INDIANAPOLIS, Oct. 12, 2017 /PRNewswire/ -- Eli Lilly and
Company (NYSE: LLY) today announced that the U.S. Food and Drug
Administration (FDA) has granted Priority Review designation for
its New Drug Application (NDA) for Verzenio™
(abemaciclib), a cyclin-dependent kinase (CDK)4 & 6 inhibitor.
The NDA was based upon the positive interim results from MONARCH 3,
a study of abemaciclib in combination with an aromatase inhibitor
as initial endocrine-based therapy for the treatment of women with
hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced or metastatic breast cancer.
The results were presented at the European Society for Medical
Oncology (ESMO) 2017 Congress, and recently published in the
Journal of Clinical Oncology.
"On the heels of our recent FDA approval of Verzenio, we are
pleased with this important step forward in the agency's
consideration to expand the use of Verzenio in metastatic breast
cancer," said Levi Garraway, M.D.,
Ph.D., senior vice president, global development and medical
affairs, Lilly Oncology. "We look forward to ongoing collaboration
with the FDA to advance this important treatment across the
spectrum of care for patients living with advanced or metastatic
breast cancer."
Priority Review aims to expedite the review of applications for
drugs that, if approved, would represent a significant advance in
treatment. With Priority Review of a new drug, the FDA's goal is to
take action within eight months of receiving an application,
compared with the standard review timeframe of 12
months.1
In the third quarter of 2017, Lilly completed EU and
Japan regulatory submissions for
abemaciclib.
Notes to Editor
About Advanced Breast Cancer
Breast cancer is the most
frequently diagnosed cancer in women worldwide with nearly 1.7
million new cases diagnosed in 2012.2 An estimated
252,710 new cases of invasive breast cancer are expected to be
diagnosed in the U.S. in women in 2017.3 Advanced breast
cancer includes metastatic breast cancer, cancer that has spread
from the breast tissue to other parts of the body, and locally or
regionally advanced breast cancer, meaning the cancer has grown
outside the organ where it started but has not yet spread to other
parts of the body.4 Of all early stage breast cancer
cases diagnosed in the U.S., approximately 30 percent will become
metastatic and an estimated six to 10 percent of all new breast
cancer cases are initially diagnosed as being
metastatic.5 Survival is lower among women with a
more advanced stage at diagnosis: 5-year relative survival is 99
percent for localized disease, 85 percent for regional disease, and
26 percent for metastatic disease. Other factors, such as tumor
size, also impact 5-year survival estimates.6
About Verzenio™
(abemaciclib)
Verzenio (abemaciclib) is an
inhibitor of CDK4 and CDK6, which are activated by binding to
D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell
lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the
retinoblastoma protein (Rb), cell cycle progression, and cell
proliferation.
Verzenio disrupts the cell cycle. Preclinically, Verzenio dosed
daily without interruption as a single agent or in combination with
antiestrogens resulted in reduction of tumor size. In vitro,
continuous exposure to Verzenio inhibited Rb phosphorylation and
blocked progression from G1 to S phase of the cell cycle, resulting
in senescence and apoptosis (cell death). Inhibiting CDK4 & 6
in healthy cells can result in side effects, some of which may be
serious. Clinical evidence also suggests that Verzenio crosses the
blood-brain barrier.7
INDICATION
Verzenio is indicated:
- in combination with fulvestrant for women with HR+, HER2-
advanced or metastatic breast cancer with disease progression
following endocrine therapy
- as monotherapy for the treatment of adult patients with HR+,
HER2- advanced or metastatic breast cancer with disease progression
following endocrine therapy and prior chemotherapy in the
metastatic setting
IMPORTANT SAFETY INFORMATION
Diarrhea occurred in 86% of patients receiving Verzenio
plus fulvestrant in MONARCH 2 and 90% of patients receiving
Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 13% of
patients receiving Verzenio plus fulvestrant in MONARCH 2 and in
20% of patients receiving Verzenio alone in MONARCH 1. Episodes of
diarrhea have been associated with dehydration and
infection.
