THOUSAND OAKS, Calif.,
Nov. 24, 2015 /PRNewswire/ -- Amgen
(NASDAQ:AMGN) today announced that the European Commission (EC) has
granted conditional marketing authorization for
BLINCYTO® (blinatumomab) for the treatment of adults
with Philadelphia
chromosome-negative (Ph-) relapsed or refractory B-precursor acute
lymphoblastic leukemia (ALL).
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ALL is a rare and rapidly progressing cancer of the blood and
bone marrow.1,2 For adults with relapsed or refractory
ALL, the median overall survival is just three to five
months.3 It is estimated that the incidence of adults
with Ph- relapsed or refractory B-precursor ALL in the European
Union (EU) is approximately 900 patients per
year.4
"We are pleased the European Commission granted conditional
marketing authorization for BLINCYTO," said Sean E. Harper, M.D., executive vice president
of Research and Development at Amgen. "BLINCYTO has demonstrated
efficacy in treating relapsed or refractory ALL, a very
difficult-to-treat disease for which historically patients had
limited therapeutic options. This approval represents an important
milestone in immunotherapy research. BLINCYTO is the first clinical
validation of the BiTE® platform, a new and
innovative approach that helps the body's own immune system fight
cancer."
The conditional marketing authorization for BLINCYTO is based on
results of two Phase 2 studies, study '211 and '206. In the pivotal
'211 trial, 42.9 percent of patients achieved complete remission
(CR) or CR with partial hematological recovery (CRh*) with
single-agent BLINCYTO.
The most serious adverse reactions that occurred during BLINCYTO
treatment in the pivotal '211 trial included infections, neurologic
events, neutropenia/febrile neutropenia, cytokine release syndrome
and tumor lysis syndrome.
"We tested BLINCYTO in ALL, the most aggressive B-cell
malignancy we know, and observed a clinically meaningful remission
rate," said Max S. Topp, M.D.,
professor, Hospital of Wuerzburg, Germany. "This is the first major advance in
more than two decades for patients with this hard-to-treat
cancer."
"The prognosis for adult patients with ALL who are refractory to
treatment or experience relapse is poor, and BLINCYTO constitutes a
new treatment option for these patients," said Herve Dombret, M.D., professor, University
Paris, Hospital Saint Louis, Paris. "It is important for clinicians and
patients to have more treatment options in this acute form of
leukemia."
Approval from the EC grants a centralized conditional marketing
authorization with unified labeling in the 28 countries that are
members of the EU. Norway,
Iceland and Liechtenstein, as members of the European
Economic Area (EEA), will take corresponding decisions on the basis
of the decision of the EC. Conditional license requires the license
to be renewed every year and it will be converted to full standard
license once post-licensing commitments have been fulfilled.
BLINCYTO was granted orphan drug designation by the European
Medicines Agency in 2009 for the treatment of ALL.
About Study '211
Study '211 evaluated BLINCYTO in an open-label, multicenter,
single-arm Phase 2 study. Eligible patients were at least 18 years
of age with Ph- relapsed or refractory B-precursor ALL relapsed
with first remission duration of less than or equal to 12 months in
first salvage, or relapsed or refractory after first salvage
therapy, or relapsed within 12 months of allogeneic hematopoietic
stem cell transplantation (HSCT), and had at least10 percent blasts
in bone marrow.
The primary endpoint was the CR/CRh* rate within two cycles of
BLINCYTO. Of the 189 patients evaluated in the trial, 42.9 percent
(81/189; 95 percent CI, 35.7 - 50.2) achieved CR or CRh* within two
cycles of treatment with BLINCYTO with the majority of responses
(79 percent [64/81]) occurring within the first cycle of treatment.
In a prespecified exploratory analysis, 82.2 percent (60/73) of
minimal residual disease (MRD) evaluable patients with CR/CRh* also
had an MRD response. The most common adverse reactions (greater
than 20 percent) were infusion-related reactions (67.2 percent),
infections (63 percent), pyrexia (59.8 percent), headache (34.4
percent), febrile neutropenia (28 percent), peripheral edema (25.9
percent), nausea (24.3 percent), hypokalemia (23.8 percent),
constipation (20.6 percent) and anemia (20.1 percent). The most
serious adverse reactions that occurred during BLINCYTO treatment
included: infections (31.7 percent), neurologic events (16.4
percent), neutropenia/febrile neutropenia (15.3 percent), cytokine
release syndrome (0.5 percent) and tumor lysis syndrome (0.5
percent).
