- ORENCIA is a First-in-Class Biologic Treatment Option Now Available for
Use in Pediatric Patients with JIA(1,2) -
PRINCETON, N.J., April 8, 2008 /PRNewswire-FirstCall/ -- Bristol-Myers
Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug
Administration (FDA) has approved ORENCIA(R) (abatacept) for reducing signs
and symptoms in pediatric patients six years and older with moderately to
severely active polyarticular juvenile idiopathic arthritis (JIA). ORENCIA
may be used as monotherapy or concomitantly with methotrexate (MTX).
ORENCIA should not be administered concomitantly with tumor necrosis factor
(TNF) antagonists and is not recommended for use concomitantly with other
biologic rheumatoid arthritis (RA) therapy, such as anakinra. This new
indication for ORENCIA provides significant evidence of its durable
efficacy and long-term safety in pediatric patients, including those
initiating biologic therapy for the first time. The safety and efficacy of
ORENCIA in JIA were assessed in a three-part study through one year. The
approval of ORENCIA in JIA represents the ongoing commitment of
Bristol-Myers Squibb in this therapeutic area.
"In a JIA clinical trial, ORENCIA provided meaningful and sustained
improvements in this patient population across three major sub-types of JIA
through one year," said Edward H. Giannini, M.Sc., Dr.P.H., Professor of
Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital
Medical Center, OH.
The approval is based on the AWAKEN (Abatacept Withdrawal study to
Assess efficacy and safety in Key Endpoints in juvenile idiopathic
arthritis Not responding to current treatment) trial, which evaluated the
efficacy and safety of ORENCIA(R) (abatacept) in patients six to 17 years
of age with moderately to severely active polyarticular JIA who had an
inadequate response to one or more disease-modifying anti-rheumatic drugs
(DMARDs), such as MTX or TNF antagonists.
"Juvenile idiopathic arthritis is the most prevalent form of arthritis
in children(3)," said Elliott Sigal, M.D., Ph.D., executive vice president,
chief scientific officer and president, Research and Development,
Bristol-Myers Squibb. "This new indication for ORENCIA offers another
treatment option to help improve signs and symptoms of this serious disease
in pediatric and adolescent patients."
In addition to the approval for JIA, Bristol-Myers Squibb has added a
post-marketing safety section to the package insert. This section states
that the post-marketing adverse event profile that was observed in adult RA
patients did not differ from that seen in the clinical trials of adult RA
patients. The FDA also has revised the adult indication to remove the
requirement that patients must first fail at least one DMARD before
initiating therapy with ORENCIA. The new indication statement is: ORENCIA
is indicated for reducing signs and symptoms, inducing major clinical
response, inhibiting the progression of structural damage and improving
physical function in adult patients with moderately to severely active RA.
ORENCIA may be used as monotherapy or concomitantly with DMARDs other than
TNF antagonists. ORENCIA should not be administered concomitantly with TNF
antagonists and is not recommended for use concomitantly with other
biologic RA therapy, such as anakinra. The revised adult indication means
that ORENCIA is an appropriate option for patients with moderate-to-severe
RA, regardless of prior treatment received.
ORENCIA JIA Study (AWAKEN Trial)
The AWAKEN trial was a three-part study which included patients with
subtypes of JIA that at disease onset included Oligoarticular JIA (16
percent), Polyarticular JIA (64 percent; 20 percent were rheumatoid factor
(RF) positive) and Systemic JIA with polyarticular course (20 percent) who
had not responded adequately to other JIA therapies. In the first phase of
this study (Period A), a total of 190 patients aged six to 17 years, with
disease duration of approximately four years with moderately to severely
active disease at study entry, were enrolled in this open-label,
four-month, lead-in phase of the study. The majority (70 percent) of these
study patients were new to biologic treatments. Nearly 30 percent of
patients had previously had an inadequate response to a TNF antagonist or
anakinra. Patients received ORENCIA(R) (abatacept) intravenously (10 mg/kg;
maximum 1,000 mg) on Days 1, 15, 29 and every month thereafter. Response
was assessed utilizing the ACR Pediatric 30 definition of improvement,
defined as greater than or equal to 30 percent improvement in at least
three of the six JIA core set variables and greater than or equal to 30
percent worsening in not more than one of the JIA core set variables.
