Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs in United States and Rest of World: A Subset Analysis
Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Conventional Disease- Modifying Antirheumatic Drugs in United States and Rest of World: A Subset Analysis
Vipin Arora . Cynthia E. Kartman 0 1 2
0 J. D. Bradley J. Alam V. Arora C. E. Kartman (&) Eli Lilly and Company , Indianapolis, IN , USA
1 M. Greenwald Desert Medical Advances , Palm Desert, CA , USA
2 A. F. Wells Rheumatology and Immunotherapy Center , Franklin, WI , USA
Introduction: This article evaluates the efficacy and safety of baricitinib 4 mg versus placebo in United States including Puerto Rico (US) and rest of the world (ROW) subpopulations using data pooled from RA-BEAM and RA-BUILD, which enrolled patients with moderate-to-severe adult-onset rheumatoid arthritis (RA). Methods: In RA-BEAM, patients with an inadequate response (IR) to methotrexate, at least one X-ray erosion, and high sensitivity C-reactive protein (hsCRP) C 6 mg/L were randomized to placebo or orally administered baricitinib 4 mg daily or subcutaneously administered adalimumab 40 mg every other week. In RABUILD, patients with an IR to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) and with hsCRP C 3.6 mg/L were randomized to placebo or baricitinib 2 or 4 mg daily. Patients in both trials were biologic naive. In this post hoc analysis, data from both studies were pooled (714 baricitinib 4 mg-treated, 716 placebo-treated patients). Results: Overall, 188 US and 1242 ROW patients were included. Subgroups differed in baseline characteristics including race, weight, age, time since RA diagnosis, current corticosteroid use, and previous csDMARD use. At weeks 12 and 24, baricitinib-treated patients had larger responses compared to placebo-treated patients for multiple efficacy outcomes: American College of Rheumatology 20/50/70 response, low disease activity, remission, Disease Activity Score 28-C-reactive protein, and Health Assessment Questionnaire-Disability Index. Overall, similar efficacy was observed in US and ROW subgroups with no notable safety differences between subgroups at weeks 12 or 24. Conclusion: Baricitinib 4 mg was efficacious compared to placebo in US and ROW subpopulations. Safety was similar between subgroups. Funding: Eli Lilly & Company and Incyte Corporation. Trial Registration: ClinicalTrials.gov identifiers, NCT01721057; NCT01710358.
Baricitinib; Clinical Trial; Rheumatoid Arthritis; United States
Rheumatoid arthritis (RA) is a systemic
inflammatory autoimmune disease with
heterogeneous disease courses that may be associated
with progressive joint destruction, reduced
quality of life, and even reduced survival [1, 2].
Management of RA has improved substantially
in recent years with improved patient outcomes
and clinical remission becoming more
achievable. Because persistent joint inflammation can
lead to progressive joint destruction and
functional impairment, current guidelines
recommend clinical remission as the primary
treatment goal [3, 4]. Joint damage can occur
within months of disease onset, and early
aggressive treatment provides increased
probability of disease control and minimizes the
longterm impact of RA [1, 5].
Conventional synthetic disease-modifying
antirheumatic drugs (csDMARDs) such as
methotrexate are generally used as initial
treatment of RA [3, 4]. However, many patients have
active disease despite the use of these agents or
are intolerant to them. Hence, there is a need
for improved RA treatments.
Baricitinib is an orally administered,
selective, reversible inhibitor of Janus kinase (JAK)1
and JAK2 , which are endogenous signal
transducers of proinflammatory cytokines
involved in inflammatory diseases such as RA
. In two global, double-blind phase 3 studies
in patients with active RA and either inadequate
response (IR) to csDMARDs (RA-BUILD)  or IR
to methotrexate (RA-BEAM) , once daily (QD)
baricitinib was associated with clinical
improvements through 24 weeks, with an
acceptable safety profile. Geographic differences
in RA presentation and its management may
affect patient outcomes. The objective was to
perform a subgroup analysis evaluating the
efficacy and safety of baricitinib 4 mg compared
to placebo in patients from the United States
including Puerto Rico (US) and the ‘‘rest of the
world’’ (ROW) using pooled data sets to identify
possible demographic and clinical
characteristics that may contribute to patient response to
therapy. Understanding these characteristics
can provide additional information for the
clinician that is relevant to their patient
population and assessment of response. The dose of
baricitinib 4 mg was chosen because it was
common to both RA-BEAM and RA-BUILD
This is a post hoc pooled analysis from
RABUILD (NCT01721057)  and RA-BEAM
(NCT01710358) . In both trials, key inclusion
criteria included C 6 out of 68 tender joints, C 6
out of 66 swollen joints, and IR to at least one
csDMARD (stable background csDMARD
permitted). In RA-BUILD, inclusion criteria
included high-sensitivity C-reactive protein
(hsCRP) C 3.6 mg/L  and in RA-BEAM
inclusion criteria included hsCRP C 6 mg/L .