About Study '206
Study '206 evaluated the safety and
efficacy of BLINCYTO in an open-label, multicenter, dose-escalation
Phase 2 study of 36 patients, who were at least 18 years of age
with B-precursor ALL relapsed after at least induction and
consolidation or having refractory disease with greater than 5
percent blasts in bone marrow, had an Eastern Cooperative Oncology
Group (ECOG) performance status of at most 2, had a life expectancy
of at least 12 weeks, and who did not have autologous HSCT within
six weeks prior to start of treatment, allogeneic HSCT within three
months prior to start of treatment, or previous treatment with
BLINCYTO. The CR/CRh* rate was 69.4 percent (25/36) with 15
patients achieving CR (41.7 percent; 95 percent CI, 25.5 percent -
59.2 percent), and 10 patients achieving CRh* (27.8 percent; 95
percent CI, 14.2 percent - 45.2 percent). Of the patients with
hematologic CR, 88 percent (22/25) also had MRD responses. Overall
safety results from this study were consistent with the known
BLINCYTO safety profile.
About Adult ALL in Europe
The incidence of adult ALL in
European countries is generally between 0.6 to 0.9 per 100,000
persons per year.5 In adult ALL, approximately 75
percent is B-precursor ALL, of which between 75-80 percent is Ph-
and roughly half of adults will experience relapse or refractory
disease.5 Thus, with a population projection of 416
million adults in the EU,6 it is estimated that the
incidence of adult Ph- relapsed or refractory B-precursor ALL in
the EU is approximately 900 patients per
year.4
About BLINCYTO® (blinatumomab)
BLINCYTO is
a bispecific CD19-directed CD3 T cell engager (BiTE®)
antibody construct that binds specifically to CD19 expressed on the
surface of cells of B-lineage origin and CD3 expressed on the
surface of T cells. BLINCYTO was granted breakthrough therapy and
priority review designations by the U.S. Food and Drug
Administration, and is now approved in the U.S. for the treatment
of Ph- relapsed or refractory B-cell precursor ALL. This indication
is approved under accelerated approval. Continued approval for this
indication may be contingent upon verification of clinical benefit
in subsequent trials.
About BiTE® Technology
BiTE® antibody constructs are a type of immunotherapy
being investigated for fighting cancer by helping the body's immune
system to detect and target malignant cells. The modified
antibodies are designed to engage two different targets
simultaneously, thereby juxtaposing T cells (a type of white blood
cell capable of killing other cells perceived as threats) to cancer
cells. BiTE® antibody constructs help place the T cells
within reach of the targeted cell, with the intent of allowing T
cells to inject toxins and trigger the cancer cell to die
(apoptosis). BiTE® antibody constructs are currently
being investigated for their potential to treat a wide variety of
cancers.
Important EU Product Safety Information
This product is subject to additional monitoring in the EU
and EEA. All suspected adverse reactions should be reported in
accordance with the national reporting system.
The adverse reactions described in this section were identified
in the pivotal clinical study (N=189).The most serious adverse
reactions that may occur during blinatumomab treatment include:
infections (31.7%), neurologic events (16.4%), neutropenia/febrile
neutropenia (15.3%) cytokine release syndrome (0.5%), and tumor
lysis syndrome (0.5%). The most common adverse reactions were:
infusion-related reactions (67.2%), infections (63.0%), pyrexia
(59.8%), headache (34.4%), febrile neutropenia (28%), peripheral
edema (25.9%), nausea (24.3%), hypokalaemia (23.8%), constipation
(20.6%), anaemia (20.1%), cough (18.5%), diarrhea (18.0%), tremor
(17.5%), neutropenia (17.5%), abdominal pain (16.9%), insomnia
(15.3%), fatigue (15.3%), and chills (15.3%).
Please refer to the Summary of Product Characteristics for
full European prescribing information.
