THOUSAND OAKS, Calif.,
July 24, 2015 /PRNewswire/
-- Amgen (NASDAQ:AMGN) today announced that the U.S. Food and
Drug Administration (FDA) approved the supplemental New Drug
Application (sNDA) for Kyprolis® (carfilzomib) for
Injection in combination with Revlimid® (lenalidomide)
and dexamethasone (KRd) for the treatment of patients with multiple
myeloma who have received one to three prior lines of therapy.
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"The expanded indication of Kyprolis provides patients with
relapsed multiple myeloma a new therapeutic option, helping to
address a real unmet need for this common blood cancer," said
Sean E. Harper, M.D., executive vice
president of Research and Development at Amgen. "The approval of a
second indication for Kyprolis in just three years demonstrates
that it is becoming a critical component in the treatment of
multiple myeloma, and underscores our commitment to advancing care
for patients with this challenging disease."
The FDA approved the expanded indication for Kyprolis based on
data from the ASPIRE study. The study showed that patients treated
in the KRd arm lived 50 percent longer (8.7 months) without their
disease worsening compared to patients treated with Revlimid and
low-dose dexamethasone (Rd) alone. The median progression-free
survival (PFS) was 26.3 months (95 percent CI, 23.3 to 30.5 months)
in the KRd arm compared to 17.6 months (95 percent CI, 15.0 to 20.6
months) in the Rd arm. The most common adverse events in the
Kyprolis arm included pneumonia (1 percent), myocardial infarction
(0.8 percent) and upper respiratory tract infection (0.8
percent).
"The ability of this Kyprolis treatment regimen to produce deep
and durable responses is critical towards extending the time
patients live without their disease progressing," said ASPIRE
principal investigator Keith
Stewart, M.D., Ch.B.
Additional regulatory applications for Kyprolis are underway and
have been submitted to health authorities worldwide.
Multiple myeloma is the second most common hematologic
cancer.1 In the U.S., there are nearly 96,000 people
living with, or in remission from, multiple myeloma.2
The estimated number of new cases of multiple myeloma in 2014 was
more than 24,000 and the estimated number of deaths was
11,090.2
About ASPIRE
The international, randomized Phase 3
ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone
versus Lenalidomide and Dexamethasone for the treatment of
PatIents with Relapsed Multiple
MyEloma) trial evaluated Kyprolis in combination with
lenalidomide and low-dose dexamethasone, versus lenalidomide and
low-dose dexamethasone alone, in patients with relapsed multiple
myeloma following treatment with one to three prior regimens. The
primary endpoint of the trial was PFS, defined as the time from
treatment initiation to disease progression or death. Secondary
endpoints included overall survival (OS), overall response rate
(ORR), duration of response (DOR), disease control rate,
health-related quality of life (HR-QoL) and safety. Patients were
randomized to receive Kyprolis (20 mg/m2 on days 1 and 2
of cycle one only, escalating to 27 mg/m2 on days 8, 9,
15 and 16 of cycle one and continuing on days 1, 2, 8, 9, 15 and 16
of subsequent cycles), in addition to a standard dosing schedule of
lenalidomide (25 mg per day for 21 days on, 7 days off) and
low-dose dexamethasone (40 mg per week in four-week cycles), versus
lenalidomide and low-dose dexamethasone alone. The study randomized
792 patients at sites in North
America, Europe and
Israel.
The OS results did not cross the pre-specified early stopping
boundary for the interim analysis. At the time of the interim
analysis, there were 143 deaths (36.1 percent) in the KRd group,
compared to 162 deaths (40.9 percent) in the Rd group. The ORR was
87 percent with KRd and 67 percent with Rd. In the KRd and Rd
groups, 14 percent versus 4 percent of patients achieved a
stringent complete response, a measurement indicating depth of
response. Median DOR was 28.6 months for patients receiving KRd (95
percent CI, 24.9 to 31.3 months) and 21.2 months for patients
receiving Rd (95 percent CI, 16.7 to 25.8 months).
The rate of deaths due to adverse events (AEs) within 30 days of
the last dose was balanced between the KRd arm and the Rd arm. The
most common causes of death occurring in patients in the KRd arm
compared to the Rd arm included cardiac disorders (3 percent versus
2 percent), infection (2 percent versus 3 percent), renal (0
percent versus less than 1 percent), and other AEs (2 percent
versus 3 percent). Serious AEs were reported in 60 percent of the
patients in the KRd arm and 54 percent of the patients in the Rd
arm. The most common serious AEs reported in the KRd arm compared
to the Rd arm were pneumonia (14 percent versus 11 percent),
respiratory tract infection (4 percent versus 1.5 percent), pyrexia
(4 percent versus 2 percent), and pulmonary embolism (3 percent
versus 2 percent). Discontinuation due to any AE occurred in 26
percent of patients in the KRd arm versus 25 percent of patients in
the Rd arm. Adverse events leading to discontinuation of Kyprolis
occurred in 12 percent of patients.
