOG) performance status (PS) of 0, 16% had an ECOG
PS of 1, and 1.6% had an ECOG PS of 2; and 84% had VHL type I
disease. The median diameter of RCC target lesions per central IRC
was 2.2 centimeters (range, 1 to 6.1). Median time from initial
radiographic diagnosis of VHL-associated RCC tumors that led to
enrollment on Study 004 to the time of treatment with WELIREG was
17.9 months (range, 2.8 to 96.7). Seventy-seven percent of patients
had prior surgical procedures for RCC.
The major efficacy endpoint for the treatment of VHL-associated
RCC was ORR measured by radiology assessment using RECIST v1.1 as
assessed by IRC. Additional efficacy endpoints included duration of
response (DoR) and time to response (TTR).
In patients with VHL-associated RCC (n=61), WELIREG showed an
ORR of 49% (95% CI, 36-62); all responses were partial responses.
Median DoR had not yet been reached (range, 2.8+ to 22.3+ months);
among responders, 56% (n=17/30) were still responding after at
least 12 months. Median TTR was eight months (range, 2.7 to
19).
In patients with
VHL-associated CNS hemangioblastomas (n=24), WELIREG showed an ORR
of 63% (95% CI, 41-81), with a complete response rate of 4% (n=1)
and a partial response rate of 58% (n=14). Median DoR had not yet
been reached (range, 3.7+ to 22.3+ months); among responders, 73%
(n=11/15) were still responding after at least 12 months. Median
TTR was three months (range, 3 to 11).
In patients with
VHL-associated pNET (n=12), WELIREG showed an ORR of 83% (95% CI,
52-98), with a complete response rate of 17% (n=2) and a partial
response rate of 67% (n=8). Median DoR had not yet been reached
(range, 10.8+ to 19.4+ months); among responders, 50% (n=5/10) were
still responding after at least 12 months. Median TTR was eight
months (range, 3 to 11).
Serious adverse reactions
occurred in 15% of patients who received WELIREG, including anemia,
hypoxia, anaphylaxis reaction, retinal detachment and central
retinal vein occlusion (1 patient each). Permanent discontinuation
of WELIREG due to adverse reactions occurred in 3.3% of
patients. Adverse reactions that resulted in permanent
discontinuation of WELIREG were dizziness and opioid overdose (1.6%
each).
Dosage interruptions of WELIREG due to an adverse reaction
occurred in 39% of patients. Adverse reactions that required dosage
interruption in >2% of patients were fatigue, decreased
hemoglobin, anemia, nausea, abdominal pain, headache and
influenza-like illness. Dose reductions of WELIREG due to an
adverse reaction occurred in 13% of patients. The most frequently
reported adverse reaction that required dose reduction was fatigue
(7%).
The most common adverse
reactions (≥25%), including laboratory abnormalities, that occurred
in patients treated with WELIREG were decreased hemoglobin (93%),
anemia (90%), fatigue (64%), increased creatinine (64%), headache
(39%), dizziness (38%), increased glucose (34%) and nausea
(31%).
About Von Hippel-Lindau Disease
The incidence of von Hippel-Lindau (VHL) syndrome is estimated
to be one in 36,000 individuals. This is a rare genetic disease
with an estimated incidence of 10,000 people in the U.S. Patients
with VHL disease are at risk for benign blood vessel tumors as well
as some cancerous ones, including renal cell carcinoma.
WELIREG™ (belzutifan) Indication in the U.S.
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.
Selected Safety Information
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. In Study 004, anemia occurred in 90% of patients and
7% had Grade 3 anemia. In Study 001, a clinical trial in patients
with advanced solid tumors (n=58) treated at the recommended dose,
anemia occurred in 76% of patients and 28% had Grade 3 anemia.
Monitor for anemia before initiation of and periodically
throughout treatment. Closely monitor patients who are dual UGT2B17
and CYP2C19 poor metabolizers due to potential increases in
exposure that may increase the incidence or severity of anemia.
Transfuse patients as clinically indicated. For patients with
hemoglobin <9g/dL, withhold WELIREG until Hb≥9g/dL, then resume
at reduced dose or permanently discontinue depending on the
severity of anemia. For life threatening anemia or when urgent
intervention is indicated, withhold WELIREG until hemoglobin
≥9g/dL, then resume at a reduced dose or permanently
discontinue.
The use of erythropoiesis stimulating agents (ESAs) for
treatment of anemia is not recommended in patients treated with
WELIREG.
Hypoxia
WELIREG can cause severe hypoxia that may require
discontinuation, supplemental oxygen, or hospitalization. In Study
004, hypoxia occurred in 1.6% of patients. In Study 001, a clinical
trial in patients with advanced solid tumors (n=58) treated at the
recommended dose, hypoxia occurred in 29% of patients; 16% were
Grade 3 hypoxia.
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.
Embryo-Fetal Toxicity
Based on findings in animal studies, WELIREG may 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 Study 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).
The most common adverse reactions (≥25%) were decreased
hemoglobin (93%), anemia (90%), fatigue (64%), increased creatinine
(64%), headache (39%), dizziness (38%), increased glucose (34%),
and nausea (31%).
In Study 001, a clinical trial in patients with advanced solid
tumors (n=58) treated at the recommended dose, the following
additional adverse reactions have been reported: edema, cough,
musculoskeletal pain, vomiting, diarrhea, and dehydration.
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, including
hormonal contraceptives, decreases concentration of CYP3A4
substrates, which may reduce the efficacy of these substrates.
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 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
Our goal is to translate breakthrough science into innovative
oncology medicines to help people with cancer worldwide. At Merck,
the potential to bring new hope to people with cancer drives our
purpose and supporting accessibility to our cancer medicines is our
commitment. As part of our focus on cancer, Merck is committed to
exploring the potential of immuno-oncology with one of the largest
development programs in the industry across more than 30 tumor
types. We also continue to strengthen our portfolio through
strategic acquisitions and are prioritizing the development of
several promising oncology candidates with the potential to improve
the treatment of advanced cancers. For more information about our
oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For 130 years, Merck, known as MSD outside of the United States
and Canada, has been inventing for life, bringing forward medicines
and vaccines for many of the world’s most challenging diseases in
pursuit of our mission to save and improve lives. We demonstrate
our commitment to patients and population health by increasing
access to health care through far-reaching policies, programs and
partnerships. Today, Merck continues to be at the forefront of
research to prevent and treat diseases that threaten people and
animals – including cancer, infectious diseases such as HIV and
Ebola, and emerging animal diseases – as we aspire to be the
premier research-intensive biopharmaceutical company in the world.
For more information, visit www.merck.com and connect with us on
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Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, 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
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the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
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# # #
Please see Prescribing Information, including information for
the Boxed Warning, 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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