THOUSAND OAKS, Calif.,
Nov. 19, 2015 /PRNewswire/
-- Amgen (NASDAQ: AMGN) today announced the European
Commission (EC) granted marketing authorization for
Kyprolis® (carfilzomib) in combination with lenalidomide
and dexamethasone for the treatment of adult patients with multiple
myeloma who have received at least one prior therapy. Kyprolis is
the first irreversible proteasome inhibitor approved in the
European Union (EU) for use in combination treatment of patients
with relapsed multiple myeloma.1
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"The approval of Kyprolis in combination provides physicians and
patients across Europe with an
important new treatment option for relapsed multiple myeloma,
helping to address a real unmet need for this rare blood cancer,"
said Sean E. Harper, M.D., executive
vice president of Research and Development at Amgen. "Multiple
myeloma is a complex blood cancer that often becomes resistant to
treatment, which is why there is a need for new therapeutic options
that provide deep and durable responses to extend the time patients
live without their disease progressing."
Multiple myeloma is an incurable blood cancer, characterized by
a recurring pattern of remission and relapse.2 It is a
rare and very aggressive orphan disease that accounts for
approximately one percent of all cancers.3-5 In
Europe, approximately 39,000
patients are diagnosed with multiple myeloma each year and 24,000
patient deaths are reported on an annual basis.3
"In clinical studies, approximately one out of three patients
achieved a complete response or better on the Kyprolis in
combination with lenalidomide and dexamethasone arm, which is three
times more frequent than in the lenalidomide and dexamethasone
arm," said Prof. Meletios A.
Dimopoulos, M.D., Department of Clinical Therapeutics,
National and Kapodistrian University of Athens, School of Medicine. "In addition, the
regimen provided patients with more than two years without disease
progression. These results are significant for patients with
relapsed multiple myeloma, who are faced with worse outcomes each
time they experience a relapse."
The EC approved Kyprolis based on data from the pivotal Phase 3
ASPIRE (CArfilzomib, Lenalidomide, and DexamethSone
versus Lenalidomide and Dexamethasone for the treatment of
PatIents with Relapsed Multiple
MyEloma) trial. The study showed that patients treated with
Kyprolis in combination with lenalidomide and dexamethasone
(regimen referred to as KRd) had increased median time to
progressive disease (PD) or death by 8.7 months compared to
patients treated with lenalidomide and dexamethasone (regimen
referred to as Rd). The median progression-free survival (PFS) was
26.3 months in the KRd arm compared to 17.6 months in the Rd arm
(HR: 0.69; 95 percent CI: 0.57 to 0.83; p=0.0001). The
most common adverse events (AEs) in the Kyprolis arm included
pneumonia (1 percent), myocardial infarction (0.8 percent) and
upper respiratory tract infection (0.8 percent). Discontinuation of
treatment due to AEs occurred in 15 percent of patients in the KRd
arm versus 18 percent of patients in the Rd arm.
Kyprolis received an accelerated assessment from the European
Medicines Agency (EMA), and orphan drug designation in 2008,
given to medicines intended for the treatment, prevention or
diagnosis of a disease that is life threatening and has a
prevalence in the EU of no more than five in 10,000 people.
Approval from the EC grants a centralized 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.
Amgen plans to submit data from the Phase 3 ENDEAVOR
(RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib
Plus DExamethAsone Vs Bortezomib Plus
DexamethasOne in Patients With Relapsed Multiple
Myeloma) trial for potential authorization of Kyprolis in
combination with dexamethasone in the EU. This data also serves as
the basis of the supplemental New Drug Application of Kyprolis in
combination with dexamethasone for patients with relapsed multiple
myeloma, which has been accepted for priority review by the U.S.
Food and Drug Administration (FDA).
About ASPIRE
The international, randomized Phase 3
ASPIRE trial evaluated Kyprolis in combination with lenalidomide
and dexamethasone, versus lenalidomide and dexamethasone, 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 randomization to disease progression
or death due to any cause, whichever is earlier. 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, escalating, if tolerated, to 27 mg/m2
subsequently), in addition to a standard dosing schedule of
lenalidomide (25 mg per day for 21 days on, 7 days off) and
dexamethasone (40 mg per week in 4 week cycles), versus
lenalidomide and dexamethasone. In the Kyprolis arm, patients were
given a 10 minute infusion on days 1, 2, 8, 9, 15 and 16. Kyprolis
was omitted on days 8 and 9 during cycles 13-18 and not
administered beyond 18 cycles. The study randomized 792 patients at
sites in North America,
Europe and Israel.
While the data for median OS were not yet mature at the time of
primary analysis, the analysis showed a trend in favor of KRd
compared with Rd (HR=0.79; 95 percent CI: 0.63-0.99; p=0.02
[1-sided]). Patients continue to be monitored for OS. The ORR was
87.1 percent with KRd and 66.7 percent with Rd. 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). In the KRd and Rd groups, 32 percent versus 9
percent of patients achieved a complete response or higher
(stringent complete response [sCR] or complete response [CR]), a
measurement indicating depth of response.
The rate of death due to AEs within 30 days of the last dose was
balanced between the KRd arm and the Rd arm. The most common causes
of death not due to PD 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 (SAEs) 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 SAEs reported in the KRd arm compared to the
Rd arm were pneumonia (14 percent versus 11 percent), respiratory
tract infection (4 percent versus 2 percent), pyrexia (4 percent
versus 2 percent) and pulmonary embolism (3 percent versus 2
percent). Discontinuation of treatment due to AEs occurred in 15
percent of patients in the KRd arm versus 18 percent of patients in
the Rd arm. AEs leading to discontinuation of Kyprolis occurred in
12 percent of patients and the most common events included
pneumonia (1 percent), myocardial infarction (1 percent) and upper
respiratory tract infection (1 percent).