In Period A of the study, ORENCIA demonstrated consistent improvement
in ACR Pedi 30 with similar responses across all JIA subtypes
(Oligoarticular extended, 59.3 percent; Polyarticular-RF positive, 68.4
percent; Polyarticular-RF negative 64.3 percent; and Systemic JIA with
polyarticular course, 64.9 percent). In patients who were inadequate
responders to DMARDs including MTX and were new to biologic treatment,
ORENCIA demonstrated meaningful ACR Pedi response rates with 76 percent of
patients achieving an ACR Pedi 30 response rate, 60 percent achieving an
ACR Pedi 50 response rate, 36 percent achieving an ACR Pedi 70 response
rate and 17 percent achieving an ACR Pedi 90 response rate. In patients who
received prior biological treatment, 38.6 percent achieved an ACR Pedi 30
response rate, 24.6 percent achieved an ACR Pedi 50 response rate, 10.5
percent achieved an ACR Pedi 70 response rate and 1.8 percent achieved an
ACR Pedi 90 response rate.
In Period B of the study, patients who completed Period A and achieved
an ACR Pedi 30 response were eligible to enter this six-month, double-blind
phase. Patients entering Period B (n=122) were randomized to remain on
ORENCIA (n=60) or receive placebo (n=62) for six months.
The primary endpoint of the study was time to occurrence of disease
flare. Disease flare was defined as a greater than or equal to 30 percent
worsening in at least three of the six JIA core set variables with greater
than or equal to 30 percent improvement in not more than one of the six JIA
core set variables; greater than or equal to two centimeters of worsening
of the Physician or Parent Global Assessment was necessary if used as one
of the three JIA core set variables used to define flare, and worsening in
greater than or equal to two joints was necessary if the number of active
joints or joints with limitation of motion was used as one of the three JIA
core set variables used to define flare.
Efficacy results included:
-- Time difference to occurrence of disease flare was statistically
significant based on the log-rank test in patients treated with
placebo compared with ORENCIA(R) (abatacept)
(p-value equals 0.0002).
-- Patients treated with ORENCIA experienced significantly fewer disease
flares compared to placebo-treated patients (20 percent vs. 53
percent, respectively, p-value less than 0.001).
-- The risk of disease flare among patients continuing on ORENCIA was
less than one-third than that for patients who withdrew from ORENCIA
treatment [Hazard Ratio: 0.31, 95 percent CI (0.16, 0.59)].
In patients receiving ORENCIA treatment throughout the study (Period A,
Period B and the open-label extension Period C), the proportion of ACR Pedi
30, 50 and 70 responders remained consistent through one year.
In both the open-label, lead-in (Period A) and double-blind (Period B)
phases of the study, the adverse reactions in pediatric patients were
similar in type and frequency to those seen in adult patients. This was
also seen in patients who participated in the open-label (Period C)
extension period.
The overall frequency of adverse events in Period A was 70 percent;
infections occurred at a frequency of 36 percent. The most common
infections were upper respiratory tract infection and nasopharyngitis. The
infections resolved without sequelae, and the types of infections were
consistent with those commonly seen in outpatient pediatric populations.
Other events that occurred at a prevalence of at least five percent were
headache, nausea, diarrhea, cough, pyrexia and abdominal pain. A total of
six serious adverse events [acute lymphocytic leukemia, ovarian cyst,
varicella infection, disease flare (2) and joint wear] were reported during
the initial four months of treatment with ORENCIA. There was one case of a
hypersensitivity reaction (0.5 percent). During Periods A, B and C, acute
infusion-related events occurred at a frequency of four percent, two
percent and three percent, respectively, and were consistent with the types
of events reported in adults. Upon continued treatment in the open-label
extension period, the types of adverse events were similar except for a
single patient diagnosed with multiple sclerosis while on open-label
treatment.
About Juvenile Idiopathic Arthritis (JIA)
JIA -- also commonly known as Juvenile Rheumatoid Arthritis (JRA) -- is
the most common chronic rheumatic disease in children, and it is an
important cause of short-term and long-term disability(3). It is an
autoimmune disease that causes chronic pain, stiffness and swelling of the
joints(4), which may ultimately lead to joint damage and deformities(5).
The disease usually begins before the age of 16(6). Juvenile arthritis may
affect up to one in every 1,000 children in the United States(6).
