AVERT trial data suggests potentially faster
onset of clinical response and greater drug-free clinical remission
with earlier use in patients taking Orencia plus methotrexate over
patients taking methotrexate alone
Exploratory data of patients with high ACPA
levels at baseline in the AMPLE trial suggest better response with
Orencia than with adalimumab
Bristol-Myers Squibb Company (NYSE:BMY) announced today data
from the Orencia Phase 3b AVERT and AMPLE trials will be presented
in three separate posters during the European League Against
Rheumatism Annual Congress (EULAR 2015). These trials included
early moderate to severe rheumatoid arthritis (RA) patients with
active disease and markers of poor prognosis, such as ACPA
(anti-citrullinated protein antibody) and rheumatoid factor (RF),
which are both associated with more severe disease progression and
joint damage. These data suggest a correlation between ACPA and
treatment outcomes, and provide further data regarding the use of
Orencia plus methotrexate (MTX) in these RA patients. In RA,
activated T-cells in the immune response drive downstream
inflammatory events that produce autoantibodies. Inhibiting T-cell
activation in the immune response may help reduce autoantibody
formation and levels.
One post hoc analysis of AVERT (Assessing Very
Early Rheumatoid arthritis Treatment) found
that in patients taking Orencia plus MTX, the proportion of
patients who maintained DAS-defined remission (DAS<2.6)
following drug withdrawal was higher in patients with disease
duration of three months or less (33%), compared with patients with
longer disease duration (>3 to ≤6 months, 14.7%; >6 months,
10.2%). Shorter disease duration was also associated with a faster
onset of clinical response.
Exploratory data from the AVERT study assessed the impact of
Orencia plus MTX on different types of ACPA and any association
with clinical response. These data suggest Orencia in combination
with MTX had greater clinical efficacy in patients who were IgM
antibody type ACPA positive at the beginning of the study than in
those who were negative for that antibody type, and in those who
seroconverted (changed from ACPA positive to negative) over time
than those who did not (61.5% vs. 41.2% achieved Boolean
remission), suggesting the impact on ACPA is associated with a
clinical benefit for RA patients.
“These data are among the first to demonstrate the potential
impact of a biologic therapy on ACPA in the early stages of RA,
which is characterized by high autoimmune activity and the presence
of autoantibodies,” said T.W.J. Huizinga, M.D., PhD, Leiden
University Medical Center, Leiden Netherlands. “The findings
further provide insight into the role of biological response
markers in helping define the disease and manage therapy.”
Additionally, an exploratory analysis of AMPLE (Abatacept
Versus Adalimumab Comparison in
Biologic-Naïve rheumatoid arthritis (RA) Subjects
With Background Methotrexate) suggests higher serum ACPA levels at
baseline correlated with a better clinical response from Orencia
plus MTX compared to adalimumab plus MTX. When patients were
divided into quartiles based on baseline ACPA titer, significant
differences in response were observed between patients in the
highest titer quartile (Q4) versus Q1–3 for DAS28 (CRP) and HAQ-DI
(p=0.003 and p=0.021, respectively) in the Orencia treated arm,
while, Q4 versus Q1–3 treatment differences were not significant
with adalimumab (p=0.358 and p=0.735).
“These analyses yield promising insights into RA disease
progression,” said Douglas Manion, M.D., Head of Specialty
Development, Bristol-Myers Squibb. “With further investigation, we
can provide additional understanding into the use of Orencia plus
methotrexate in patients with early, active, moderate to severe
RA.”
New Analyses from the AVERT Trial
The primary results of the AVERT Phase 3b trial have been
previously reported. New data being presented at EULAR 2015 include
two analyses exploring the impact of earlier treatment with Orencia
and the impact of Orencia on the RA disease process.
AVERT Outcomes By Baseline Disease
Duration / June 12, 2015 at 12:05 PM CET: On Drug and Drug-free
Remission by Baseline Disease Duration in the AVERT Trial:
Abatacept versus Methotrexate Comparison in Patients with Early
Rheumatoid Arthritis. VP Bykerk, et al.
