CAMBRIDGE, Mass., July 25, 2016 /PRNewswire/ -- Merrimack
Pharmaceuticals, Inc. (Nasdaq: MACK) today announced that the
Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency (EMA) has issued a positive opinion for
ONIVYDE® (irinotecan liposome injection), also known as "nal-IRI",
in combination with fluorouracil (5-FU) and leucovorin for the
treatment of patients with metastatic pancreatic
adenocarcinoma who have progressed after gemcitabine-based therapy.
The CHMP positive opinion for ONIVYDE will now be reviewed by the
European Commission (EC) for marketing authorization.
Shire plc (LSE: SHP, NASDAQ: SHPG) is responsible for the
development and commercialization of ONIVYDE outside of the
United States and Taiwan pursuant to an exclusive
licensing agreement with Merrimack.
"This recommendation advances our mission to expand the
availability of the ONIVYDE regimen to metastatic pancreatic cancer
patients worldwide," said Robert
Mulroy, President and CEO of Merrimack. "The CHMP's positive
opinion is further validation of the clinical importance of the
ONIVYDE regimen. We are grateful to all of the patients, families
and investigators who contributed to the development of ONIVYDE,
and to our partner Shire, together with whom we are committed to
advancing the availability of this important therapy to patients
facing this devastating disease with few treatment options."
"This regulatory milestone is an important step for patients
with metastatic pancreatic adenocarcinoma who have progressed after
gemcitabine-based therapy," said Philip J.
Vickers, Ph.D., Head of R&D, Shire. "There has been
little improvement in prognosis for patients in this setting for
over 20 years, and given this high unmet need we look forward to
receiving the final approval decision from the European
Commission."
The opinion was based on data from the pivotal Phase 3 NAPOLI-1
study, which demonstrated that ONIVYDE in combination with 5-FU and
leucovorin met its primary endpoint of significantly increased
overall survival when compared to 5-FU and leucovorin alone:
6.1 months vs 4.2 months (p=0.012, unstratified hazard ratio
(HR) =0.67, 95% CI: [0.49-0.92]) i. Findings from an
updated analysis of the NAPOLI-1
data showed that one in four patients treated with the ONIVYDE
combination regimen survived a milestone one year or more: 12-month
overall survival estimates of 26% (95% CI, 18-35%) were observed in
the ONIVYDE combination treatment arm representing a 63%
improvement when compared to 16% (95% CI, 10-24%) for 5-FU and
leucovorin aloneii. This updated analysis was presented
at the American Society of Clinical Oncology 2016 Gastrointestinal
Cancers Symposium.
The primary NAPOLI-1 study
results were the basis for the October
2015 U.S. Food and Drug Administration (FDA) and Taiwan FDA
approvals of the ONIVYDE combination regimen for the treatment of
patients with metastatic pancreatic adenocarcinoma whose disease
progressed after gemcitabine-based therapy. It is the first and
only U.S. FDA-approved therapy in this setting. The ONIVYDE
combination is also designated as a category 1 treatment option in
the 2016 National Comprehensive Cancer Network (NCCN) guidelines
for pancreatic adenocarcinoma in the U.S. as well as a category 2B
status in the 2015 European Society for Medical Oncology (ESMO)
clinical practice guidelines in the EU.
About Pancreatic Cancer
Pancreatic cancer is a rare and deadly disease with only 7% of
all patients surviving five years or longeriii. There
are approximately 50,000 patients diagnosed with pancreatic cancer
each year in the United
Statesiv, the overwhelming majority of which have
adenocarcinomav. Globally there are approximately
338,000 new cases each yearvi. Most patients
receive gemcitabine-based therapy during either
adjuvant/neoadjuvant treatment for locally advanced disease or
during first- or second-line therapy for metastatic
diseasevii, but are left with no standard of care
therapy upon progression. ONIVYDE in combination with 5-FU and
leucovorin is approved in the United
States and Taiwan for these patients whose disease
has progressed following gemcitabine-based therapy.
About ONIVYDE® [pronounced 'on - ih – vide
]
ONIVYDE® (irinotecan liposome injection), also known as MM-398
or "nal-IRI," is a novel encapsulation of irinotecan in a liposomal
formulation. The activated form of irinotecan is SN-38, which
functions by inhibiting topoisomerase I (an essential enzyme
involved in DNA transcription and replication) and promoting cell
death. ONIVYDE was approved by the U.S. FDA in combination
with fluorouracil and leucovorin for the treatment of patients with
metastatic adenocarcinoma of the pancreas after disease progression
following gemcitabine-based therapy. For full prescribing
information, including Boxed WARNING, please visit
www.ONIVYDE.com.