ORENCIA(R) (abatacept) is one treatment option indicated in pediatric
patients ages six and older with moderately to severely active
polyarticular JIA. ORENCIA may be used as monotherapy or concomitantly with
MTX. ORENCIA should not be administered concomitantly with TNF antagonists
and is not recommended for use concomitantly with other biologic RA
therapy, such as anakinra.
Important Safety Information for ORENCIA
Concomitant use with TNF antagonists: Concurrent therapy with ORENCIA
and a biologic DMARD is not recommended. In controlled clinical trials,
adult patients receiving concomitant ORENCIA and TNF antagonist therapy
experienced more infections (63 percent) and serious infections (4.4
percent) compared to patients treated with only TNF antagonists (43 percent
and 0.8 percent, respectively), without an important enhancement of
efficacy.
Hypersensitivity: Less than one percent of adult patients treated with
ORENCIA experienced hypersensitivity reactions, including some cases of
anaphylaxis or anaphylactoid reactions. Other events potentially associated
with drug hypersensitivity, such as hypotension, urticaria, and dyspnea,
each occurred in less than 0.9 percent of patients treated with ORENCIA and
generally occurred within 24 hours of infusion. There was one case of a
hypersensitivity reaction with ORENCIA in JIA clinical trials (0.5 percent;
n =190). Appropriate medical support measures for treating hypersensitivity
reactions should be available for immediate use in the event of a reaction.
Infections: Caution should be exercised in patients with a history of
infection or underlying conditions which predispose them to infections.
Treatment with ORENCIA should be discontinued if a patient develops a
serious infection. Patients should be screened for tuberculosis, and viral
hepatitis in accordance with published guidelines, and if positive treated
according to standard medical practice prior to therapy with ORENCIA.
Immunizations: Live vaccines should not be given concurrently with
ORENCIA(R) (abatacept) or within three months of its discontinuation as it
may blunt the effectiveness of some immunizations. It is recommended that
JIA patients be brought up to date with all immunizations in agreement with
current immunization guidelines prior to initiating therapy with ORENCIA.
Use in Patients with Chronic Obstructive Pulmonary Disease (COPD):
Adult COPD patients treated with ORENCIA developed adverse events more
frequently than those treated with placebo (97 percent vs. 88 percent,
respectively). Respiratory disorders occurred more frequently in patients
treated with ORENCIA compared to those on placebo (43 percent vs. 24
percent, respectively), including COPD exacerbations, cough, rhonchi and
dyspnea. A greater percentage of patients treated with ORENCIA developed a
serious adverse event compared to those on placebo (27 percent vs. six
percent), including COPD exacerbation [three of 37 patients (eight
percent)] and pneumonia [one of 37 patients (three percent)]. Use of
ORENCIA in patients with RA and COPD should be undertaken with caution, and
such patients monitored for worsening of their respiratory status.
Blood Glucose Testing: ORENCIA contains maltose, which may result in
falsely elevated blood glucose readings on the day of infusion when using
blood glucose monitors with test strips utilizing glucose dehydrogenase
pyrroloquinolinequinone (GDH-PQQ). Consider using monitors and advising
patients to use monitors that do not react with maltose, such as those
based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD),
glucose oxidase or glucose hexokinase test methods.
Pregnant and Nursing Mothers: ORENCIA should be used during pregnancy
only if clearly needed. The risk for development of autoimmune diseases in
humans exposed in utero to abatacept has not been determined. Nursing
mothers should be informed of the risk/benefit of continued breast-feeding
or discontinuation of the drug. A pregnancy registry has been established
to monitor fetal outcomes. Healthcare professionals are encouraged to
register pregnant patients exposed to ORENCIA by calling 1-877-311-8972.
Most Serious Adverse Reactions: Serious infections (three percent
ORENCIA vs. 1.9 percent placebo) and malignancies (1.3 percent ORENCIA vs.
1.1 percent placebo). In general, adverse events in pediatric and
adolescent patients were similar in frequency and type to those seen in
adult patients.
Malignancies: The overall frequency of malignancies was similar between
adult patients treated with ORENCIA(R) (abatacept) or placebo. However,
more cases of lung cancer were observed in patients treated with ORENCIA
(0.2 percent) than those on placebo (zero percent). A higher rate of
lymphoma was seen compared to the general population; however, patients
with RA, particularly those with highly active disease, are at a higher
risk for the development of lymphoma. The potential role of ORENCIA in the
development of malignancies in humans is unknown.
