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