IMPORTANT SAFETY INFORMATION – UNITED STATES
INDICATION
ONIVYDE® (irinotecan liposome injection) is
indicated, in combination with fluorouracil (5-FU) and leucovorin
(LV), for the treatment of patients with metastatic adenocarcinoma
of the pancreas after disease progression following
gemcitabine-based therapy.
Limitation of Use: ONIVYDE is not indicated as a single agent
for the treatment of patients with metastatic adenocarcinoma of the
pancreas.
WARNING: SEVERE
NEUTROPENIA and SEVERE DIARRHEA
Fatal neutropenic
sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or
life-threatening neutropenic fever or sepsis occurred in 3%
and severe or life-threatening neutropenia occurred in 20%
of patients receiving ONIVYDE in combination with
fluorouracil (5-FU) and leucovorin (LV). Withhold ONIVYDE for
absolute neutrophil count below 1500/mm3 or neutropenic
fever. Monitor blood cell counts periodically during
treatment.
Severe diarrhea
occurred in 13% of patients receiving ONIVYDE in combination with
5-FU/LV. Do not administer ONIVYDE to patients with bowel
obstruction. Withhold ONIVYDE for diarrhea of Grade 2-4 severity.
Administer loperamide for late diarrhea of any severity. Administer
atropine, if not contraindicated, for early diarrhea of any
severity.
|
CONTRAINDICATION
ONIVYDE is contraindicated in
patients who have experienced a severe hypersensitivity reaction to
ONIVYDE or irinotecan HCl.
WARNINGS AND PRECAUTIONS
Severe Neutropenia
ONIVYDE can cause severe or
life-threatening neutropenia and fatal neutropenic sepsis. In a
clinical study, the incidence of fatal neutropenic sepsis was 0.8%
among patients receiving ONIVYDE, occurring in 1/117 patients in
the ONIVYDE/5-FU/LV arm and 1/147 patients receiving ONIVYDE as a
single agent. Severe or life-threatening neutropenia occurred in
20% of patients receiving ONIVYDE/5-FU/LV vs 2% of patients
receiving 5-FU/LV. Grade 3/4 neutropenic fever/neutropenic sepsis
occurred in 3% of patients receiving ONIVYDE/5-FU/LV, and did not
occur in patients receiving 5-FU/LV.
In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade
3/4 neutropenia was higher among Asian (18/33 [55%]) vs White
patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis was
reported in 6% of Asian vs 1% of White patients.
Severe Diarrhea
ONIVYDE can cause severe and
life-threatening diarrhea. Do not administer ONIVYDE to patients
with bowel obstruction. Severe and life-threatening late-onset
(onset >24 hours after chemotherapy) and early-onset diarrhea
(onset ≤24 hours after chemotherapy, sometimes with other symptoms
of cholinergic reaction) were observed. An individual patient may
experience both early- and late-onset diarrhea.
In a clinical study, Grade 3/4 diarrhea occurred in 13% of
patients receiving ONIVYDE/5-FU/LV vs 4% receiving 5-FU/LV. Grade
3/4 late-onset diarrhea occurred in 9% of patients receiving
ONIVYDE/5-FU/LV vs 4% in patients receiving 5-FU/LV; the incidences
of early-onset diarrhea were 3% and no Grade 3/4 incidences,
respectively. Of patients receiving ONIVYDE/5-FU/LV, 34% received
loperamide for late-onset diarrhea and 26% received atropine for
early-onset diarrhea.
Interstitial Lung Disease (ILD)
Irinotecan HCl can
cause severe and fatal ILD. Withhold ONIVYDE in patients with new
or progressive dyspnea, cough, and fever, pending diagnostic
evaluation. Discontinue ONIVYDE in patients with a confirmed
diagnosis of ILD.
Severe Hypersensitivity Reactions
Irinotecan HCl can
cause severe hypersensitivity reactions, including anaphylactic
reactions. Permanently discontinue ONIVYDE in patients who
experience a severe hypersensitivity reaction.
Embryo-Fetal Toxicity
Based on animal data with
irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can
cause fetal harm when administered to a pregnant woman. Advise
pregnant women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during and
for 1 month after ONIVYDE treatment.
