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April 3, 2018 5:00 am ET

If Approved, AstraZeneca and Merck’s LYNPARZA Would be the First PARP Inhibitor to Treat Patients with Breast Cancer in Europe

AstraZeneca and Merck (NYSE:MRK), known as MSD outside the US and
Canada, today announced that the European Medicines Agency has validated
for review the Marketing Authorization Application (MAA) for LYNPARZA^®
(olaparib) for use in patients with deleterious or suspected
deleterious BRCA-mutated, human epidermal growth factor receptor
2 (HER2)-negative metastatic breast cancer who have been previously
treated with chemotherapy in the neoadjuvant, adjuvant or metastatic
setting.

This is the first regulatory submission for a poly ADP-ribose polymerase
(PARP) inhibitor in breast cancer in Europe. If approved, the
identification of a patient’s BRCA status could become a critical
step in the management of their disease alongside current consideration
of their hormone receptor and HER2 status. The MAA is based on data from
the randomized, open-label, phase
3 OlympiAD trial, which investigated LYNPARZA versus chemotherapy
(physician’s choice of capecitabine, eribulin, or vinorelbine). In the
trial, LYNPARZA significantly prolonged progression-free survival
compared with chemotherapy, and reduced the risk of disease progression
or death by 42 percent (HR 0.58; 95% CI 0.43-0.80; P=0.0009 median 7.0
vs 4.2 months).

In January 2018, LYNPARZA was approved by the U.S. Food and Drug
Administration for use in the treatment of BRCA-mutated
HER2-negative metastatic breast cancer, becoming the first PARP
inhibitor to be approved beyond ovarian cancer. LYNPARZA is available in
nearly 60 countries and has been used to treat more than 20,000
patients. AstraZeneca and Merck are working together to bring LYNPARZA
to more patients across multiple cancers.

About OlympiAD

OlympiAD is a global, randomized, open-label, multi-center phase 3 trial
of 302 patients, assessing the efficacy and safety of LYNPARZA tablets
(300 mg twice daily) compared to physician’s choice of chemotherapy. 205
patients were randomized to receive LYNPARZA and 97 patients were
randomized to receive chemotherapy.

Patients in the OlympiAD trial had germline BRCA-mutated, HER2-negative
(hormone receptor-positive or triple-negative) breast cancer, and
received LYNPARZA for treatment in the metastatic setting. Prior
to enrollment, 71 percent of patients had received no more than two
previous chemotherapy treatments for metastasized breast cancer and 28
percent of patients had received prior platinum-based chemotherapy. Also
enrolled, were patients with HR+ breast cancer who had received at least
one endocrine therapy (adjuvant therapy or therapy for metastatic
disease) and had disease progression during therapy unless they had
disease for which the endocrine therapy was considered inappropriate.

About Metastatic Breast Cancer

Progesterone receptors (PR), estrogen receptors (ER) and HER2 receptors
may be expressed on breast cancer cells. A patient’s breast cancer will
test either negative or positive for these three receptors. If a tumor
tests positive for PR and/or ER, it is considered HR+. If a tumor tests
negative for all three receptors, it is considered triple negative.
These receptors indicate which hormones or other proteins may be
promoting growth of the cancer.

Metastatic breast cancer (MBC) is the most advanced stage of breast
cancer (Stage IV), and occurs when cancer cells have spread beyond the
initial tumor site to other parts of the body outside of the breast and
nearby lymph nodes.

Despite the increase in treatment options during the past three decades,
there is currently no cure for patients diagnosed with MBC and only 26.9
percent of patients survive for five years after diagnosis. Thus, the
primary aim of treatment is to slow progression of the disease for as
long as possible, improving, or at least maintaining, a patient’s
quality of life.

Breast cancer is the most common cancer in women, with an estimated 1.67
million new cases diagnosed worldwide in 2012 alone – one in four of all
cancer cases. Approximately 30 percent of women who are diagnosed with
early breast cancer will go on to develop advanced disease.

About BRCA Mutations

BRCA1 and BRCA2 are human genes that produce proteins
responsible for repairing damaged DNA and play an important role
maintaining the genetic stability of cells. When either of these genes
is mutated, or altered, such that its protein product either is not made
or does not function correctly, DNA damage may not be repaired properly
and cells become unstable. As a result, cells are more likely to develop
additional genetic alterations that can lead to cancer.

