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October 16, 2018 5:30 am ET

Fourth Orphan Drug Designation in the U.S. for AstraZeneca and Merck’s LYNPARZA

KENILWORTH, N.J.–(BUSINESS WIRE)–AstraZeneca and Merck (NYSE:MRK), known as MSD outside the United States
and Canada, today announced that the U.S. Food and Drug Administration
(FDA) granted orphan drug designation (ODD) for LYNPARZA for the
treatment of pancreatic cancer. LYNPARZA is currently being investigated
as maintenance therapy in patients with germline BRCA-mutated (gBRCAm)
metastatic pancreatic cancer whose disease has not progressed following
first-line platinum-based chemotherapy.

Pancreatic cancer is a rare, life-threatening disease that accounts for
about 3 percent of all cancers in the U.S. Due to the late onset of
symptoms, patients are often diagnosed after the cancer has progressed
to locally advanced or metastatic stages of the disease. Five-year
survival rates remain low in the U.S. at 8.5 percent.

Sean Bohen, executive vice president, Global Medicines Development, and
chief medical officer at AstraZeneca, said, “Pancreatic cancer is an
area of significant unmet medical need. This is especially true for
patients with metastatic disease, where the benefits of current
treatment options are very limited.”

Dr. Roy Baynes, senior vice president and head of Global Clinical
Development, chief medical officer, Merck Research Laboratories, said,
“Pancreatic cancer is a relatively less common, but life-threatening,
form of cancer. The FDA Orphan Drug Designation reinforces the
importance of our collaboration in bringing LYNPARZA to patients in
need.”

This is the fourth ODD in the U.S. for LYNPARZA. ODD status was granted
for the treatment of ovarian cancer in October 2013. Earlier this year,
an amended ODD status was granted to include both fallopian tube and
primary peritoneal cancers following the expanded U.S. approval of
LYNPARZA in August 2017 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. The FDA grants ODD status to medicines
intended for the treatment, diagnosis or prevention of rare diseases or
disorders that affect fewer than 200,000 people in the U.S. Through the
ODD program, the FDA provides incentives for pharmaceutical companies to
develop products for rare diseases.

The use of LYNPARZA in pancreatic cancer is being assessed in the
ongoing Phase 3 POLO trial, which is investigating LYNPARZA as
maintenance monotherapy versus placebo in patients with gBRCAm
metastatic pancreatic cancer whose disease has not progressed following
first-line platinum-based chemotherapy. Results from the POLO trial are
expected in the first half of 2019.

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—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 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 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).

Indications

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.

Please see complete

Prescribing
Information

, including Patient Information (Medication Guide).

About POLO Phase 3 Trial

POLO is a Phase 3, randomized, double-blind, placebo-controlled trial to
evaluate the efficacy and safety of LYNPARZA tablets (300 mg
twice-daily) as maintenance monotherapy compared with placebo, in
patients with germline BRCA-mutated metastatic pancreatic cancer
whose disease has not progressed following first-line platinum-based
chemotherapy. The trial randomized 145 patients to receive LYNPARZA or
placebo (3:2). The primary endpoint is progression-free survival.

About LYNPARZA

^®

(olaparib)

LYNPARZA is 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 studies 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 is being tested in a
range of DDR-deficient tumor types.

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
deliver it as quickly as possible to more patients across multiple
cancer types.

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,
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and LinkedIn.

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