ADVERSE REACTIONS
- The most common (≥20%) adverse reactions in which patients
receiving ONIVYDE/5-FU/LV experienced a ≥5% higher incidence of any
Grade vs the 5-FU/LV arm, were diarrhea (any 59%, 26%; severe 13%,
4%) (early diarrhea [any 30%, 15%; severe 3%, 0%], late diarrhea
[any 43%, 17%; severe 9%, 4%]), fatigue/asthenia (any 56%, 43%;
severe 21%, 10%), vomiting (any 52%, 26%; severe 11%, 3%), nausea
(any 51%, 34%; severe 8%, 4%), decreased appetite (any 44%, 32%;
severe 4%, 2%), stomatitis (any 32%, 12%; severe 4%, 1%), pyrexia
(any 23%, 11%; severe 2%, 1%).
- Of less common (<20%) adverse reactions, patients receiving
ONIVYDE/5-FU/LV who experienced Grade 3/4 adverse reactions at a
≥2% higher incidence of Grade 3/4 toxicity vs the 5-FU/LV arm,
respectively, were sepsis (3%, 1%), neutropenic fever/neutropenic
sepsis (3%, 0%), gastroenteritis (3%, 0%), intravenous
catheter-related infection (3%, 0%), weight loss (2%, 0%), and
dehydration (4%, 2%).
- The laboratory abnormalities in which patients receiving
ONIVYDE/5-FU/LV experienced a ≥5% higher incidence vs the 5-FU/LV
arm, were anemia (any 97%, 86%; severe 6%, 5%), lymphopenia (any
81%, 75%; severe 27%, 17%), neutropenia (any 52%, 6%; severe 20%,
2%), thrombocytopenia (any 41%, 33%; severe 2%, 0%), increased
alanine aminotransferase (any 51%, 37%; severe 6%, 1%),
hypoalbuminemia (any 43%, 30%; severe 2%, 0%), hypomagnesemia (any
35%, 21%; severe 0%, 0%), hypokalemia (any 32%, 19%; severe 2%,
2%), hypocalcemia (any 32%, 20%; severe 1%, 0%), hypophosphatemia
(any 29%, 18%; severe 4%, 1%), hyponatremia (any 27%, 12%; severe
5%, 3%), increased creatinine (any 18%, 13%; severe 0%, 0%).
- ONIVYDE can cause cholinergic reactions manifesting as
rhinitis, increased salivation, flushing, bradycardia, miosis,
lacrimation, diaphoresis, and intestinal hyperperistalsis with
abdominal cramping and early-onset diarrhea. Grade 1/2 cholinergic
symptoms other than early diarrhea occurred in 12 (4.5%)
ONIVYDE-treated patients.
- Infusion reactions, consisting of rash, urticaria, periorbital
edema, or pruritus, occurring on the day of ONIVYDE administration
were reported in 3% of patients receiving ONIVYDE or
ONIVYDE/5-FU/LV.
- The most common serious adverse reactions (≥2%) of ONIVYDE were
diarrhea, vomiting, neutropenic fever or neutropenic sepsis,
nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia,
acute renal failure, and thrombocytopenia.
DRUG INTERACTIONS
Avoid the use of strong CYP3A4
inducers, if possible, and substitute non-enzyme–inducing therapies
≥2 weeks prior to initiation of ONIVYDE. Avoid the use of strong
CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong
CYP3A4 inhibitors ≥1 week prior to starting therapy.
USE IN SPECIFIC POPULATIONS
Pregnancy and Reproductive Potential
Advise pregnant
women of the potential risk to a fetus. Advise males with female
partners of reproductive potential to use effective contraception
during and for 4 months after ONIVYDE treatment.
Lactation
Advise nursing women not to breastfeed
during and for 1 month after ONIVYDE treatment.
Pediatric
Safety and effectiveness of ONIVYDE have not
been established in pediatric patients.
DOSAGE AND ADMINISTRATION
The recommended dose of
ONIVYDE is 70 mg/m2 intravenous (IV) infusion over 90
minutes every 2 weeks, administered prior to LV and 5-FU. The
recommended starting dose of ONIVYDE in patients known to be
homozygous for the UGT1A1*28 allele is 50 mg/m2
administered by IV infusion over 90 minutes. There is no
recommended dose of ONIVYDE for patients with serum bilirubin above
the upper limit of normal. Premedicate with a corticosteroid and an
anti-emetic 30 minutes prior to ONIVYDE. Withhold ONIVYDE for Grade
3/4 adverse reactions. Resume ONIVYDE with reduced dose once
adverse reaction recovered to ≤Grade 1. Discontinue ONIVYDE in
patients who experience a severe hypersensitivity reaction and in
patients with a confirmed diagnosis of ILD.
Do not substitute ONIVYDE for other drugs containing irinotecan
HCl.