In MONARCH 2, diarrhea incidence was greatest during the first
month of Verzenio dosing. The median time to onset of the first
diarrhea event was 6 days, and the median duration of diarrhea for
Grades 2 and 3 were 9 days and 6 days, respectively. Twenty-two
percent of patients with diarrhea required a dose omission and 22%
required a dose reduction. In the MONARCH 1 study, the time to
onset and resolution for diarrhea were similar to those in MONARCH
2.
Instruct patients that at the first sign of loose stools, they
should start antidiarrheal therapy such as loperamide, increase
oral fluids, and notify their healthcare provider for further
instructions and appropriate follow-up. For Grade 3 or 4 diarrhea,
or diarrhea that requires hospitalization, discontinue Verzenio
until toxicity resolves to ≤Grade 1, and then resume Verzenio at
the next lower dose.
Neutropenia occurred in 46% of patients receiving
Verzenio plus fulvestrant in MONARCH 2 and 37% of patients
receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in
neutrophil count (based on laboratory findings) occurred in 32% of
patients receiving Verzenio plus fulvestrant in MONARCH 2 and in
27% of patients receiving Verzenio in MONARCH 1. In MONARCH 2 and
MONARCH 1, the median time to first episode of Grade >3
neutropenia was 29 days, and the median duration of Grade ≥3
neutropenia was 15 days.
Monitor complete blood counts prior to the start of Verzenio
therapy, every 2 weeks for the first 2 months, monthly for the next
2 months, and as clinically indicated. Dose interruption, dose
reduction, or delay in starting treatment cycles is recommended for
patients who develop Grade 3 or 4 neutropenia.
Febrile neutropenia has been reported in 1% of patients exposed
to Verzenio in MONARCH 2 and MONARCH 1. Two deaths due to
neutropenic sepsis were observed in MONARCH 2. Inform patients to
promptly report any episodes of fever to their healthcare
provider.
Grade ≥3 increases in alanine aminotransferase (ALT) (4%
versus 2%) and aspartate aminotransferase (AST) (2% versus
3%) were reported in the Verzenio and placebo arms respectively, in
MONARCH 2.
In MONARCH 2, for patients receiving Verzenio plus fulvestrant
with Grade ≥3 ALT increased, median time to onset was 57 days, and
median time to resolution to Grade <3 was 14 days. For patients
with Grade ≥3 AST increased, median time to onset was 185 days, and
median time to resolution was 13 days.
For assessment of potential hepatotoxicity, monitor liver
function tests (LFTs) prior to the start of Verzenio therapy, every
2 weeks for the first 2 months, monthly for the next 2 months, and
as clinically indicated. Dose interruption, dose reduction, dose
discontinuation, or delay in starting treatment cycles is
recommended for patients who develop persistent or recurrent Grade
2, or Grade 3 or 4, hepatic transaminase elevation.
Venous thromboembolic events were reported in 5% of
patients treated with Verzenio plus fulvestrant in MONARCH 2 as
compared to 0.9% of patients treated with fulvestrant plus placebo.
Venous thromboembolic events included deep vein thrombosis,
pulmonary embolism, cerebral venous sinus thrombosis, subclavian
and axillary vein thrombosis, and inferior vena cava thrombosis.
Across the clinical development program, deaths due to venous
thromboembolism have been reported. Monitor patients for signs and
symptoms of venous thrombosis and pulmonary embolism and treat as
medically appropriate.
Verzenio can cause fetal harm when administered to a
pregnant woman based on findings from animal studies and the
mechanism of action. In animal reproduction studies, administration
of abemaciclib to pregnant rats during the period of organogenesis
caused teratogenicity and decreased fetal weight at maternal
exposures that were similar to the human clinical exposure based on
area under the curve (AUC) at the maximum recommended human dose.
