THOUSAND OAKS, Calif.,
Jan. 5, 2018 /PRNewswire/ -- Amgen
(NASDAQ:AMGN) today announced that the U.S. Food and Drug
Administration (FDA) has approved the supplemental Biologics
License Application (sBLA) for XGEVA® (denosumab) to
expand the currently approved indication for the prevention of
skeletal-related events in patients with bone metastases from solid
tumors to include patients with multiple myeloma. The approval is
based on data from the pivotal Phase 3 '482 study, the largest
international multiple myeloma clinical trial ever conducted, which
enrolled 1,718 patients.
"Up to 40 percent of patients remain untreated for the
prevention of bone complications, and the percentage is highest
among patients with renal impairment at the time of diagnosis,"
said Noopur Raje, M.D., director,
Center for Multiple Myeloma, Massachusetts General Hospital Cancer
Center, Boston. "Denosumab, which
is not cleared through the kidneys, offers multiple myeloma
patients bone protection with a convenient subcutaneous
administration, providing patients with a novel treatment
option."
"Bone complications can be devastating for patients with
multiple myeloma. Previously, treatment options for the prevention
of bone complications were limited to bisphosphonates, which unlike
XGEVA, are cleared by the kidneys," said David M. Reese, M.D., senior vice president of
Translational Sciences and Oncology at Amgen. "We are pleased that
the FDA has approved the expanded indication for XGEVA, providing a
new option for patients and physicians, underscoring our commitment
to advancing care for patients with multiple myeloma."
XGEVA is a fully human monoclonal antibody that binds to and
neutralizes RANK ligand (RANKL) – a protein essential for the
formation, function and survival of osteoclasts, which break down
bone – thereby inhibiting osteoclast-mediated bone destruction.
XGEVA is currently the number one prescribed bone-targeting agent
in the U.S. for the prevention of skeletal-related events in
patients with bone metastases from solid tumors. Additional
regulatory applications for XGEVA for the prevention of
skeletal-related events in patients with multiple myeloma are
underway and have been submitted to health authorities
worldwide.
About '482 Study (NCT01345019)
The '482 study was an
international, Phase 3, randomized, double-blind, multicenter trial
of XGEVA compared with zoledronic acid for the prevention of
skeletal-related events in adult patients with newly diagnosed
multiple myeloma and bone disease. In the study, a total of
1,718 patients (859 on each arm) were randomized to receive
either subcutaneous XGEVA 120 mg and intravenous placebo every four
weeks, or intravenous zoledronic acid 4 mg (adjusted for renal
function) and subcutaneous placebo every four weeks. The primary
endpoint of the study was non-inferiority of XGEVA versus
zoledronic acid with respect to time to first on-study
skeletal-related event (pathologic fracture, radiation to bone,
surgery to bone or spinal cord compression). Secondary endpoints
included superiority of XGEVA versus zoledronic acid with respect
to time to first on-study skeletal-related event and
first-and-subsequent on-study skeletal-related event and evaluation
of overall survival. Progression-free survival was an exploratory
endpoint. The safety and tolerability of XGEVA were also compared
with zoledronic acid.
The study met the primary endpoint, demonstrating
non-inferiority of XGEVA to zoledronic acid in delaying the time to
first on-study skeletal-related event in patients with multiple
myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01).
The secondary endpoints, delaying time to first skeletal-related
event and delaying time to first-and-subsequent skeletal-related
events, did not demonstrate superiority. Overall survival was
comparable between XGEVA and zoledronic acid, with a hazard ratio
of 0.90 (95 percent CI: 0.70, 1.16; p=0.41). The median difference
in progression-free survival favored XGEVA by 10.7 months (HR=0.82,
95 percent CI: 0.68-0.99; descriptive p=0.036). Median
progression-free survival was 46.1 months (95 percent CI: 34.3
months, not estimable [NE], n=219) for XGEVA and 35.4 months (95
percent CI: 30.2 months, NE, n=260) for zoledronic acid.
Adverse events observed in patients treated with XGEVA were
generally consistent with the known safety profile of XGEVA. The
most common adverse reactions (greater than or equal to 10 percent)
were diarrhea (34 percent), nausea (32 percent), anemia (22
percent), back pain (21 percent), thrombocytopenia (19 percent),
peripheral edema (17 percent), hypocalcemia (16 percent), upper
respiratory tract infection (15 percent), rash (14 percent) and
headache (11 percent). The most common adverse reaction
resulting in discontinuation of XGEVA (greater than or equal to 1.0
percent) was osteonecrosis of the jaw (ONJ). In the primary
treatment phase of the '482 study, ONJ was confirmed in 4.1 percent
of patients in the XGEVA group (median exposure of 16 months;
range: 1 - 50) and 2.8 percent of patients in the zoledronic acid
group (median 15 months, range: 1 - 45 months).