The post hoc analysis examined the association of disease
duration with the effects of Orencia plus MTX versus MTX treatment
on DAS–defined remission (DAS28 [CRP] <2.6) and improvement in
physical function (HAQ-DI; ≥0.3 units from baseline). The analysis
included the following subgroups: 36 patients on Orencia plus MTX
and 48 on MTX with ≤3 months disease duration; 34 patients on
Orencia plus MTX and 29 on MTX with >3 to ≤6 months disease
duration; 49 patients on Orencia plus MTX and 39 on MTX with >6
months disease duration. The results showed the combination of
Orencia and MTX provided greater benefits than MTX alone in
patients with a disease duration of ≤3 months: 33% of these
patients maintained DAS-defined remission, compared to 14.7% of
patients with a disease duration of >3 to ≤6 months and 10.2%
with a duration of >6 months. Patients with ≤3 months disease
duration also had the fastest onset of clinical response from
Orencia plus MTX; as early as Day 29, 25% of patients treated with
Orencia plus MTX with a disease duration of ≤3 months achieved
DAS-defined remission, compared with 11.8% of patients with a
disease duration of >3 to ≤6 months and 6.1% of patients with a
disease duration of >6 months, and 8.3% with MTX alone (≤3 month
disease duration). In the MTX arm, 10.4% of patients with a disease
duration of ≤3 months maintained DAS-defined remission, compared to
13.8% of patients with a disease duration of >3 to ≤6 months and
5.1% with a duration of >6 months.
AVERT ACPA – Efficacy By Baseline CCP2
Titers and Sero-Conversion Status / June 11, 2015 at 1:45 p.m. CET:
Effect of Anti-Cyclic Citrullinated Peptide 2 Immunoglobulin M
Serostatus on Efficacy Outcomes Following Treatment with Abatacept
Plus Methotrexate in the AVERT Trial. TWJ Huizinga, et
al.
This analysis explored the association between patients’ ACPA
and ACPA seroconversion status and efficacy outcomes of remission
rate at 12 months (remission was assessed using CDAI, SDAI,
Boolean, and DAS28 [CRP] <2.6-defined remission) and mean change
in DAS28 (CRP) and HAQ-DI over time. A total of 200 out of the 342
patients included in the analysis were baseline anti-CCP2 IgM
positive: Orencia plus MTX (n=66), Orencia monotherapy (n=62) and
MTX (n=72). The results showed ACPA-IgM positive patients treated
with Orencia plus MTX achieved the greatest mean improvements in
DAS28 (CRP) and HAQ-DI over time, as well as remission in all four
indices, compared with patients who were ACPA-IgM negative at
baseline. In addition, 61.5% of patients in the Orencia plus MTX
group who seroconverted (i.e., changed from ACPA-IgM positive at
baseline to ACPA-IgM negative at Month 12) achieved the more
stringent Boolean remission, compared to 41.2% who remained
positive, suggesting an association between remission and the
impact on IgM ACPA.
New Analysis from the AMPLE Trial
The primary results of the AMPLE Phase 3b trial have been
previously reported. AMPLE is the first non-inferiority,
head-to-head study in adults with RA comparing biologic agents,
Orencia and adalimumab, on a background of MTX. New data being
presented at EULAR 2015 includes an exploratory analysis examining
outcomes in early RA patients stratified by ACPA titer.
Comparison of Patient-Reported Outcomes
by Baseline ACPA Category in AMPLE / June 13, 2015 at 10:15 a.m.
CET: Effect of Baseline Anti-Cyclic Citrullinated Peptide 2
Antibody Titre on Patient-Reported Outcomes Following Treatment
with Subcutaneous Abatacept or Adalimumab. J Sokolove, et
al.
This post hoc analysis assessed patient-reported outcomes (PROs)
in 388 patients who were grouped into quartiles based on increasing
ACPA titers (Q1=28-235 AU/mL; Q2=236-609 AU/mL; Q3=613-1046 AU/mL;
Q4=1060-4894 AU/mL). There were 97 patients per quartile. The
number of patients per treatment group in each quartile were
(abatacept, adalimumab): Q1=42, 55; Q2=51, 46; Q3=46, 51; Q4=46,
51. PROs assessed included pain, quality of life, disability, and
physical functioning. The results showed Orencia plus MTX-treated
patients with the highest ACPA titers reported greater improvement
than those in the lowest ACPA quartiles across measures of pain,
physical function and clinical outcomes. These patterns were less
pronounced among patients treated with adalimumab.
