CAMBRIDGE, Mass., Oct. 11, 2016 /PRNewswire/ -- Merrimack
Pharmaceuticals, Inc. (NASDAQ: MACK) today announced final results
from the pivotal Phase 3 NAPOLI-1 study validating the use of
ONIVYDE® (irinotecan liposome injection) in combination with
fluorouracil (5-FU) and leucovorin, which represents a new standard
of care for patients with metastatic pancreatic ductal
adenocarcinoma (mPDAC) following treatment with gemcitabine-based
therapy. The final NAPOLI-1
results were presented in a poster discussion session and a
separate analysis of NAPOLI-1
safety-over-time data was presented in a poster session at the
European Society for Medical Oncology 2016 Congress in Copenhagen.
"The final results of the NAPOLI-1 study provide a high level of
clinical evidence establishing the ONIVYDE regimen as a meaningful
treatment option for patients with metastatic pancreatic cancer,"
said Prof. Li-Tzong Chen, M.D.,
Ph.D., corresponding author, Investigator on the NAPOLI-1 trial and Director, National
Institute of Cancer Research, National Health Research Institutes
in Tainan, Taiwan. "Pancreatic
cancer is a devastating disease with a poor prognosis. In a patient
population with few treatment options, the ONIVYDE regimen provides
an opportunity for extended overall survival while maintaining
baseline quality-of-life and represents a new standard of care. We
thank all of the patients, caregivers and investigators who
participated in this pivotal study."
The extended data cutoff occurred at final database lock in
November 2015 after 382 OS events
that had occurred in the intention-to-treat (ITT) population. In
this extended analysis of NAPOLI-1, the previously described overall
survival advantage was maintained for ONIVYDE in combination with
5-FU and leucovorin versus 5-FU and leucovorin alone: 6.2 months
versus 4.2 months (p=0.039, hazard ratio (HR) =0.75, 95% CI: [.057
- .99]). Findings also showed that one in four patients treated
with the ONIVYDE combination regimen survived one year or more, a
significant milestone. This was represented by a 26% probability of
survival at one year for patients receiving ONIVYDE in combination
with 5-FU and leucovorin versus 16% for patients who received 5-FU
and leucovorin alone. Furthermore, disease control was achieved in
twice as many patients treated with ONIVYDE in combination with
5-FU and leucovorin (52%) compared to 5-FU and leucovorin alone
(24%). The demonstrated improvements in overall survival for the
ONIVYDE combination regimen were achieved with little or no impact
on quality of life over 12 weeks despite the addition of a second
chemotherapeutic agent to 5-FU and leucovorin, a therapy recognized
as a well-managed treatment for metastatic pancreatic cancer.
Results from a separate analysis of the NAPOLI-1 data evaluating the incidence and
prevalence of gastrointestinal toxicities and neutropenia during
the course of treatment with ONIVYDE plus 5-FU and leucovorin
showed that the majority of these adverse events occurred early in
treatment with decreased incidence and severity thereafter. Dose
reductions or dose delays were commonly used to manage these
adverse events and may account for the decreased incidence and/or
severity that was observed.
The primary Phase 3 NAPOLI-1 data were the basis of the US Food
and Drug Administration (FDA) and Taiwan FDA approvals of the
ONIVYDE® (irinotecan liposome injection) combination regimen in
October 2015. They were also the
basis of the European Union's Committee for Medicinal Products for
Human Use (CHMP) positive opinion issued in July 2016. The ONIVYDE combination is designated
as a category 1 treatment option in the 2016 National Comprehensive
Cancer Network (NCCN) guidelines for pancreatic adenocarcinoma in
the United States as well as a
category 2B status in the 2015 European Society for Medical
Oncology (ESMO) clinical practice guidelines in the European
Union.
About Pancreatic Cancer
Pancreatic cancer is a rare and deadly disease with only 7% of
all patients surviving five years or longer1. There are
approximately 50,000 patients diagnosed with pancreatic cancer each
year in the United
States2, the overwhelming majority of which have
adenocarcinoma3. Globally there are approximately
338,000 new cases each year4. Most patients receive
gemcitabine-based therapy during either adjuvant/neoadjuvant
treatment for locally advanced disease or during first- or
second-line therapy for metastatic disease5, 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.
