Aranesp Combined Patient Level Analyses Provide Additional Evidence of Efficacy and Safety
Amgen (NASDAQ:AMGN) today announced data from a Phase 2,
randomized, multicenter, open-label study that suggest extended dosing
of Aranesp(R) (darbepoetin alfa) paired with chemotherapy treatment
(every two or every three weeks depending on chemotherapy regimen)
appeared to be efficacious with respect to changes in hemoglobin (Hb),
with no unexpected adverse events observed when compared to weekly
dosing.
Additionally, results from two combined patient level analyses
suggest that patients treated with Aranesp experienced a decrease in
blood transfusions and improvement in hematologic response. These
analyses do not suggest a negative impact on overall survival or
progression-free survival between patients receiving chemotherapy
treatment with Aranesp and those that did not receive Aranesp
treatment. These data were presented at the 14th European Cancer
Conference (ECCO) in Barcelona, Spain (Abstract # 1.141, 1.120,
1.104).
About the Phase 2 Study
This Phase 2 study is the first prospective trial illustrating how
various Aranesp dosing regimens can be paired with chemotherapy
administered across a range of dosing schedules.
"Flexibility in dosing is important for physicians to optimize
anemia management and meet patient needs," said Timothy Rearden, M.D.,
Hematology Oncology Consultant, Inc. "In this study, Aranesp was
consistently effective regardless of dosing frequency, providing
healthcare professionals with the ability to adapt Aranesp treatment
as required."
The mean change in Hb from baseline to week 13 was comparable
between extended dosing (every two or every three weeks depending on
chemotherapy regimen) and weekly dosing. The percentage of patients
who achieved a Hb greater than or equal to 11 g/dL by Kaplan-Meier
estimates was also similar (76 percent for weekly dosing and 71
percent for extended dosing).
The trial was a Phase 2, 25-week open-label study to evaluate
non-inferiority of Aranesp in patients with anemia as a result of
chemotherapy treatment who were randomized 1:1 to either an extended
dosing schedule (n=378) or a weekly schedule (n=374).
Patients in the arm receiving an extended dose schedule of Aranesp
received 300 mcg Q2W if chemotherapy treatment (CTX) was QW, Q2W, or
Q4W or 500 mcg Q3W if CTX was Q3W. Patients in the arm receiving a
weekly schedule of Aranesp (DA-QW) received 150 mcg QW regardless of
CTX schedule. The QW and Q2W fixed dosing schedules utilized in this
study are not approved dosing options. Q3W 500 mcg fixed dosing is the
recommended initial dose with alternate weight based dosing options
available at QW and Q3W.
Stratification factors were chemotherapy cycle length, screening
Hb (less than 10 g/dL versus greater than or equal to 10 g/dL) and
type of cancer (lung/gynecological versus other cancers). The primary
endpoint was change in Hb from baseline to week 13. Demographics
between the two groups were broadly similar.
Aranesp Combined Patient Level Analyses Results
Two combined analyses reported patient level data from six
Amgen-sponsored, placebo-controlled, randomized trials of Aranesp to
treat anemia as a result of chemotherapy in patients with screening Hb
less than or equal to 11 - 13 g/dL, nonmyeloid malignancies, greater
than or equal to one prior chemotherapy cycle, and additional planned
chemotherapy cycles. Amgen presented the results of these combined
patient level analyses at the U.S. Food and Drug Administration's
Oncologic Drugs Advisory Committee meeting in May 2007.
While preserving initial randomization, patient level data from
2,112 patients was analyzed to determine differences between Aranesp
(n=1,200) treatment and placebo (n=912). The results suggest that
patients treated with Aranesp experienced a decrease in blood
transfusions, improvement in hematologic response, and an expected
increased risk of thromboembolic events (TE). No differences in risks
of death, disease progression or progression-free survival were
observed between the two groups.
"The results of these combined patient level analyses further add
to the large scientific body of evidence that ESAs are safe and
effective when used according to their approved label. The increased
risk of TEs has long been observed and appropriately represented for
in class labeling for ESAs," said Heinz Ludwig, M.D., Center for
Oncology and Haematology, Wilhelminen Hospital, Vienna, Austria.
The Aranesp group had an approximate 54 percent relative risk
reduction for transfusions (HR: 0.46, 95 percent CI: 0.39, 0.55) and
also were approximately more than twice as likely to achieve a
hematopoietic response (HR: 2.40, 95 percent CI: 2.10, 2.75). The
relative risk for TEs was approximately 50 percent higher in the
Aranesp group (HR: 1.57, 95 percent CI: 1.10, 2.26). The rates of TEs
were eight percent in patients treated with Aranesp and five percent
in placebo patients. These rates are similar to what has been reported
in current product labeling.
A second combined analysis evaluated the association between
achieved Hb levels or rates of Hb increase and safety outcomes in
anemic cancer patients undergoing chemotherapy. The analysis included
1,200 patients treated with Aranesp. Achieving a Hb greater than 12 or
13 g/dL or a Hb increase of greater than 1 g/dL in 14 days or greater
than 2 g in 28 days did not appear to be associated with an increased
risk of death or disease progression. Risk of TEs was not clearly
related to achieving Hb of greater than 12 or greater than 13,
although rates of rise greater than 1g in 14 days and greater than 2 g
in 28 days were associated with a trend towards increased risk. These
risks of TEs are consistent with those already noted in ESA product
labels.