About LYNPARZA (olaparib)

LYNPARZA was the first in class PARP inhibitor and the first targeted
treatment to potentially exploit DNA damage response (DDR) pathway
deficiencies, such as BRCA mutations, to preferentially kill cancer
cells. Specifically, in vitro trials have shown that LYNPARZA-induced
cytotoxicity may involve inhibition of PARP enzymatic activity and
increased formation of PARP-DNA complexes, resulting in DNA damage and
cancer cell death.

LYNPARZA, which has the broadest clinical development program of any
PARP inhibitor, is being investigated in a range of DDR-deficient tumor
types.

The most frequently observed adverse reactions across clinical trials in
patients receiving LYNPARZA monotherapy (≥10%) were nausea, vomiting,
diarrhea, dyspepsia, fatigue, headache, dysgeusia, decreased appetite,
dizziness and anemia.

LYNPARZA, the first poly ADP-ribose polymerase (PARP) inhibitor
approved, was initially licensed as a capsule formulation. The new
tablet formulation will reduce dosing from eight capsules twice daily to
two tablets twice daily.

LYNPARZA is available in nearly 60 countries and has treated more than
20,000 patients globally. It has the broadest clinical development
program of any PARP inhibitor, and AstraZeneca and Merck are working
together to bring LYNPARZA to more patients across multiple cancers. In
January 2018, LYNPARZA was approved by the U.S. Food and Drug
Administration for use in metastatic breast cancer, becoming the first
PARP inhibitor licensed beyond ovarian cancer.

Indications for LYNPARZA (olaparib) in the U.S.

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

For the maintenance treatment of adult patients with recurrent
epithelial ovarian, fallopian tube, or primary peritoneal cancer, who
are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected
deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who
have been treated with 3 or more prior lines of chemotherapy. Select
patients for therapy based on an FDA-approved companion diagnostic for
LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm, human
epidermal growth factor receptor 2 (HER2)-negative metastatic breast
cancer who have previously been treated with chemotherapy in the
neoadjuvant, adjuvant or metastatic setting. Patients with hormone
receptor (HR)-positive breast cancer should have been treated with a
prior endocrine therapy or be considered inappropriate for endocrine
treatment. Select patients for therapy based on an FDA-approved
companion diagnostic for LYNPARZA.

Important Safety Information for LYNPARZA

^®


(olaparib)

Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred
in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority
of events had a fatal outcome. The duration of therapy in patients who
developed secondary MDS/AML varied from <6 months to >2 years. All of
these patients had previous chemotherapy with platinum agents and/or
other DNA-damaging agents, including radiotherapy, and some also had a
history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological
toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete
blood count for cytopenia at baseline and monthly thereafter for
clinically significant changes during treatment. For prolonged
hematological toxicities, interrupt LYNPARZA (olaparib) and monitor
blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer
the patient to a hematologist for further investigations, including bone
marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA
if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and
some cases were fatal. If patients present with new or worsening
respiratory symptoms such as dyspnea, cough, and fever, or a
radiological abnormality occurs, interrupt LYNPARZA treatment and
initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is
confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and
findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is
recommended for females of reproductive potential prior to initiating
treatment.

Females

Advise females of reproductive potential of the potential risk to a
fetus and to use effective contraception during treatment and for 6
months following the last dose.

Males

Advise male patients with female partners of reproductive potential or
who are pregnant to use effective contraception during treatment and for
3 months following the last dose of LYNPARZA and to not donate sperm
during this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in
clinical trials of LYNPARZA in the maintenance setting for SOLO-2:
nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting
(37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza
(36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%),
headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%),
vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract
infection (22%), constipation (22%), headache (21%), and decreased
appetite (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in
clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19)
were: increase in mean corpuscular volume (89%/82%), decrease in
hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in
lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%),
increase in serum creatinine (44%/45%), and decrease in platelets
(42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in
clinical trials of LYNPARZA (olaparib) for advanced gBRCAm ovarian
cancer after 3 or more lines of chemotherapy (pooled from 6 studies)
were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%),
anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract
infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased
appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in
clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled
from 6 studies) were: decrease in hemoglobin (90%), increase in mean
corpuscular volume (57%), decrease in lymphocytes (56%), increase in
serum creatinine (30%), decrease in platelets (30%), and decrease in
absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in
OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia)
(37%), vomiting (30%), neutropenia (27%), respiratory tract infection
(27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in
OlympiAD were: decrease in hemoglobin (82%), decrease in
lymphocytes (73%), decrease in leukocytes (71%), increase in mean
corpuscular volume (71%), decrease in absolute neutrophil count (46%),
and decrease in platelets (33%).