Additionally, inclusion in RA-BEAM required
either C 1 joint erosion in the hand, wrist, or
foot with rheumatoid factor (RF) or
anti-citrullinated peptide antibody (ACPA) positive status
or C 3 joint erosions regardless of RF or ACPA
status . Exclusion criteria in both studies
included previous biologic DMARD use [8, 9].
Both studies were conducted in accordance
with ethical principles of the Declaration of
Helsinki and Good Clinical Practice guidelines
and approved by ethical review boards for each
center. All patients provided written informed
consent before enrollment.
In RA-BUILD, patients were randomly assigned
1:1:1 to placebo or orally administered
baricitinib (2 or 4 mg QD) and treated for 24 weeks
. In RA-BEAM, patients were randomized
3:3:2 to placebo, orally administered baricitinib
4 mg QD, or subcutaneously administered
adalimumab 40 mg every other week,
respectively, and treated for 52 weeks . In both
trials, randomization was stratified by region and
baseline joint erosion status, and the primary
endpoint was American College of
Rheumatology 20% response (ACR20) at week 12 [8, 9]. At
week 16 or subsequent visits, inadequate
responders received baricitinib 4 mg QD as
rescue therapy. Inadequate response was defined as
lack of improvement of at least 20% in both
tender joint count and swollen joint count at
both week 14 and week 16 compared to
baseline. The pooled data set presented focuses on
baricitinib 4 mg and placebo. Geographically
defined subpopulations were US and ROW.
The efficacy endpoints were the proportion of
patients achieving ACR20, ACR 50% response
(ACR50), and ACR 70% response (ACR70) [
and the proportions of patients achieving low
disease activity as measured by a Clinical
Disease Activity Index (CDAI) [
] score of
B 10, a Simplified Disease Activity Index (SDAI)
] score of B 11, and clinical remission as
measured by an SDAI score of B 3.3 or a CDAI
score of B 2.8 [
4, 12, 14
]. Change from baseline
in physical function was assessed by the Health
Assessment Questionnaire-Disability Index
(HAQ-DI) score [
] and change from
baseline in disease activity was assessed by the
Disease Activity Score using 28 joint counts and
hsCRP (DAS28-hsCRP) [
For the safety analyses, all randomized patients
who received at least one dose of the study drug
and who did not discontinue from the study for
the reason ‘‘lost to follow-up’’ at the first
postbaseline visit were included. An overview of
adverse events from both trials is reported.
Patient demographics and baseline
characteristics, including sample size and percentages by
treatment group, are presented using summary
statistics. In the current subgroup analyses,
comparisons between each baricitinib 4 mg
group and placebo group were performed across
subgroups (US and ROW) at weeks 12 and 24 on
the modified intent-to-treat (mITT) population
using summary statistics. The mITT population
was defined as all randomized patients who
received at least one dose of study drug.
For the categorical outcomes, nonresponder
imputation was used in the analysis for patients
who received either rescue therapy or
discontinued from the study or study treatment. To
detect significant interactions between
treatment and subgroups at week 12, the following
logistic regression model was used for each
efficacy endpoint: treatment group ?
subgroup ? treatment-by-subgroup
interaction ? study.
An interaction p value B 0.10 was considered
statistically significant for this analysis. When
the sample size requirements were not met (if
any of the treatment groups in the US or ROW
subgroups had less than 30 patients in a stratum
within a subgroup or less than five responders
in any level of the factors in the model), the
interaction p value was not calculated. Within a
subgroup, the odds ratio and 95% CI are from a
logistic regression model: treatment group ?
study. When the aforementioned sample size
requirements were not met, the p value from
the Cochran–Mantel–Haenszel test was used
instead of the odds ratio and 95% CI.
Interpretation of subgroup interaction
analyses that had a p value of B 0.10 began with an
examination of the direction (same as or
opposite to overall treatment effect) followed by
the magnitude of the treatment effect across the
The pooled data set consisted of 714 (96 US; 618
ROW) and 716 (92 US; 624 ROW) patients in
the baricitinib 4 mg and placebo groups,
respectively. The proportions of patients who
were White or Black/African-American were
higher in US, whereas Asians were more
represented in ROW (Table 1).