About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and
it develops in plasma cells located in the bone marrow
microenvironment.1,2 It is typically characterized
by osteolytic bone lesions as well as renal failure, which are both
part of diagnosis (CRAB criteria).3,4 Each year an
estimated 114,000 new cases of multiple myeloma are diagnosed
worldwide, resulting in more than 80,000 deaths per
year.1
More than 90 percent of patients develop osteolytic lesions
during the course of the disease.4 Preventing bone
complications is a critical aspect of caring for patients with
multiple myeloma, because these events can cause significant
morbidity.5 Current treatment options for
fractures and other bone complications are limited to
bisphosphonates, including zoledronic acid, which are cleared
through the kidneys.6 Approximately 60 percent of
all multiple myeloma patients have or will develop renal impairment
over the course of the disease.7
About XGEVA® (denosumab)
XGEVA targets
the RANKL pathway to prevent the formation, function and survival
of osteoclasts, which break down bone. XGEVA is indicated for the
prevention of skeletal-related events in patients with multiple
myeloma and in patients with bone metastases from solid tumors.
XGEVA is also indicated for treatment of adults and skeletally
mature adolescents with giant cell tumor of bone that is
unresectable or where surgical resection is likely to result in
severe morbidity and for the treatment of hypercalcemia of
malignancy refractory to bisphosphonate therapy.
U.S. Important Safety Information
Hypocalcemia
Pre-existing hypocalcemia must be
corrected prior to initiating therapy with XGEVA®.
XGEVA® can cause severe symptomatic hypocalcemia, and
fatal cases have been reported. Monitor calcium levels, especially
in the first weeks of initiating therapy, and administer calcium,
magnesium, and vitamin D as necessary. Monitor levels more
frequently when XGEVA® is administered with other drugs
that can also lower calcium levels. Advise patients to contact a
healthcare professional for symptoms of hypocalcemia.
An increased risk of hypocalcemia has been observed in clinical
trials of patients with increasing renal dysfunction, most commonly
with severe dysfunction (creatinine clearance less than 30
mL/minute and/or on dialysis), and with inadequate/no calcium
supplementation. Monitor calcium levels and calcium and vitamin D
intake.
Hypersensitivity
XGEVA® is contraindicated
in patients with known clinically significant hypersensitivity to
XGEVA®, including anaphylaxis that has been reported
with use of XGEVA®. Reactions may include hypotension,
dyspnea, upper airway edema, lip swelling, rash, pruritus, and
urticaria. If an anaphylactic or other clinically significant
allergic reaction occurs, initiate appropriate therapy and
discontinue XGEVA® therapy permanently.
Drug Products with Same Active Ingredient
Patients
receiving XGEVA® should not take Prolia®
(denosumab).
Osteonecrosis of the Jaw
Osteonecrosis of the jaw
(ONJ) has been reported in patients receiving XGEVA®,
manifesting as jaw pain, osteomyelitis, osteitis, bone erosion,
tooth or periodontal infection, toothache, gingival ulceration, or
gingival erosion. Persistent pain or slow healing of the mouth or
jaw after dental surgery may also be manifestations of ONJ. In
clinical trials in patients with osseous metastasis, the incidence
of ONJ was higher with longer duration of exposure.
Patients with a history of tooth extraction, poor oral hygiene,
or use of a dental appliance are at a greater risk to develop ONJ.
Other risk factors for the development of ONJ include
immunosuppressive therapy, treatment with angiogenesis inhibitors,
systemic corticosteroids, diabetes, and gingival infections.
Perform an oral examination and appropriate preventive dentistry
prior to the initiation of XGEVA® and periodically
during XGEVA® therapy. Advise patients regarding oral
hygiene practices. Avoid invasive dental procedures during
treatment with XGEVA®. Consider temporarily interrupting
XGEVA® therapy if an invasive dental procedure must be
performed.
Patients who are suspected of having or who develop ONJ while on
XGEVA® should receive care by a dentist or an oral
surgeon. In these patients, extensive dental surgery to treat ONJ
may exacerbate the condition.