The ASPIRE data were presented at the 56th Annual
Meeting of the American Society of Hematology and published in
The New England Journal of Medicine in December 2014.
About Kyprolis® (carfilzomib) for
Injection
Kyprolis® (carfilzomib) for Injection
is indicated in combination with lenalidomide and dexamethasone for
the treatment of patients with multiple myeloma who have received
one to three prior lines of therapy.
Kyprolis® is also indicated under FDA accelerated
approval as a single agent for the treatment of patients with
multiple myeloma who have received at least two prior therapies
including bortezomib and an immunomodulatory agent and have
demonstrated disease progression on or within 60 days of completion
of the last therapy. Approval is based on response rate. Clinical
benefit, such as improvement in survival or symptoms, has not been
verified.
Kyprolis is a product of Onyx Pharmaceuticals, Inc. Onyx
Pharmaceuticals is a subsidiary of Amgen and holds development and
commercialization rights to Kyprolis globally, excluding
Japan. Kyprolis is also approved
for use in Argentina, Israel,
Mexico and Thailand. For more information about Kyprolis,
visit www.kyprolis.com.
Important Safety Information Regarding Kyprolis®
(carfilzomib) for Injection
WARNINGS AND PRECAUTIONS
Cardiac
Toxicities:
New onset or worsening of pre-existing cardiac
failure (e.g., congestive heart failure, pulmonary edema, decreased
ejection fraction), restrictive cardiomyopathy, myocardial
ischemia, and myocardial infarction including fatalities have
occurred following administration of Kyprolis. In clinical studies
with Kyprolis, these events typically occurred early in the course
of Kyprolis therapy (< 5 cycles). Death due to cardiac arrest
has occurred within a day of Kyprolis administration. Withhold
Kyprolis for Grade 3 or 4 cardiac adverse events until recovery,
and consider whether to restart Kyprolis at 1 dose level reduction
based on a benefit/risk assessment. While adequate hydration is
required prior to each dose in Cycle 1, all patients should also be
monitored for evidence of volume overload, especially patients at
risk for cardiac failure. Adjust total fluid intake as clinically
appropriate in patients with baseline cardiac failure or who are at
risk for cardiac failure. In patients > 75 years of age,
the risk of cardiac failure is increased. Patients with New York
Heart Association Class III and IV heart failure, recent myocardial
infarction, and conduction abnormalities uncontrolled by
medications were not eligible for the clinical trials. These
patients may be at greater risk for cardiac complications.
Acute Renal Failure:
Cases of acute renal failure have
occurred in patients receiving Kyprolis. Renal insufficiency
adverse events (renal impairment, acute renal failure, renal
failure) have occurred with an incidence of approximately 8% in a
randomized controlled trial. Acute renal failure was reported more
frequently in patients with advanced relapsed and refractory
multiple myeloma who received Kyprolis monotherapy. This risk was
greater in patients with a baseline reduced estimated creatinine
clearance (calculated using Cockcroft and Gault equation). Monitor
renal function with regular measurement of the serum creatinine
and/or estimated creatinine clearance. Reduce or withhold dose as
appropriate.
Tumor Lysis Syndrome:
Cases of tumor lysis syndrome (TLS), including fatal outcomes, have
been reported in patients who received Kyprolis. Patients with
multiple myeloma and a high tumor burden should be considered to be
at greater risk for TLS. Ensure that patients are well hydrated
before administration of Kyprolis in Cycle 1, and in subsequent
cycles as needed. Consider uric acid lowering drugs in patients at
risk for TLS. Monitor for evidence of TLS during treatment and
manage promptly including interruption of Kyprolis until TLS is
resolved.
Pulmonary Toxicity:
Acute Respiratory Distress Syndrome (ARDS), acute respiratory
failure, and acute diffuse infiltrative pulmonary disease such as
pneumonitis and interstitial lung disease have occurred in less
than 1% of patients receiving Kyprolis. Some events have been
fatal. In the event of drug-induced pulmonary toxicity, discontinue
Kyprolis.
Pulmonary Hypertension:
Pulmonary arterial hypertension (PAH) was reported in approximately
1% of patients treated with Kyprolis and was Grade 3 or greater in
less than 1% of patients. Evaluate with cardiac imaging and/or
other tests as indicated. Withhold Kyprolis for pulmonary 11
hypertension until resolved or returned to baseline and consider
whether to restart Kyprolis based on a benefit/risk assessment.
Dyspnea:
Dyspnea was reported in 28% of patients
treated with Kyprolis and was Grade 3 or greater in 4% of patients.
Evaluate dyspnea to exclude cardiopulmonary conditions including
cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3
or 4 dyspnea until resolved or returned to baseline. Consider
whether to restart Kyprolis based on a benefit/risk assessment.
Hypertension:
Hypertension, including hypertensive crisis and hypertensive
emergency, has been observed with Kyprolis. Some of these events
have been fatal. Monitor blood pressure regularly in all patients.