Advise pregnant women of the potential risk to a fetus. Advise
females of reproductive potential to use effective contraception
during treatment with Verzenio and for at least 3 weeks after the
last dose. There are no data on the presence of Verzenio in
human milk or its effects on the breastfed child or on milk
production. Advise lactating women not to breastfeed during
Verzenio treatment and for at least 3 weeks after the last dose
because of the potential for serious adverse reactions in breastfed
infants. Based on findings in animals, Verzenio may impair
fertility in males of reproductive potential.
The most common adverse reactions (all grades,
≥10%) observed in MONARCH 2 for Verzenio plus
fulvestrant and ≥2% higher than placebo plus
fulvestrant were diarrhea (86% vs 25%), neutropenia (46% vs
4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs
25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia
(28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs
10%), headache (20% vs 15%), dysgeusia (18% vs 3%),
thrombocytopenia (16% vs 3%), alopecia (16% vs 2%), stomatitis (15%
vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough
(13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%),
peripheral edema (12% vs 7%), creatinine increased (12% vs <1%),
rash (11% vs 4%), pyrexia (11% vs 6%), and weight decreased (10% vs
2%).
The most common adverse reactions (all grades,
≥10%) observed in MONARCH 1 with Verzenio were
diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite
(45%), abdominal pain (39%), neutropenia (37%), vomiting (35%),
infections (31%), anemia (25%), thrombocytopenia (20%), headache
(20%), cough (19%), leukopenia (17%), constipation (17%),
arthralgia (15%), dry mouth (14%), weight decreased (14%),
stomatitis (14%), creatinine increased (13%), alopecia (12%),
dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration
(10%).
The most frequently reported ≥5% Grade 3 or
4 adverse reactions that occurred in the Verzenio arm of
MONARCH 2 were neutropenia (27% vs 2%), diarrhea (13% vs
<1%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections
(6% vs 3%).
The most frequently reported ≥5% Grade 3
or 4 adverse reactions from MONARCH 1 with Verzenio were
neutropenia (24%), diarrhea (20%), fatigue (13%), infections (7%),
leukopenia (6%), anemia (5%), and nausea (5%).
Lab abnormalities (all grades; Grade 3 or 4) for
MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher
than placebo plus fulvestrant were increased serum creatinine
(98% vs 74%; 1% vs 0%), decreased white blood cells (90% vs 33%;
23% vs 1%), decreased neutrophil count (87% vs 30%; 33% vs 4%),
anemia (84% vs 33%; 3% vs <1%), decreased lymphocyte count (63%
vs 32%; 12% vs 2%), decreased platelet count (53% vs 15%; 2% vs
0%), increased ALT (41% vs 32%; 5% vs 1%), and increased AST (37%
vs 25%; 4% vs 4%).
Lab abnormalities (all grades; Grade 3 or 4) for
MONARCH 1 with Verzenio were increased serum creatinine (98%;
<1%), decreased white blood cells (91%; 28%), decreased
neutrophil count (88%; 27%), anemia (68%; 0%), decreased lymphocyte
count (42%; 14%), decreased platelet count (41%; 2%), increased ALT
(31%; 3%), and increased AST (30%; 4%).
Strong CYP3A inhibitors increased the exposure of
abemaciclib plus its active metabolites to a clinically meaningful
extent and may lead to increased toxicity. Avoid concomitant use of
ketoconazole. Ketoconazole is predicted to increase the AUC of
abemaciclib by up to 16-fold. In patients with recommended starting
doses of 200 mg twice daily or 150 mg twice daily, reduce the
Verzenio dose to 100 mg twice daily with concomitant use of other
strong CYP3A inhibitors. In patients who have had a dose reduction
to 100 mg twice daily due to adverse reactions, further reduce the
Verzenio dose to 50 mg twice daily with concomitant use of other
strong CYP3A inhibitors. If a patient taking Verzenio discontinues
a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5
half-lives of the inhibitor) to the dose that was used before
starting the strong inhibitor. Patients should avoid grapefruit
products.