A similar pattern was seen when deaths were identified during a
study's follow-up period. No increased risk of disease progression and
progression-free survival was seen in patients who achieved a Hb
greater than 12 g/dL, Hb greater than 13 g/dL, a Hb increase of
greater than 1 g/dL in 14 days or greater than 2 g in 28 days. It
should be recognized that in this combined analysis, the patients
ability to respond is an important potential confounder.
The results of the combined analyses presented at ECCO appear to
suggest that patients receiving chemotherapy who are able to reach a
Hb level of above 12 g/dL do not experience an increased risk of
on-study death and disease progression. A higher rate of TEs was
associated with increased rates of Hb increase, which is a recognized
risk in this patient population treated with ESAs. These data provide
further information regarding the relationship of achieved Hb and
safety outcomes for Aranesp.
About Aranesp
Aranesp is a recombinant erythropoiesis-stimulating protein (a
protein that stimulates production of red blood cells, which carry
oxygen). Amgen revolutionised the treatment of anaemia with the
development of recombinant erythropoietin, Epoetin alfa. Building on
this heritage, Amgen developed Aranesp, a unique erythropoiesis
stimulating protein, which contains two additional sialic
acid-containing carbohydrate chains compared to the epoetin alfa and
epoetin beta molecule and remains in the bloodstream longer than
epoetin alfa and epoetin beta as demonstrated by its longer half-life.
Aranesp was granted marketing authorisation by the European
Commission in 2001 for the treatment of anaemia associated with
chronic renal failure (CRF), also known as chronic kidney disease
(CKD), in adults and paediatric subjects 11 years of age or older. In
2002, the European Commission approved Aranesp for the treatment of
anemia in adult cancer patients receiving chemotherapy with solid
tumors. This patient population was subsequently expanded in 2003 to
include treatment of symptomatic anaemia in adult cancer patients with
non-myeloid malignancies receiving chemotherapy. Approval was granted
in 2004 for extended dosing intervals of once-every-three-weeks in the
treatment of anemia in adult cancer patients with non-myeloid
malignancies who are receiving chemotherapy and up to once-per-month
Aranesp administration in the treatment of anemia in CKD patients not
on dialysis. In 2006, the Aranesp label was updated to allow CKD
patients on dialysis to switch from rHuEPO one to three times a week
to Aranesp every two weeks. In 2007, the Aranesp label was updated to
allow for treatment of anaemia associated with CRF, in all European
paediatric patients on dialysis or not on dialysis.
Aranesp was approved by the U.S. Food and Drug Administration
(FDA) in September 2001 for the treatment of anemia associated with
CRF for patients on dialysis and patients not on dialysis. In July
2002, the FDA approved weekly dosing of Aranesp for the treatment of
anemia caused by concomitantly administered chemotherapy in patients
with nonmyeloid malignancies and in March 2006, the FDA approved
every-three-week dosing in these patients.
Important EU Aranesp Safety Information
Aranesp is contraindicated in patients with uncontrolled
hypertension. Erythropoietic therapies may increase the risk of
thrombotic and other serious events; regional guidelines should be
referred to for target and maximum hemoglobin levels, and dose
adjustment rules should be performed in line with regional prescribing
information.
The most commonly reported side effects in clinical trials were
arthralgia, edema, injection site pain and thromembolic event
reactions. Prescribers are recommended to consult regional prescribing
information before prescribing Aranesp, including side-effects,
precautions and contra-indications.
Important U.S. Aranesp Safety Information
Use the lowest dose of Aranesp(R) that will gradually increase the
hemoglobin concentration to the lowest level sufficient to avoid the
need for red blood cell transfusion.
Aranesp(R) and other erythropoiesis-stimulating agents (ESAs)
increased the risk for death and for serious cardiovascular events
when administered to target a hemoglobin of greater than 12 g/dL
Cancer Patients: Use of ESAs
-- Shortened the time to tumor progression in patients with
advanced head and neck cancer receiving radiation therapy when
administered to target a hemoglobin of greater than 12 g/dL,
-- Shortened overall survival and increased deaths attributed to
disease progression at 4 months in patients with metastatic
breast cancer receiving chemotherapy when administered to
target a hemoglobin of greater than 12 g/dL,
-- Increased the risk of death when administered to target a
hemoglobin of 12 g/dL in patients with active malignant
disease receiving neither chemotherapy or radiation therapy.
ESAs are not indicated for this population.
Patients receiving ESAs pre-operatively for reduction of
allogeneic red blood cell transfusions: A higher incidence of deep
venous thrombosis was documented in patients receiving Epoetin alfa
who were not receiving prophylactic anticoagulation. Aranesp(R) is not
approved for this indication.
Aranesp is contraindicated in patients with uncontrolled
hypertension.
About Amgen
Amgen discovers, develops and delivers innovative human
therapeutics. A biotechnology pioneer since 1980, Amgen was one of the
first companies to realize the new science's promise by bringing safe
and effective medicines from lab, to manufacturing plant, to patient.
Amgen therapeutics have changed the practice of medicine, helping
millions of people around the world in the fight against cancer,
kidney disease, rheumatoid arthritis and other serious illnesses. With
a deep and broad pipeline of potential new medicines, Amgen remains
committed to advancing science to dramatically improve people's lives.
To learn more about our pioneering science and our vital medicines,
visit www.amgen.com.
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