Atypical Subtrochanteric and Diaphyseal Femoral
Fracture
Atypical femoral fracture has been reported with
XGEVA®. These fractures can occur anywhere in the
femoral shaft from just below the lesser trochanter to above the
supracondylar flare and are transverse or short oblique in
orientation without evidence of comminution.
Atypical femoral fractures most commonly occur with minimal or
no trauma to the affected area. They may be bilateral and many
patients report prodromal pain in the affected area, usually
presenting as dull, aching thigh pain, weeks to months before a
complete fracture occurs. A number of reports note that patients
were also receiving treatment with glucocorticoids (e.g.
prednisone) at the time of fracture. During XGEVA®
treatment, patients should be advised to report new or unusual
thigh, hip, or groin pain. Any patient who presents with thigh or
groin pain should be suspected of having an atypical fracture and
should be evaluated to rule out an incomplete femur fracture.
Patients presenting with an atypical femur fracture should also be
assessed for symptoms and signs of fracture in the contralateral
limb. Interruption of XGEVA® therapy should be
considered, pending a risk/benefit assessment, on an individual
basis.
Hypercalcemia Following Treatment Discontinuation in Patients
with Growing Skeletons
Clinically significant hypercalcemia
has been reported in XGEVA® treated patients with
growing skeletons, weeks to months following treatment
discontinuation. Monitor patients for signs and symptoms of
hypercalcemia and treat appropriately.
Embryo-Fetal Toxicity
XGEVA® can cause
fetal harm when administered to a pregnant woman. Based on findings
in animals, XGEVA® is expected to result in adverse
reproductive effects.
Advise females of reproductive potential to use highly effective
contraception during therapy, and for at least 5 months after the
last dose of XGEVA®. Apprise the patient of the
potential hazard to a fetus if XGEVA® is used during
pregnancy or if the patient becomes pregnant while patients are
exposed to XGEVA®.
Adverse Reactions
The most common adverse reactions
in patients receiving XGEVA® with bone metastasis from
solid tumors were fatigue/asthenia, hypophosphatemia, and nausea.
The most common serious adverse reaction was dyspnea. The most
common adverse reactions resulting in discontinuation were
osteonecrosis and hypocalcemia.
For multiple myeloma patients receiving XGEVA®, the
most common adverse reactions were diarrhea, nausea, anemia, back
pain, thrombocytopenia, peripheral edema, hypocalcemia, upper
respiratory tract infection, rash, and headache. The most common
serious adverse reaction was pneumonia. The most common adverse
reaction resulting in discontinuation of XGEVA® was
osteonecrosis of the jaw.
The most common adverse reactions in patients receiving
XGEVA® for giant cell tumor of bone were arthralgia,
headache, nausea, back pain, fatigue, and pain in extremity. The
most common serious adverse reactions were osteonecrosis of the jaw
and osteomyelitis. The most common adverse reactions resulting in
discontinuation of XGEVA® were osteonecrosis of the jaw
and tooth abscess or tooth infection.
The most common adverse reactions in patients receiving
XGEVA® for hypercalcemia of malignancy were nausea,
dyspnea, decreased appetite, headache, peripheral edema, vomiting,
anemia, constipation, and diarrhea.
Denosumab is also marketed as Prolia® in other
indications.
Please
visit www.amgen.com or www.xgeva.com for Full
U.S. Prescribing Information.
About Amgen's Commitment to Oncology
Amgen Oncology is
committed to helping patients take on some of the toughest cancers,
such as those that have been resistant to drugs, those that
progress rapidly through the body and those where limited treatment
options exist. Amgen's supportive care treatments help patients
combat certain side effects of strong chemotherapy, and our
targeted medicines and immunotherapies focus on more than a dozen
different malignancies, ranging from blood cancers to solid tumors.
With decades of experience providing therapies for cancer patients,
Amgen continues to grow its portfolio of innovative and biosimilar
oncology medicines.
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 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
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http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed
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Myeloma.
http://imwg.myeloma.org/international-myeloma-working-group-imwg-criteria-for-the-diagnosis-of-multiple-myeloma/.
Accessed Aug. 25, 2017.
- Drake MT. Bone disease in multiple myeloma. Oncology
(Williston Park). 2009;23(14
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- Terpos E, et al. International Myeloma Working Group
recommendations for the treatment of multiple myeloma-related bone
disease. J Clin Oncol. 2013;31(18):2347-57.
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With Multiple Myeloma: Analysis Of Real-World Database. Journal
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