Avoid concomitant use of strong CYP3A inducers and consider
alternative agents. Coadministration of Verzenio with rifampin,
a strong CYP3A inducer, decreased the plasma concentrations of
abemaciclib plus its active metabolites and may lead to reduced
activity.
With severe hepatic impairment (Child-Pugh Class C),
reduce the Verzenio dosing frequency to once daily. The
pharmacokinetics of Verzenio in patients with severe renal
impairment (CLcr <30 mL/min), end stage renal disease, or in
patients on dialysis is unknown. No dosage adjustments are
necessary in patients with mild or moderate hepatic (Child-Pugh A
or B) and/or renal impairment (CLcr ≥30-89 mL/min).
Please see full Prescribing Information for
Verzenio.
AL HCP ISI 02OCT2017
About Lilly Oncology
For more than 50 years, Lilly has
been dedicated to delivering life-changing medicines and support to
people living with cancer and those who care for them. Lilly is
determined to build on this heritage and continue making life
better for all those affected by cancer around the world. To learn
more about Lilly's commitment to people with cancer, please visit
www.LillyOncology.com.
About Eli Lilly and Company
Lilly is a global
healthcare leader that unites caring with discovery to make life
better for people around the world. We were founded more than a
century ago by a man committed to creating high-quality medicines
that meet real needs, and today we remain true to that mission in
all our work. Across the globe, Lilly employees work to discover
and bring life-changing medicines to those who need them, improve
the understanding and management of disease, and give back to
communities through philanthropy and volunteerism. To learn more
about Lilly, please visit us at www.lilly.com and
newsroom.lilly.com/social-channels. P-LLY
© Lilly USA, LLC 2017. ALL
RIGHTS RESERVED.
Verzenio ™ is a trademark owned by or licensed
to Eli Lilly and Company, its subsidiaries, or affiliates.
Lilly Forward-Looking Statement
This press release contains forward-looking statements (as
that term is defined in the Private Securities Litigation Reform
Act of 1995) about abemaciclib as a potential treatment for
patients with breast cancer and reflects Lilly's current beliefs.
However, as with any pharmaceutical product, there are substantial
risks and uncertainties in the process of development and
commercialization. Among other things, there can be no guarantee
that abemaciclib will receive additional regulatory approvals or be
commercially successful. For further discussion of these and other
risks and uncertainties, see Lilly's most recent Form 10-K and Form
10-Q filings with the United States Securities and Exchange
Commission. Except as required by law, Lilly undertakes no duty to
update forward-looking statements to reflect events after the date
of this release.
1
|
U.S. Food and Drug
Administration. CDER 21st Century Review Process Desk Reference
Guide.
https://wayback.archive-it.org/7993/20170405202655/https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM218757.pdf
Accessed: October 11, 2017.
|
2
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World Cancer Research
Fund International. Breast Cancer Statistics.
http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/breast-cancer-statistics.
Accessed: October 11, 2017.
|
3
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American Cancer
Society. Cancer Facts & Figures 2017.
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf.
Accessed: October 11, 2017.
|
4
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American Cancer
Society. Understanding Advanced Cancer, Metastatic Cancer and Bone
Metastases.
https://www.cancer.org/treatment/understanding-your-diagnosis/advanced-cancer/what-is.html.
Accessed: October 11, 2017.
|
5
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Metastatic Breast
Cancer Network. 13 Facts about Metastatic Breast Cancer.
http://www.mbcn.org/13-facts-about-metastatic-breast-cancer/.
Accessed: October 11, 2017.
|
6
|
American Cancer
Society. Breast Cancer Facts & Figures 2015-2016.
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2015-2016.pdf.
Accessed: October 11, 2017.
|
7
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Verzenio [package
insert]. Indianapolis, IN: Eli Lilly and Company; 2017.
|
Refer
to:
|
Erin Graves;
graves_erin_elissa@lilly.com ; 908-541-8257 (media)
|
|
Phil Johnson;
johnson_philip_l@lilly.com ; 317-655-6874 (investors)
|
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