Drug Interactions

Anticancer Agents: Clinical studies of LYNPARZA in combination
with other myelosuppressive anticancer agents, including DNA-damaging
agents, indicate a potentiation and prolongation of myelosuppressive
toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate
CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be
co-administered, reduce the dose of LYNPARZA. Advise patients to avoid
grapefruit, grapefruit juice, Seville oranges, and Seville orange juice
during LYNPARZA (olaparib) treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A
inducers when using LYNPARZA. If a moderate inducer cannot be avoided,
there is a potential for decreased efficacy of LYNPARZA.

Use In Specific Populations

Lactation: No data are available regarding the presence of
olaparib in human milk, its effects on the breastfed infant or on milk
production. Because of the potential for serious adverse reactions in
the breastfed infant, advise a lactating woman not to breastfeed during
treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been
established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is
required in patients with mild hepatic impairment (Child-Pugh
classification A). There are no data in patients with moderate or severe
hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary
in patients with mild renal impairment (CLcr=51-80 mL/min). In patients
with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to
200 mg twice daily. There are no data in patients with severe renal
impairment or end-stage renal disease (CLcr ≤30 mL/min).

Dosing and Administration

To avoid substitution errors and overdose, do not substitute LYNPARZA
tablets with LYNPARZA capsules on a milligram-to-milligram basis
due to differences in the dosing and bioavailability of each
formulation. Recommended tablet dose is 300 mg, taken orally twice
daily, with or without food. Continue treatment until disease
progression or unacceptable toxicity. For adverse reactions, consider
dose interruption or dose reduction.

About the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck (known as MSD outside the United
States and Canada) announced a global strategic oncology collaboration
to co-develop and co-commercialize LYNPARZA, the world’s first PARP
inhibitor and potential new medicine selumetinib, a MEK inhibitor, for
multiple cancer types. The collaboration is based on increasing evidence
that PARP and MEK inhibitors can be combined with PD-L1/PD-1 inhibitors
for a range of tumor types. Working together, the companies will develop
LYNPARZA and selumetinib in combination with other potential new
medicines and as a monotherapy. Independently, the companies will
develop LYNPARZA and selumetinib in combination with their respective
PD-L1 and PD-1 medicines.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology
medicines to help people with cancer worldwide. At Merck, helping people
fight cancer is our passion and supporting accessibility to our cancer
medicines is our commitment. Our focus is on pursuing research in
immuno-oncology and we are accelerating every step in the journey – from
lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the
potential of immuno-oncology with one of the fastest-growing development
programs in the industry. We are currently executing an expansive
research program evaluating our anti-PD-1 therapy across more than 30
tumor types. We also continue to strengthen our immuno-oncology
portfolio through strategic acquisitions and are prioritizing the
development of several promising immunotherapeutic 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 more than a century, Merck, a leading global biopharmaceutical
company 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. Through our prescription
medicines, vaccines, biologic therapies and animal health products, we
work with customers and operate in more than 140 countries to deliver
innovative health solutions. We also demonstrate our commitment to
increasing access to health care through far-reaching policies, programs
and partnerships. Today, Merck continues to be at the forefront of
research to advance the prevention and treatment of diseases that
threaten people and communities around the world – including cancer,
cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease
and infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect
with us on Twitter, Facebook, Instagram, YouTube
and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., 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 management and are subject to
significant risks and uncertainties. There can be no guarantees with
respect to pipeline products that the products 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
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The company undertakes no obligation to publicly update any
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future events or otherwise. Additional factors that could cause results
to differ materially from those described in the forward-looking
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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 complete 

Prescribing
Information

for LYNPARZA (olaparib), including Patient
Information (Medication Guide)

Media:
Pamela Eisele, 267-305-3558
Courtney Ronaldo, 908-740-6132
Investor:
Teri Loxam, 908-740-1986
Michael DeCarbo, 908-740-1807