About the AVERT Trial
AVERT is a Phase 3b, active-controlled study including 351 adult
patients with symptoms of moderate to severe RA for less than two
years, positive for ACPA, DAS28 CRP >3.2, and naïve to treatment
with MTX and biologic therapies for RA. The patients were randomly
assigned to 12 months of weekly treatment in one of three groups:
Orencia 125 mg subcutaneous plus MTX; Orencia 125 mg subcutaneous
alone; or MTX alone. Participants who had a DAS28 CRP <3.2
(indicating low disease activity) after the 12-month treatment
phase were able to continue in a withdrawal period up to 12 months,
where all RA treatment including Orencia, MTX and steroids were
withdrawn. The co-primary endpoints compared the proportion of
patients with DAS28 CRP <2.6 (defined as disease remission in
the trial) at month 12 and both months 12 and 18 for combination
therapy versus MTX alone. Results demonstrated Orencia plus MTX
achieved significantly higher rates of DAS-defined remission at 12
months than treatment with MTX alone (60.9% vs. 45.2%,
respectively, p=0.010). Similar results at 12 months were seen with
more stringent measures of efficacy including Boolean remission
(37.0%, Orencia plus MTX; 22.4%, MTX alone), CDAI remission (42%,
Orencia plus MTX; 27.6% MTX alone), and SDAI remission (42%,
Orencia plus MTX; 25% MTX alone). Greater benefits on MRI endpoints
were also observed with combination therapy vs. MTX alone,
including improvements in synovitis and osteitis, and less
progression of joint erosions. Specifically at 12 months, mean
change from baseline in radiographic non-progression rates as
assessed using the RAMRIS method for the synovitis score (-2.35,
-1.4 and -0.68, respectively), osteitis score (-2.58, -1.36 and
-0.68, respectively) and erosion score (0.19, 1.47 and 1.52,
respectively) were observed for the Orencia with MTX, Orencia
monotherapy and MTX groups, respectively. Serious adverse events,
serious infection events and discontinuation due to serious adverse
events were comparable to patients treated with MTX. Rates of
serious adverse events were 6.7% and 7.8%, overall infections were
57.1% and 59.5%, serious infections were 0.8% and 0%, malignancies
were 0.8% and 0.9%, and autoimmune events were 0.8% and 2.6% for
the Orencia combination and MTX groups, respectively.
About the AMPLE Trial
AMPLE is a Phase 3b, randomized, investigator-blinded,
multinational study of 24 months duration with a 12-month efficacy
primary endpoint (non-inferiority for ACR20). The study included
646 adult biologic-naïve patients with active moderate to severe RA
and inadequate response to MTX; 318 in the Orencia plus MTX group
and 328 in the adalimumab plus MTX group. Patients were stratified
by disease activity and randomized to either 125 mg Orencia SC
weekly or 40 mg adalimumab every other week, both on background
MTX. The primary endpoint was to determine non-inferiority of
Orencia plus MTX to adalimumab plus MTX based on ACR20 response at
12 months. Secondary endpoints included injection site reactions,
radiographic non-progression as assessed using the van der Heijde
modified total Sharp score (mTSS) method, safety and retention. The
complete year-one study results were published in the January 2013
volume of Arthritis & Rheumatism, the official
monthly journal of the American College of Rheumatology.
Year 2 data were consistent with Year 1. Radiographic progression
was also assessed at two years with 85% of patients on the Orencia
regimen and 84% of patients on the adalimumab regimen achieving
radiographic non-progression. At 24 months, overall safety data
were similar for both groups, including frequency of adverse events
(92.8% and 91.5%), serious adverse events (13.8% and 16.5%), and
malignancies (2.2% and 2.1%) for the Orencia regimen and the
adalimumab regimen, respectively.
About Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a systemic, chronic, autoimmune
disease characterized by inflammation in the lining of joints (or
synovium), causing joint damage with chronic pain, stiffness, and
swelling. RA causes limited range of motion and decreased joint
function. The condition is more common in women than in men, who
account for 75% of patients diagnosed with RA.
About ORENCIA® (abatacept)
ORENCIA SC and IV 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 rheumatoid arthritis.
ORENCIA may be used as monotherapy or concomitantly with
disease-modifying antirheumatic drugs (DMARDs) other than tumor
necrosis factor (TNF) antagonists.
ORENCIA IV is indicated for reducing signs and symptoms in
pediatric patients 6 years of age and older with moderately to
severely active polyarticular juvenile idiopathic arthritis.
ORENCIA IV may be used as monotherapy or concomitantly with
methotrexate (MTX). ORENCIA SC has not been studied in pediatric
patients.
ORENCIA should not be administered concomitantly with TNF
antagonists.
ORENCIA is not recommended for use concomitantly with other
biologic rheumatoid arthritis (RA) therapy, such as anakinra.
ORENCIA is intended for use under the guidance of a physician or
healthcare practitioner.
Indications/Usage and Important Safety Information for
ORENCIA® (abatacept)
Indications/Usage
Adult Rheumatoid Arthritis (RA): ORENCIA® (abatacept) 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 disease-modifying, anti-rheumatic drugs (DMARDs)
other than tumor necrosis factor (TNF) antagonists.
Juvenile Idiopathic Arthritis (JIA): ORENCIA is indicated
for reducing signs and symptoms in pediatric patients aged 6 years
and older with moderately to severely active polyarticular JIA.