BLINCYTO® U.S. Product Safety Information
Important Safety Information Regarding BLINCYTO®
(blinatumomab) U.S. Indication
This safety information is
specific to the current U.S. approved indication.
U.S. INDICATION
BLINCYTO® is indicated for the treatment of
Philadelphia chromosome-negative
relapsed or refractory B-cell precursor acute lymphoblastic
leukemia (ALL).
This indication is approved under accelerated approval.
Continued approval for this indication may be contingent upon
verification of clinical benefit in subsequent trials.
U.S. IMPORTANT SAFETY INFORMATION
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL
TOXICITIES
- Cytokine Release Syndrome (CRS), which may be
life-threatening or fatal, occurred in patients receiving
BLINCYTO®. Interrupt or discontinue BLINCYTO®
as recommended.
- Neurological toxicities, which may be severe,
life-threatening or fatal, occurred in patients receiving
BLINCYTO®. Interrupt or discontinue BLINCYTO®
as recommended.
Contraindications
BLINCYTO® is contraindicated in patients with a known
hypersensitivity to blinatumomab or to any component of the product
formulation.
Warnings and Precautions
- Cytokine Release Syndrome (CRS): Life-threatening or
fatal CRS occurred in patients receiving BLINCYTO®.
Infusion reactions have occurred and may be clinically
indistinguishable from manifestations of CRS. Closely monitor
patients for signs and symptoms of serious events such as pyrexia,
headache, nausea, asthenia, hypotension, increased alanine
aminotransferase (ALT), increased aspartate aminotransferase (AST),
increased total bilirubin (TBILI), disseminated intravascular
coagulation (DIC), capillary leak syndrome (CLS), and
hemophagocytic lymphohistiocytosis/macrophage activation syndrome
(HLH/MAS). Interrupt or discontinue BLINCYTO® as
outlined in the Prescribing Information (PI).
- Neurological Toxicities: Approximately 50% of patients
receiving BLINCYTO® in clinical trials experienced
neurological toxicities. Severe, life-threatening, or fatal
neurological toxicities occurred in approximately 15% of patients,
including encephalopathy, convulsions, speech disorders,
disturbances in consciousness, confusion and disorientation, and
coordination and balance disorders. The median time to onset of any
neurological toxicity was 7 days. Monitor patients for signs or
symptoms and interrupt or discontinue BLINCYTO® as
outlined in the PI.
- Infections: Approximately 25% of patients receiving
BLINCYTO® experienced serious infections, some of which were
life-threatening or fatal. Administer prophylactic antibiotics and
employ surveillance testing as appropriate during treatment.
Monitor patients for signs or symptoms of infection and treat
appropriately, including interruption or discontinuation of
BLINCYTO® as needed.
- Tumor Lysis Syndrome (TLS): Life-threatening or fatal
TLS has been observed. Preventive measures, including pretreatment
nontoxic cytoreduction and on treatment hydration, should be used
during BLINCYTO® treatment. Monitor patients for signs
and symptoms of TLS and interrupt or discontinue
BLINCYTO® as needed to manage these events.
- Neutropenia and Febrile Neutropenia, including
life-threatening cases, have been observed. Monitor appropriate
laboratory parameters during BLINCYTO® infusion and
interrupt BLINCYTO® if prolonged neutropenia
occurs.
- Effects on Ability to Drive and Use Machines: Due to the
possibility of neurological events, including seizures, patients
receiving BLINCYTO® are at risk for loss of
consciousness, and should be advised against driving and engaging
in hazardous occupations or activities such as operating heavy or
potentially dangerous machinery while BLINCYTO® is being
administered.
- Elevated Liver Enzymes: Transient elevations in liver
enzymes have been associated with BLINCYTO® treatment.
The majority of these events were observed in the setting of CRS.
The median time to onset was 15 days. Grade 3 or greater elevations
in liver enzymes occurred in 6% of patients outside the setting of
CRS and resulted in treatment discontinuation in less than 1% of
patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and
TBILI prior to the start of and during BLINCYTO®
treatment. BLINCYTO® treatment should be interrupted if
transaminases rise to > 5 times the upper limit of normal (ULN)
or if TBILI rises to > 3 times ULN.
