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June 19, 2019 5:45 am ET

LYNPARZA is the Only PARP Inhibitor Approved in Japan

KENILWORTH, N.J.–(BUSINESS WIRE)–AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United
States and Canada, today announced that Japan’s Pharmaceuticals and
Medical Devices Agency (PMDA) has approved LYNPARZA as a maintenance
treatment after first-line chemotherapy in patients with BRCA-mutated
(BRCAm) ovarian cancer.

The approval in Japan was based on data from the randomized,
double-blinded Phase 3 SOLO-1 trial which evaluated LYNPARZA as
maintenance monotherapy compared with placebo in patients with BRCAm
advanced ovarian cancer following first-line platinum-based chemotherapy.

Dave Fredrickson, executive vice-president, oncology, AstraZeneca, said,
“This approval in Japan is a critical advance for women with ovarian
cancer and a BRCA mutation. The goals of front-line therapy are
long-term remission or a cure, yet currently 70% of patients relapse
within three years of initial treatment. The progression-free survival
benefit of Lynparza observed in SOLO-1 represents a major step forward
in our ambition to improve patient outcomes.”

Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories, said,
“Advances in understanding the role of BRCA mutations and PARP
inhibition have fundamentally changed how physicians can treat this
aggressive type of cancer. With the approval of this new indication,
patients in Japan with BRCA-mutated advanced ovarian cancer who
respond to chemotherapy will have the opportunity to benefit from
LYNPARZA in the first-line maintenance setting.”

Results from the SOLO-1 trial showed that LYNPARZA reduced the risk of
disease progression or death by 70% versus placebo following response to
platinum-based chemotherapy (HR 0.30 [95% CI 0.23-0.41], p<0.001).

LYNPARZA is the only PARP inhibitor approved in Japan. AstraZeneca and
Merck are exploring additional trials in ovarian cancer, including the
ongoing Phase 3 PAOLA-1 trial, which is testing LYNPARZA in combination
with bevacizumab as a first-line maintenance treatment for women with
advanced, stage IIIB-IV high-grade serous or endometrioid, fallopian
tube or peritoneal ovarian cancer, regardless of BRCA status.

About SOLO-1

SOLO-1 was a Phase 3, randomized, double-blinded, placebo-controlled,
multi-center trial to evaluate the efficacy and safety of LYNPARZA
tablets (300 mg twice daily) as maintenance monotherapy compared with
placebo in patients with BRCAm advanced ovarian cancer following
first-line platinum-based chemotherapy. The trial randomized 391
patients with a deleterious or suspected deleterious germline or somatic BRCA1
or BRCA2 mutation who were in clinical complete or partial
response following platinum-based chemotherapy. Patients were randomized
(2:1) to receive LYNPARZA or placebo for up to two years or until
disease progression. Patients who had a partial response at two years
were permitted to stay on therapy at the investigator’s discretion. The
primary endpoint was progression-free survival (PFS) and key secondary
endpoints included time to second disease progression or death, time to
first subsequent treatment and overall survival.

The data were presented on Oct. 21, 2018, at the Presidential Symposium
of the ESMO 2018 Congress in Munich, Germany and published
simultaneously online in the New England Journal of Medicine.

Summary of PFS

^i,ii

		Lynparza (n=260)		Placebo (n=131)
Number of patients with event (%) iii		102 (39)		96 (73)
Median (in months)		Not reached		13.8
Hazard ratio (95% CI)		0.30 (0.23-0.41)
P-value		p<0.001

^{i Investigator-assessed}

^{ii Median (interquartile range) duration of follow-up 40.7 months
(34.9–42.9) for Lynparza and 41.2 months (32.2–41.6) for
placebo}

^{iii Analysis was done at 50.6% maturity}

The SOLO-1 safety profile was in line with that observed in prior
clinical trials. The most common adverse events (AEs) ≥ 20% were nausea
(77%), fatigue (64%), vomiting (40%), anemia (39%) and diarrhea (34%).
The most common ≥ Grade 3 AEs were anemia (22%) and neutropenia (8%).
Seventy-one percent of patients on LYNPARZA remained on the recommended
starting dose. Additionally, 88% of patients on LYNPARZA continued
treatment without an AE-related discontinuation. Further, 48% of
patients on LYNPARZA did not have a dose interruption as a result of an
AE.