The ASPIRE data were presented at the 56th Annual Meeting of the
American Society of Hematology (ASH) and published in The New
England Journal of Medicine in December
2014.1
About Kyprolis® (carfilzomib)
Proteasomes play an important role in cell function and growth by
breaking down proteins that are damaged or no longer
needed.6 Kyprolis has been shown to block proteasomes,
leading to an excessive build-up of proteins within
cells.7 In some cells, Kyprolis can cause cell death,
especially in myeloma cells because they are more likely to contain
a higher amount of abnormal proteins.7 The
irreversibility of Kyprolis' binding has also been shown to offer a
more sustained inhibition of the targeted enzymes.8
Kyprolis is currently approved in the U.S. 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 also approved in Argentina, Israel, Kuwait, Mexico, Thailand and Colombia. Additional regulatory applications
for Kyprolis are underway and have been submitted to health
authorities worldwide.
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.
Important EU Product Safety Information
This medicinal product is subject to additional monitoring. This
will allow quick identification of new safety information.
Healthcare professionals are asked to report any suspected adverse
reactions.
Kyprolis treatment should be supervised by a physician
experienced in the use of anti-cancer therapy. The most serious
side effects that may occur during Kyprolis treatment include:
cardiac toxicity, pulmonary toxicities, pulmonary hypertension,
dyspnoea, hypertension including hypertensive crises, acute renal
failure, tumour lysis syndrome, infusion reactions,
thrombocytopenia, hepatic toxicity, posterior reversible
encephalopathy syndrome (PRES) and thrombotic thrombocytopenic
purpura/haemolytic uremic syndrome (TTP/HUS). The most common side
effects are anaemia, fatigue, diarrhoea, thrombocytopenia, nausea,
pyrexia, dyspnoea, respiratory tract infection, cough and
peripheral oedema.
Please refer to the Summary of Product Characteristics for full
European prescribing information.
Important U.S. Product Safety Information
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. 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 based on a
benefit/risk assessment.
Adequate hydration is required prior to each dose in Cycle 1.
Monitor all patients 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.
Patients > 75 years, 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 may be at greater risk for cardiac complications.
Acute Renal Failure
Cases of acute renal failure and
renal insufficiency adverse events (renal impairment, acute renal
failure, renal failure) have occurred in patients receiving
Kyprolis. 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. 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 occurred in patients
receiving Kyprolis. Patients with multiple myeloma and a high tumor
burden should be considered at greater risk for TLS. Adequate
hydration is required prior to each dose 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. Withhold 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 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 patients treated with Kyprolis. Evaluate with
cardiac imaging and/or other tests as indicated. Withhold Kyprolis
for PAH until resolved or returned to baseline and consider whether
to restart Kyprolis based on a benefit/risk assessment.
Dyspnea
Dyspnea was reported in patients treated with
Kyprolis. 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. 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. Premedicate with dexamethasone to
reduce the incidence and severity of infusion reactions. Inform
patients of the risk and of symptoms of an infusion reaction and to
contact a physician immediately if they occur.
Thrombocytopenia
Kyprolis causes thrombocytopenia with
recovery to baseline platelet count usually by the start of the
next cycle. Thrombocytopenia was reported in patients receiving
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 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 (TTP/HUS)
Cases of TTP/HUS including fatal outcome
have occurred in patients receiving Kyprolis. Monitor for signs and
symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is
suspected. 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 occurred in patients receiving
Kyprolis. PRES was formerly known as Reversible Posterior
Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging
(MRI) for onset of visual or neurological symptoms, such as
seizure, headache, lethargy, confusion, blindness, and altered
consciousness, along with hypertension.. 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.
Females of reproductive potential should be advised to avoid
becoming pregnant while being treated with Kyprolis and the
potential hazard to the fetus if Kyprolis is used during
pregnancy.
ADVERSE REACTIONS
The most common adverse events of
all grades occurring in at least 20 percent 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 of all grades occurring in
at least 20 percent 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.
Full prescribing information for the U.S. 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.
Forward Looking Statements
This news release contains
forward-looking statements that are based on the current
expectations and beliefs of Amgen Inc. and its subsidiaries (Amgen,
we or us) and are subject to a number of risks, uncertainties and
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CONTACT:
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References:
- Stewart KA, Rajkumar VS, Dimopoulos MA, et al. Carfilzomib,
Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. N
Engl J Med. 2015; 372:142-152.
- Jakubowiak A. Management Strategies for Relapsed/Refractory
Multiple Myeloma: Current Clinical Perspectives. Seminars in
Hematology. 2012; 49(3)(1),S16-S32.
- GLOBCAN 2012, Global Prevalence and Incidence, available at
http://globocan.iarc.fr/old/summary_table_pop_prev.asp?selection=224900&title=World&sex=0&window=1&sort=0&submit=%C2%A0Execute%C2%A0,
accessed on March 9, 2015.
- American Cancer Society. Multiple myeloma.
http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf.
Accessed on: October 30, 2015.
- Palumbo A and Anderson K, Multiple myeloma, N Engl J
Med, 2011;364:1046–60
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in Multiple Myeloma: 10 Years Later. Blood. 2012;
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- Kyprolis® [package insert]. Thousand Oaks, CA: Amgen; 2015.
- Kortuem KM and Stewart AK. Carfilzomib. Blood. 2012;
121(6):893-897.
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