If hypertension cannot be adequately controlled, withhold Kyprolis
and evaluate. Consider whether to restart Kyprolis based on a
benefit/risk assessment.
Venous Thrombosis:
Venous thromboembolic events (including deep venous thrombosis and
pulmonary embolism) have been observed with Kyprolis. In the
combination study, the incidence of venous thromboembolic events in
the first 12 cycles was 13% in the Kyprolis combination arm versus
6% in the control arm. With Kyprolis monotherapy, the incidence of
venous thromboembolic events was 2%. Thromboprophylaxis is
recommended and should be based on an assessment of the patient's
underlying risks, treatment regimen, and clinical status.
Infusion Reactions:
Infusion reactions, including life-threatening reactions, have
occurred in patients receiving Kyprolis. Symptoms include fever,
chills, arthralgia, myalgia, facial flushing, facial edema,
vomiting, weakness, shortness of breath, hypotension, syncope,
chest tightness, or angina. These reactions can occur immediately
following or up to 24 hours after administration of Kyprolis.
Administer dexamethasone prior to Kyprolis to reduce the incidence
and severity 12 of infusion reactions. Inform patients of the risk
and of symptoms and to contact a physician immediately if symptoms
of an infusion reaction occur.
Thrombocytopenia:
Kyprolis causes thrombocytopenia
with platelet nadirs observed between Day 8 and Day 15 of each
28-day cycle with recovery to baseline platelet count usually by
the start of the next cycle. Thrombocytopenia was reported in
approximately 40% of patients in clinical trials with Kyprolis.
Monitor platelet counts frequently during treatment with Kyprolis.
Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure:
Cases of hepatic failure, including fatal cases, have been reported
(< 1%) during treatment with Kyprolis. Kyprolis can cause
increased serum transaminases. Monitor liver enzymes regularly.
Reduce or withhold dose as appropriate.
Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic
Syndrome:
Cases of thrombotic thrombocytopenic purpura/hemolytic uremic
syndrome (TTP/HUS) including fatal outcome have been reported in
patients who received Kyprolis. Monitor for signs and symptoms of
TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate.
If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted.
The safety of reinitiating Kyprolis therapy in patients previously
experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES):
Cases of PRES have been reported in patients receiving Kyprolis.
Posterior reversible encephalopathy syndrome (PRES), formerly
termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is
a neurological disorder which can present with seizure, headache,
lethargy, confusion, blindness, altered consciousness, and other
visual and neurological disturbances, along with hypertension, and
the diagnosis is confirmed by neuro-radiological imaging (MRI).
Discontinue Kyprolis if PRES is suspected and evaluate. The
safety of reinitiating Kyprolis therapy in patients previously
experiencing PRES is not known.
Embryo-fetal Toxicity:
Kyprolis can cause fetal harm when administered to a pregnant woman
based on its mechanism of action and findings in animals. There are
no adequate and well-controlled studies in pregnant women using
Kyprolis. Kyprolis caused embryo-fetal toxicity in pregnant rabbits
at doses that were lower than in patients receiving the recommended
dose. Females of reproductive potential should be advised to avoid
becoming pregnant while being treated with Kyprolis. If this drug
is used during pregnancy, or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential
hazard to the fetus.
ADVERSE REACTIONS
The most common adverse events
occurring in at least 20% of patients treated with Kyprolis in
monotherapy trials: anemia, fatigue, thrombocytopenia, nausea,
pyrexia, decreased platelets, dyspnea, diarrhea, decreased
lymphocyte, headache, decreased hemoglobin, cough, edema
peripheral.
The most common adverse events occurring in at least 20% of
patients treated with Kyprolis in the combination therapy trial:
decreased lymphocytes, decreased absolute neutrophil count,
decreased phosphorus, anemia, neutropenia, decreased total white
blood cell count, decreased platelets, diarrhea, fatigue,
thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory
tract infection, decreased hemoglobin, hypokalemia.
USE IN SPECIFIC POPULATIONS
Patients on dialysis:
Administer Kyprolis after the dialysis procedure.
POST-MARKETING EXPERIENCE
The following adverse
reactions were reported in the post-marketing experience:
dehydration, thrombotic thrombocytopenic purpura/hemolytic uremic
syndrome (TTP/HUS), tumor lysis syndrome including fatal outcomes,
and posterior reversible encephalopathy syndrome (PRES). Because
these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug
exposure.
Full prescribing information is available at
www.kyprolis.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.
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- Dimopoulos, MA and Terpos E. Multiple Myeloma. Annals of
Oncology 21 (Supplement 7): vii143–vii150, 2010.
- Leukemia & Lymphoma Society. Facts 2014-2015. Available at:
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts.pdf
Accessed July 2015.
CONTACT: Amgen, Thousand
Oaks
Kristen Davis, 805-447-3008
(media)
Trish Hawkins, 805-447-5631
(media)
Arvind Sood, 805-447-1060
(investors)
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