Patients in the US subgroup were slightly
older with higher mean weight and body mass
index (BMI), fewer years of RA from time of
diagnosis, and a lower percentage was
RF/ACPApositive and/or used corticosteroids. Mean
ACPA anti-citrullinated peptide antibody, csDMARD conventional synthetic disease-modifying antirheumatic drug,
DAS28-hsCRP Disease Activity Score for the 28-joint count based on high-sensitivity C-reactive protein, ESR erythrocyte
sedimentation rate, HAQ-DI Health Assessment Questionnaire-Disability Index, mTSS van der Heijde modified total Sharp
score, MTX methotrexate, N population size, n number in group, QD daily, RA rheumatoid arthritis, RF rheumatoid factor,
ROW rest of the world, SD standard deviation, US United States including Puerto Rico
a RA-BUILD, ROW: Argentina, Australia, Belgium, Canada, Croatia, Czech Republic, Germany, Hungary, India, Italy,
Japan, Republic of Korea, Mexico, Poland, Portugal, Romania, Russia, Slovakia, Spain, Taiwan, UK; RA-BEAM, ROW:
Argentina, Belgium, Canada, China, Croatia, Czech Republic, France, Germany, Greece, Hungary, Japan, Republic of
Korea, Latvia, Lithuania, Mexico, Netherlands, Poland, Portugal, Romania, Russian Federation, Slovakia, Slovenia, South
Africa, Spain, Switzerland, Taiwan, UK
modified total Sharp score (mTSS) and hsCRP
were higher in the ROW than the US subgroup.
More patients in the US subgroup had
previously used only one csDMARD whereas more
patients in the ROW subgroup had previously
used at least two csDMARDs.
At week 12, the proportions of patients
achieving ACR20, ACR50, and ACR70 responses were
higher in the baricitinib group compared to the
placebo group within both the US and ROW
subgroups (Fig. 1a). The odds ratios for multiple
efficacy measures for the baricitinib versus
placebo comparisons were between 2- to 3-fold
among the US subgroup and 3- to 6-fold among
the ROW subgroup (Fig. 1b) favoring a positive
baricitinib treatment effect compared to
placebo. At week 12, the interaction p values were
not significant (ACR20, p = 0.852; ACR50,
p = 0.424; ACR70, p value not calculated
because of small sample size). Similarly, a higher
proportion of baricitinib-treated patients
compared to placebo-treated patients responded at
24 weeks (Fig. 1c, d).
At week 12 and week 24, baricitinib-treated
patients experienced greater improvements in
their DAS28-hsCRP and HAQ-DI scores relative
to placebo-treated patients within both the US
and ROW subgroups (Fig. 2). At weeks 12 and
24, a greater proportion of baricitinib-treated
patients achieved low disease activity (CDAI
B 10 and SDAI B 11) and remission (CDAI
B 2.8 and SDAI B 3.3) compared to
placebotreated patients in both the US and ROW
subgroups (Figs. 3, 4). In summary, the baricitinib
treatment effect versus placebo was similar in
the US and ROW subgroups for multiple efficacy
Full adverse event and safety information was
previously reported in the RA-BUILD and
RABEAM manuscripts [8, 9]. As a result of the small
number of patients in the US subgroup, limited
analyses were conducted in this subpopulation
to evaluate the incidence of adverse events in
ACR20, 20% improvement using American College of
Rheumatology criteria; ACR50, 50% improvement using
American College of Rheumatology criteria; ACR70, 70%
improvement using American College of Rheumatology
criteria; BARI, baricitinib 4 mg; CI, confidence interval;
N, population size; PBO, placebo; ROW, rest of the world;
US, United States including Puerto Rico
US compared to the ROW. Safety through 12
and 24 weeks is summarized in Table 2. At both
12 and 24 weeks, there were no notable
differences between the US and ROW subgroups.
Herpes zoster events were more frequently
observed with baricitinib treatment. There were
few malignancies and deaths, with no
notable differences between groups.
In this post hoc, pooled subset analysis of two
phase 3 studies in patients with an IR to
csDMARDs, baricitinib 4 mg was efficacious
compared to placebo in both the US and the
ROW subgroups. There were no notable
between-subgroup differences in safety.
