THOUSAND OAKS, Calif.,
June 19, 2017 /PRNewswire/
-- Amgen (NASDAQ: AMGN) today announced that the U.S. Food and
Drug Administration (FDA) has accepted the XGEVA®
(denosumab) supplemental Biologics License Application (sBLA) that
seeks to expand the currently approved indication for the
prevention of fractures and other skeletal-related events in
patients with bone metastases from solid tumors to include patients
with multiple myeloma. The FDA has set a Prescription Drug User Fee
Act (PDUFA) action date of Feb. 3,
2018.
"Multiple myeloma patients with fractures and other bone
complications have a very poor prognosis. Bisphosphonates are the
only approved class of agents for the prevention of
skeletal-related events in this patient population. However, these
agents have several limitations, including kidney toxicity and
acute phase reactions," said Sean E.
Harper, M.D., executive vice president of Research and
Development at Amgen. "Based on the data we have submitted to the
FDA, we look forward to potentially making XGEVA available as a
novel option for patients with multiple myeloma."
XGEVA is the first 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 not cleared by the kidneys. XGEVA is
indicated for the prevention of skeletal-related events in patients
with bone metastases from solid tumors and is the number one
prescribed agent by oncologists for this indication
in the U.S. In the U.S., XGEVA
currently has a limitation of use noting that it is not indicated
for the prevention of skeletal-related events in patients with
multiple myeloma.
The sBLA, submitted on April 3,
2017, is based on the efficacy and safety data from the
pivotal Phase 3 '482 study, the largest international multiple
myeloma trial ever conducted, which successfully demonstrated that
XGEVA is non-inferior to zoledronic acid in delaying the time to
first on-study skeletal-related event in patients with multiple
myeloma. The secondary endpoints of superiority in delaying time to
first on-study skeletal-related event and delaying time to
first-and-subsequent skeletal-related event were not met in this
study. Progression-free survival was an exploratory endpoint. The
hazard ratio of XGEVA versus zoledronic acid for progression-free
survival was 0.82 (95 percent CI: 0.68, 0.99; descriptive
p=0.036) and the median difference in progression-free
survival between arms was 10.7 months in favor of XGEVA. Data from
the '482 study are also the basis of an application for a variation
to the marketing authorization submitted to the European Medicines
Agency (EMA).
About '482 Study (NCT01345019)
The
'482 study was an international, Phase 3, randomized, double-blind,
multicenter trial of XGEVA compared with zoledronic acid in the
prevention of skeletal-related events in adult patients with newly
diagnosed multiple myeloma. 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 over zoledronic acid with respect to
time to first on-study and first-and-subsequent on-study
skeletal-related event and evaluation of overall survival. The
hazard ratio of overall survival was 0.90 for XGEVA as compared to
zoledronic acid (95 percent CI: 0.70, 1.16). The hazard ratio of
XGEVA versus zoledronic acid for progression-free survival, an
exploratory endpoint, was 0.82 (95 percent CI: 0.68, 0.99;
descriptive p=0.036). The median difference in
progression-free survival between arms was 10.7 months in favor of
XGEVA. The safety and tolerability of XGEVA were also compared with
zoledronic acid in the study. The most common adverse events
(greater than or equal to 25 percent) in both arms were diarrhea
and nausea.
About Multiple Myeloma and Bone Complications
(Skeletal-Related Events)
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 and renal impairment,
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.3 Current
treatment options for bone complications are limited to
bisphosphonates, including zoledronic acid; these are cleared by
the kidneys and are associated with renal toxicity which is a
common complication among multiple myeloma patients.5
The majority (approximately six out of 10) of all multiple myeloma
patients have or will develop renal impairment over the course of
the disease.6 Preventing bone complications is a
critical aspect of caring for patients with multiple myeloma,
because these events can cause significant
morbidity.7
About XGEVA® (denosumab)
XGEVA targets the RANKL pathway to prevent the formation,
function and survival of osteoclasts, which break down bone. As a
monoclonal antibody, XGEVA is not cleared by the kidneys. XGEVA is
indicated for the prevention of skeletal-related events in patients
with bone metastases from solid tumors. In the U.S.,
XGEVA currently has a limitation of use noting that it is not
indicated for the prevention of skeletal-related events in patients
with multiple myeloma. XGEVA is also indicated for the
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. XGEVA is also indicated in
the U.S. 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.
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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CONTACT: Amgen, Thousand
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Kristen
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(Investors)
References:
- Globocan 2012: Estimated Cancer Incidence, Mortality and
Prevalence in 2012.
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed
April 25, 2017.
- Multiple Myeloma Research Foundation. What is Multiple
Myeloma?
https://www.themmrf.org/multiple-myeloma/what-is-multiple-myeloma/.
Accessed April 25, 2017.
- Roodman GD. Pathogenesis of myeloma bone disease.
Leukemia. 2009;23(3):435–441.
- International Myeloma Working Group. International
Myeloma Working Group (IMWG) Criteria for the Diagnosis of Multiple
Myeloma.
http://imwg.myeloma.org/international-myeloma-working-group-imwg-criteria-for-the-diagnosis-of-multiple-myeloma/.
Accessed April 25, 2017.
- 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.
- Amgen Data on File.
- Drake MT. Bone disease in multiple myeloma. Oncology
(Williston Park). 2009;23(14
Suppl 5):28-32.
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