Methodology and Results
Final results of NAPOLI-1: A
Phase 3 study of nal-IRI (MM-398) ± 5-fluorouracil and leucovorin
(5-FU/LV) vs 5-FU/LV in metastatic pancreatic cancer (mPAC)
previously treated with gemcitabine-based
therapy (Abstract 622PD)
The final results of the NAPOLI-1 study evaluate the robustness of the
previously described overall survival and progression free survival
benefits of ONIVYDE in combination with 5-FU and leucovorin
compared with 5-FU and leucovorin alone. This analysis also
assesses the long-term safety and tolerability of the ONIVYDE
combination regimen. The extended analysis is based on 382 OS
events. Highlights include:
- The overall survival advantage of ONIVYDE in combination with
5-FU and leucovorin versus 5-FU and leucovorin alone was maintained
in this extended analysis: 6.2 months versus 4.2 months (p=0.039,
hazard ratio (HR) =0.75, 95% CI: [.057-.99]).
- The probability of survival at one year was greater in the
ONIVYDE combination arm of the study when compared to the 5-FU and
leucovorin arm: 12-month overall survival estimates of 26% (95% CI,
18-35%) were observed in the ONIVYDE combination treatment arm
compared to 16% (95% CI, 10-24%) for 5-FU and leucovorin arm.
- The overall response rate (ORR) for the ONIVYDE plus 5-FU and
leucovorin arm was 16% versus 1% for the 5-FU and leucovorin arm
(P< 0.0001).
- Treatment with ONIVYDE in combination with 5-FU and leucovorin
provided a 2-fold improvement in disease control rate compared with
5-FU and leucovorin alone (52% vs 24%, respectively).
- Final results suggest that patients treated with ONIVYDE in
combination with 5-FU and leucovorin had no notable deterioration
in quality of life at 12 weeks despite the addition of a second
chemotherapeutic agent to 5-FU and leucovorin.
- No new safety concerns were noted and the overall safety
profile was manageable with the most common Grade ≥3 adverse events
of neutropenia, diarrhea, fatigue, vomiting and asthenia.
Time course of selected treatment emergent adverse events
(TEAEs) in NAPOLI-1: A Phase 3
study of nal-IRI (MM-398) ± 5-fluorouracil and leucovorin (5-FU/LV)
vs 5-FU/LV in metastatic pancreatic cancer (mPAC) previously
treated with gemcitabine-based therapy
The basis of this subset analysis is to characterize the safety
profile of the ONIVYDE combination regimen through the evaluation
of the incidence and prevalence of adverse events across all three
arms of the NAPOLI-1 study.
Incidence (first occurrence of an event) and prevalence (first
occurrence, ongoing event or recurrence) were analyzed by three
treatment periods: 1-6 weeks, 6-12 weeks and greater than 12 weeks.
Findings from the analysis suggest neutropenia, diarrhea, nausea
and vomiting typically first occur early during the course of
treatment with the ONIVYDE combination regimen and decrease in
incidence and severity thereafter.
Data shows that the prevalence of nausea and vomiting in the
ONIVYDE regimen arm decreased over time, with a greater frequency
at 1-6 weeks when compared to greater than 12 weeks. During this
same period, the prevalence of neutropenia increased slightly but
decreased in severity. The prevalence of diarrhea was relatively
consistent throughout treatment. This analysis suggests the median
duration of adverse events of all grades was 5 to 11 days in the
ONIVYDE combination arm of NAPOLI-1. Dose reductions and delays were used
to manage adverse events and increased over time from the period
1-6 weeks and greater than 12-week period.
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 (LSE: SHP, NASDAQ:
SHPG) entered into an exclusive licensing agreement for the
development and commercialization of ONIVYDE outside of the
United States and Taiwan. Shire's marketing
authorization application for the treatment of patients with
metastatic adenocarcinoma of the pancreas who have been previously
treated with gemcitabine-based therapy is currently under review
with the European Medicines Agency. 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 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," "hope" and similar expressions. In this press
release, Merrimack's forward-looking statements include statements
about the potential effectiveness and safety profile of ONIVYDE and
quality of life of patients receiving 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, availability of data from ongoing clinical trials,
expectations for regulatory approvals, development progress of
Merrimack's companion diagnostics and other matters that could
affect the availability or commercial potential of Merrimack's drug
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 August 4, 2016 and other reports Merrimack files
with the SEC.
Contacts:
Geoffrey Grande, CFA
617-441-7602
ggrande@merrimack.com
1 American Cancer Society. Cancer Facts and Figures
2016. Atlanta: American Cancer Society; 2016
2 American Cancer Society. Cancer Facts and Figures
2016. Atlanta: American Cancer Society; 2016
3 American Cancer Society. Cancer Facts and Figures
2016. Atlanta: American Cancer Society; 2016
4 World Health Organization. GLOBOCAN 2012: Estimated
Cancer Incidence, Mortality and Prevalence Worldwide in
2012; Lyon, Fr.: International Agency for Research on
Cancer; 2012
5 Data presented at ASCO 2014 (Abrams et al.)
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