About Ovarian Cancer

Worldwide, ovarian cancer is the eighth most-commonly diagnosed cancer
and seventh most-common cause of cancer deaths in women. In Japan, an
estimated 10,672 new cases were expected to be diagnosed in 2018, with
approximately 5,215 deaths. For all types of ovarian cancer, the
five-year relative survival is approximately 47%. For newly-diagnosed
advanced ovarian cancer, the primary aim of treatment is to delay
progression of the disease for as long as possible.

About BRCA Mutations

Breast cancer susceptibility gene 1/2 (BRCA1 and BRCA2)
are human genes that produce proteins responsible for repairing damaged
DNA and play an important role in 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 is a 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. Inhibition of PARP with LYNPARZA leads to the trapping of
PARP bound to DNA single-strand breaks, stalling of replication forks,
their collapse and the generation of DNA double-strand breaks and cancer
cell death. LYNPARZA is being tested in a range of tumor types with
defects and dependencies in the DDR.

LYNPARZA, which is being jointly developed and commercialized by
AstraZeneca and Merck, has a broad and advanced clinical trial
development program, and AstraZeneca and Merck are working together to
understand how it may affect multiple PARP-dependent tumors as a
monotherapy and in combination across multiple cancer types.

IMPORTANT SAFETY INFORMATION

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 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—First-Line Maintenance BRCAm Advanced
Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in
clinical trials of LYNPARZA in the first-line maintenance setting
for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain
(45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%),
upper respiratory tract infection/influenza/ nasopharyngitis/bronchitis
(28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%),
neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI
(13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in
clinical trials of LYNPARZA in the first-line maintenance setting for
SOLO-1 were: decrease in hemoglobin (87%), increase in mean
corpuscular volume (87%), decrease in leukocytes (70%), decrease in
lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease
in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in
clinical trials of LYNPARZA in the maintenance setting for SOLO-2
were: 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%), decreased appetite
(21%), and dyspepsia (20%).

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 for advanced gBRCAm ovarian cancer after 3 or more
lines of chemotherapy (pooled from 6 studies) were: fatigue/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%), mean corpuscular
volume elevation (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 metastatic 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 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 or moderate hepatic impairment
(Child-Pugh classification A and B). There are no data in patients with
severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No adjustment to the starting dose is necessary
in patients with mild renal impairment (CLcr=51-80 mL/min) but patients
should be monitored closely for toxicity. 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).

INDICATIONS

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

First-Line Maintenance BRCAm Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or
suspected deleterious germline or somatic BRCA-mutated (gBRCAm
or sBRCAm) advanced epithelial ovarian, fallopian tube or
primary peritoneal cancer who are in complete or partial response to
first-line platinum-based chemotherapy. Select patients with gBRCAm
advanced epithelial ovarian, fallopian tube or primary peritoneal cancer
for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer

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.

Advanced gBRCAm ovarian cancer

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.

gBRCAm, HER2-negative metastatic breast cancer

In patients with deleterious or suspected deleterious gBRCAm, human
epidermal growth factor receptor 2 (HER2)-negative metastatic breast
cancer who have 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 therapy.
Select patients for therapy based on an FDA-approved companion
diagnostic for LYNPARZA.

Please

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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. Working together, the companies will develop
LYNPARZA and selumetinib in combination with other potential new
medicines and as monotherapies. 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, 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 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

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“company”) includes “forward-looking statements” within the meaning of
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respect to pipeline products that the products will receive the
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