Please see full U.S. Prescribing Information for
ONIVYDE.
Global Partnerships
In 2014, Merrimack and Shire plc entered into an
exclusive licensing agreement for the development and
commercialization of ONIVYDE outside of the United
States and Taiwan. PharmaEngine, Inc. (Taipei, Taiwan) holds the rights to
commercialize ONIVYDE in Taiwan and received the Taiwan
FDA approval of ONIVYDE in October 2015.
About Merrimack
Merrimack is a fully integrated biopharmaceutical company that
views cancer as a complex engineering challenge. Through systems
biology, which brings together the fields of biology, computing and
engineering, Merrimack aims to decrease uncertainty in drug
development and clinical validation, and move discovery efforts
beyond trial and error. Such an approach has the potential to make
individualized treatment of patients a reality. Merrimack's first
commercial product, ONIVYDE® (irinotecan liposome injection), was
approved by the U.S. FDA in October 2015. With four
additional candidates in clinical studies, several in preclinical
development and multiple biomarkers designed to support patient
selection, Merrimack is building one of the most robust oncology
pipelines in the industry. For more information, please visit
Merrimack's website at www.merrimack.com or connect on
Twitter at @MerrimackPharma.
Forward-looking Statements
To the extent that statements contained in this press release
are not descriptions of historical facts, they are forward-looking
statements reflecting the current beliefs and expectations of
management made pursuant to the safe harbor provisions of the
Private Securities Litigation Reform Act of 1995, as amended.
Forward-looking statements include any statements about Merrimack's
strategy, future operations, future financial position, future
revenues and future expectations and plans and prospects for
Merrimack, and any other statements containing the words
"anticipate," "believe," "estimate," "expect," "intend," "may,"
"plan," "predict," "project," "target," "potential," "will,"
"would," "could," "should," "continue," and similar expressions. In
this press release, Merrimack's forward-looking statements include,
among others, statements about the potential approval of ONIVYDE in
the European Union and the potential effectiveness and safety
profile of ONIVYDE. Such forward-looking statements involve
substantial risks and uncertainties that could cause Merrimack's
clinical development programs, future results, performance or
achievements to differ significantly from those expressed or
implied by the forward-looking statements. Such risks and
uncertainties include, among others, the uncertainties inherent in
the initiation of future clinical trials, availability of data from
ongoing clinical trials, expectations for regulatory approvals and
other matters that could affect the availability or commercial
potential of Merrimack's products, product candidates or companion
diagnostics. Merrimack undertakes no obligation to update or revise
any forward-looking statements. Forward-looking statements should
not be relied upon as representing Merrimack's views as of any date
subsequent to the date hereof. For a further description of the
risks and uncertainties that could cause actual results to differ
from those expressed in these forward-looking statements, as well
as risks relating to Merrimack's business in general, see the "Risk
Factors" section of Merrimack's Quarterly Report on Form 10-Q filed
with the Securities and Exchange Commission (SEC) on May
2, 2016 and other reports Merrimack files with
the SEC.
Contacts:
Media Contact
Marianne McMorrow
774-776-1478
mmcmorrow@merrimack.com
Investor Contact
Geoffrey Grande, CFA
617-441-7602
ggrande@merrimack.com
i Wang-Gillam A, et.al. Nanoliposomal irinotecan with
fluorouracil and folinic acid in metastatic pancreatic cancer after
previous gemcitabine-based therapy (NAPOLI-1): a global, randomized, open-label
phase 3 trial. The Lancet.
Vol. 387, No. 10018, p545-557, 6 Feb
2016
ii Wang-Gillam A, et.al. Updated overall survival
analysis of NAPOLI-1: Phase III
study of nanoliposomal irinotecan (nal-IRI, MM-398), with or
without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in
metastatic pancreatic cancer (mPAC) previously treated with
gemcitabine-based therapy. J Clin Oncol 34, 2016 (suppl 4S; abstr
417)
iii American Cancer Society. Cancer Facts and Figures
2016. Atlanta: American Cancer Society; 2016
iv American Cancer Society. Cancer Facts and Figures
2016. Atlanta: American Cancer Society; 2016
v American Cancer Society. Cancer Facts and Figures
2016. Atlanta: American Cancer Society; 2016
vi World Health Organization. GLOBOCAN 2012:
Estimated Cancer Incidence, Mortality and Prevalence Worldwide in
2012; Lyon, Fr.: International Agency for Research on
Cancer; 2012
vii Data presented at ASCO 2014 (Abrams et al.)
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SOURCE Merrimack Pharmaceuticals, Inc.