Most Frequent Adverse Events (greater than or equal to 10 percent):
Headache, upper respiratory tract infection, nasopharyngitis and nausea
were the most commonly reported adverse events in the adult RA clinical
studies.
Please see accompanying Full Prescribing Information or visit
http://www.ORENCIA.com or http://www.BMS.com.
About ORENCIA
ORENCIA is indicated for reducing signs and symptoms, inducing major
clinical response, inhibiting the progression of structural damage, and
improving physical function in adult patients with moderately to severely
active RA. ORENCIA may be used as monotherapy or concomitantly with DMARDs
other than TNF antagonists. ORENCIA is also indicated for reducing signs
and symptoms in pediatric patients aged six years and older with moderately
to severely active polyarticular JIA. ORENCIA may be used as monotherapy or
concomitantly with MTX in pediatric patients. ORENCIA should not be
administered concomitantly with TNF antagonists. ORENCIA is not recommended
for use concomitantly with other biologic RA therapy, such as anakinra.
For adult patients with RA, ORENCIA, a lyophilized powder for
intravenous infusion, should be administered by a healthcare professional
as a 30-minute intravenous infusion at a fixed dose based on body weight
range approximating 10 mg/kg. Following the initial administration, ORENCIA
should be given at two and four weeks after the first infusion and every
four weeks thereafter. Acute infusion-related reactions were experienced in
nine percent of people treated with ORENCIA and in six percent of people
treated with placebo. The most frequently reported infusion-related adverse
events (one percent to two percent) were dizziness, headache, and
hypertension. In clinical studies, premedications were not required.
However, appropriate medical support measure of the treatment of
hypersensitivity reactions should be available for immediate use in the
event of a reaction.
For pediatric and adolescent patients with JIA who weigh less than 75
kg, ORENCIA(R) (abatacept) should be administered as a 30-minute
intravenous infusion at a dose of 10 mg/kg specifically calculated based on
the patient's body weight at each administration, not to exceed a maximum
dose of 1000 mg. Pediatric patients weighing 75 kg or more should be
administered ORENCIA following the adult dosing regimen. Following the
initial administration, ORENCIA should be given at two and four weeks after
the first infusion and every four weeks thereafter. ORENCIA may be used as
monotherapy or concomitantly with MTX.
About Bristol-Myers Squibb
Bristol-Myers Squibb Company is a global biopharmaceutical and related
health care products company whose mission is to extend and enhance human
life.
1 FDA Website. Approval History: sBLA 125057/114. Available at:
http://www.fda.gov/cder/foi/appletter/2008/125057s114ltr.pdf. Accessed
March 10, 2008.
2 FDA Website. Approval History: sBLA 103795/1001. Available at:
http://www.fda.gov/cder/foi/appletter/1999/etanimm052799L.htm. Accessed
March 10, 2008.
3 Ravelli A. Juvenile Idiopathic Arthritis. The Lancet. 2007:369:767-778.
4 Medline Plus. Juvenile Rheumatoid Arthritis. US National Library of
Medicine, National Institute of Health. Available at
http://www.nlm.nih.gov/medlineplus/juvenilerheumatoidarthritis.html.
Accessed March 10, 2008.
5 Zeginni E. Association of HLA-DRB1*13 with susceptibility to uveitis in
juvenile idiopathic arthritis in two independent data sets.
Rheumatology. 2006;45:972–974.
6 American College of Rheumatology Web site. Arthritis in Children.
Available at:
http://www.rheumatology.org/public/factsheets/arth_in_children.asp?aud=pat
Accessed March 11, 2008.
SOURCE Bristol-Myers Squibb Company
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Related links:
http://www.bms.com
http://www.ORENCIA.com
CONTACT:
David M. Rosen, of Bristol-Myers Squibb
Company, +1-609-252-5675, Cell: +1-856-873-1407,
david.rosen@bms.com; Investors: John Elicker, +1-212-546-3775,
john.elicker@bms.com, or Suketu Desai, +1-609-252-5796,
suketu.desai@bms.com, both of Bristol-Myers Squibb Company
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