ORENCIA may be used as monotherapy or concomitantly with
methotrexate (MTX).
Important Limitations of Use: 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
Concomitant Use with TNF Antagonists: Concurrent therapy
with ORENCIA® (abatacept) and a TNF antagonist is not recommended.
In controlled clinical trials, adult patients receiving concomitant
intravenous ORENCIA and TNF antagonist therapy experienced more
infections (63%) and serious infections (4.4%) compared to patients
treated with only TNF antagonists (43% and 0.8%, respectively),
without an important enhancement of efficacy.
Hypersensitivity: Anaphylaxis or anaphylactoid reactions
can occur during or after an infusion and can be life-threatening.
There were 2 cases (<0.1%; n=2688) of anaphylaxis or
anaphylactoid reactions in clinical trials with adult RA patients
treated with intravenous ORENCIA. Other reactions potentially
associated with drug hypersensitivity, such as hypotension,
urticaria, and dyspnea, each occurred in <0.9% of patients.
There was one case of a hypersensitivity reaction with ORENCIA in
JIA clinical trials (0.5%; n=190). In postmarketing experience, a
case of fatal anaphylaxis following the first infusion of ORENCIA
was reported. Appropriate medical support measures for treating
hypersensitivity reactions should be available for immediate use.
If an anaphylactic or other serious allergic reaction occurs,
administration of ORENCIA should be stopped immediately and
permanently discontinued, with appropriate therapy instituted.
Infections: Serious infections, including sepsis and
pneumonia, have been reported in patients receiving ORENCIA. Some
of these infections have been fatal. Many of the serious infections
have occurred in patients on concomitant immunosuppressive therapy
which in addition to their underlying disease, could further
predispose them to infection. Caution should be exercised in
patients with a history of infection or underlying conditions which
may 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 or within 3 months of its
discontinuation. The efficacy of vaccination in patients receiving
ORENCIA is not known. ORENCIA 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%
vs 88%, respectively). Respiratory disorders occurred more
frequently in patients treated with ORENCIA compared to those on
placebo (43% vs 24%, respectively), including COPD exacerbations,
cough, rhonchi, and dyspnea. A greater percentage of patients
treated with ORENCIA® (abatacept) developed a serious adverse event
compared to those on placebo (27% vs 6%), including COPD
exacerbation [3 of 37 patients (8%)] and pneumonia [1 of 37
patients (3%)]. 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 for intravenous
administration 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 pyrroloquinoline quinone (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. ORENCIA for subcutaneous (SC)
administration does not contain maltose; therefore, patients do not
need to alter their glucose monitoring.
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 (3%
ORENCIA vs 1.9% placebo) and malignancies (1.3% ORENCIA vs 1.1%
placebo).
Malignancies: The overall frequency of malignancies was
similar between adult patients treated with ORENCIA or placebo.
However, more cases of lung cancer were observed in patients
treated with ORENCIA (0.2%) than those on placebo (0%). 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 (≥10%): Headache, upper
respiratory tract infection, nasopharyngitis, and nausea were the
most commonly reported adverse events in the adult RA clinical
studies. Other events reported in ≥5% of JIA patients were
diarrhea, cough, pyrexia, and abdominal pain. In general, the
adverse events in pediatric patients were similar in frequency and
type to those seen in adult patients.
Note concerning SC ORENCIA® (abatacept): The safety and
efficacy of SC ORENCIA have not been studied in patients under 18
years of age.
Please see Full Prescribing Information at
http://packageinserts.bms.com/pi/pi_orencia.pdf.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases.
For more information about Bristol-Myers Squibb,
visit www.bms.com, or follow us on Twitter
at http://twitter.com/bmsnews
ORENCIA® (abatacept) is a registered trademark of
Bristol-Myers Squibb Company.
About Bristol-Myers Squibb Immunoscience
The immune system is the body’s natural defense against disease.
These processes come into play in almost every human disease. That
is why Bristol-Myers Squibb is focused on exploring ways to harness
the body’s own immune system to treat immune-related diseases with
high unmet medical needs, including RA – a chronic, systemic,
inflammatory autoimmune disorder that affects the joints.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Forward-looking statements in this press release
should be evaluated together with the many uncertainties that
affect Bristol-Myers Squibb's business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb's Annual Report on Form 10-K for the year ended December 31,
2014 in our Quarterly Reports on Form 10-Q and our Current Reports
on Form 8-K. Bristol-Myers Squibb undertakes no obligation to
publicly update any forward-looking statement, whether as a result
of new information, future events or otherwise.
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