- Leukoencephalopathy: Although the clinical significance
is unknown, cranial magnetic resonance imaging (MRI) changes
showing leukoencephalopathy have been observed in patients
receiving BLINCYTO®, especially in patients previously
treated with cranial irradiation and anti-leukemic
chemotherapy.
- Preparation and administration errors have occurred with
BLINCYTO® treatment. Follow instructions for preparation
(including admixing) and administration in the PI strictly to
minimize medication errors (including underdose and overdose).
Adverse Reactions
- The most commonly reported adverse reactions (≥ 20%) in
clinical trials were pyrexia (62%), headache (36%), peripheral
edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia
(23%), rash (21%), tremor (20%), diarrhea (20%), and constipation
(20%).
- Serious adverse reactions were reported in 65% of patients. The
most common serious adverse reactions (≥ 2%) included febrile
neutropenia, pyrexia, pneumonia, sepsis, neutropenia,
device-related infection, tremor, encephalopathy, infection,
overdose, confusion, Staphylococcal bacteremia, and headache.
U.S. Dosage and Administration Guidelines
- BLINCYTO® is administered as a continuous
intravenous infusion at a constant flow rate using an infusion pump
which should be programmable, lockable, non-elastomeric, and have
an alarm.
- It is very important that the instructions for preparation
(including admixing) and administration provided in the full
Prescribing Information are strictly followed to minimize
medication errors (including underdose and overdose).
- Please see full U.S. Prescribing Information and medication
guide for BLINCYTO at www.BLINCYTO.com.
About Amgen
Amgen is committed to
unlocking the potential of biology for patients suffering from
serious illnesses by discovering, developing, manufacturing and
delivering innovative human therapeutics. This approach begins by
using tools like advanced human genetics to unravel the
complexities of disease and understand the fundamentals of human
biology.
Amgen focuses on areas of high unmet medical need and
leverages its biologics manufacturing expertise to strive for
solutions that improve health outcomes and dramatically improve
people's lives. A biotechnology pioneer since
1980, Amgen has grown to be one of the world's leading
independent biotechnology companies, has reached millions of
patients around the world and is developing a pipeline of medicines
with breakaway potential.
For more information, visit www.amgen.com and follow
us on www.twitter.com/amgen.
Forward-Looking Statements
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forward-looking statements that are based on the current
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or us) and are subject to a number of risks, uncertainties and
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information as of Nov. 23,
2015, and expressly disclaims any duty to update information
contained in this news release.
No forward-looking statement can be guaranteed and actual
results may differ materially from those we project. Discovery or
identification of new product candidates or development of new
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guarantee that any particular product candidate or development of a
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CONTACT:
Amgen, Thousand Oaks
Kristen Davis,
805-447-3008 (media)
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(media)
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Emma Gilbert, +41 41 369 2542
(media)
References:
1. Cancer Research UK. Acute lymphoblastic
leukaemia risks and causes.
_http://www.cancerresearchuk.org/about-cancer/type/all/about/acute-lymphoblastic-leukaemia-risks-and-causes.
Accessed November 16, 2015.
2. Mayo Clinic. "Acute lymphocytic leukemia."
Available at:
_http://www.mayoclinic.com/health/acute-lymphocytic-leukemia/DS00558.
Accessed on November 16, 2015.
3. Advani A.S. New
immune strategies for the treatment of acute lymphoblastic
leukemia: Antibodies and chimeric antigen receptors. Hematology Am
Soc Hematol Educ Program. 2013;2013:131-7. Retrieved from:
http://asheducationbook.hematologylibrary.org/content/2013/1/131.long.
4. Amgen data on file.
5. Katz AJ, Chia VM, Schoonen M, Kelsh MA. Acute
lymphoblastic leukemia: an assessment of international incidence,
survival, and disease burden. Cancer Causes Control.
2015;26(11):1627-1642.
6. United Nations, Department of Economic and
Social Affairs, Population Division (2013) World Population
Prospects: The 2012 Revision.
http://esa.un.org/wpp/unpp/panel_indicators.htm. Accessed
November 16, 2014.
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