28 joints high sensitivity C-reactive protein; HAQ-DI,
Health Assessment Questionnaire-Disability Index;
mLOCF, modified last observation carried forward;
LSM, least squares mean; N, population size; PBO,
placebo; ROW, rest of the world; US, United States
including Puerto Rico
The geo-epidemiology of RA and other
inflammatory autoimmune diseases has been
discussed in the literature [
development of RA is complex and multifactorial
with the development and severity of RA being
linked to both environmental and genetic
factors, such as exposure to tobacco smoke and
pollutants and/or the presence of specific
shown. The numbers within the bars are the actual
percentages. BARI, baricitinib 4 mg; CI, confidence
interval; CDAI, Clinical Disease Activity Index; N, population
size; NRI nonresponder imputation; PBO, placebo; ROW,
rest of the world; US, United States including Puerto Rico
genetic markers, respectively. At least among
women in the United States, there is geographic
variation in the incidence of RA even after
controlling for confounders, suggesting that
regional differences in behavior, climate,
environmental exposures, genetic factors, or
diagnosis may exist .
Despite numerous geo-epidemiological
studies, little is known about treatment differences
between the US and the ROW and whether
geographic subpopulations of RA patients
respond differently to specific treatments. Within
the racially and ethnically diverse US population,
it is unknown whether there are differences in
efficacy and safety of therapeutic agents among
the various racial and ethnic subgroups. Although
it is known that race-related patient preferences
and access play a role in the types of RA drugs
taken by Black/African-Americans [
issues should not affect results in a clinical trial
Fig. 4 SDAI at 12 and 24 weeks: baricitinib 4 mg versus
placebo. The percentage (95% CI) of patients achieving
low disease activity defined as SDAI B 11 at 12 weeks
(a) and 24 weeks (b) and remission defined as SDAI B 3.3
at 12 weeks (c) and 24 weeks (d) using NRI are shown.
The numbers within the bars are the actual percentages.
setting. Unfortunately, these studies enrolled a
very small number of Black/African-Americans
across the two trials (14 placebo; 11 baricitinib)
(Table 1), so it is difficult to make meaningful
comparisons between this subgroup and other
races in this study. Similarly, the sample sizes were
too small to perform additional subgroup analyses
such as by age, ethnicity, or disease characteristics.
The predominant limitation of this post hoc
pooled analysis was the small sample size of the
US subgroup (n = 188) compared to the ROW
BARI, baricitinib 4 mg; CI, confidence interval; N,
population size; NRI, nonresponder imputation; PBO,
placebo; ROW, rest of the world; SDAI, Simplified
Disease Activity Index; US, United States including Puerto
subgroup (n = 1242), as well as differences in
the baseline demographics between the US and
ROW subpopulations, which included time
since RA diagnosis, weight, BMI, proportion of
RF/ACPA-positive patients, hsCRP, number of
csDMARDs previously used, corticosteroid use,
and evidence of damage (mean mTSS), all of
which were greater in the ROW subpopulation
with the exception of weight and BMI, which
were greater in the US. However, baseline
disease activity scores were similar in the US and
AE adverse event, N population size, n number in group, QD daily, ROW rest of the world, SAE serious adverse event, US
United States including Puerto Rico
a Includes data up to rescue. Pooled data from studies RA-BUILD and RA-BEAM
b Squamous cell carcinoma (skin)
c Basal cell carcinoma and squamous cell carcinoma
d Breast cancer; ovarian cancer
e Breast cancer; squamous cell carcinoma (lung)
f Two deaths occurred in RA-BUILD in the placebo group, one due to ‘ renal failure during hospitalization for pneumonia’
and the other due to ‘ stroke following surgical intervention for subarachnoid hemorrhage’ . Two deaths occurred in
RABEAM during weeks 0–24 in the baricitinib group, one due to ‘ circulatory failure after duodenal ulcer hemorrhage’ and the
other due to ‘ hospital-acquired pneumonia after bypass surgery post-myocardial infarction’ [8, 9]
ROW subgroups. It is possible that RA patients
in the US may not have progressed as far as
patients from some other countries because of
earlier treatment and access to care, including
earlier use of csDMARDs; this is reflected in the
higher percentage of US patients that had
previously used only one csDMARD before
enrolling in the clinical trials.
Published literature has demonstrated that
high BMI/obesity may negatively impact the
response to TNF inhibitors [
] and that the
presence of baseline autoantibodies and
autoantibody levels have been correlated with
clinical responses. In the AMPLE trial, baseline
ACPA positivity (versus ACPA negativity) as
measured by an anti-CCP2 ELISA was associated
with better responses to abatacept or
adalimumab; patients with the highest baseline
ACPA antibody concentrations had better
clinical response to abatacept than patients with
lower concentrations, which was not observed
with adalimumab [
]. These analyses were not
possible here because of the limited sample sizes
in this subpopulation analyses.
Additionally, we previously performed an
integrated subgroup analysis through 12 weeks
for an all-phase csDMARD-IR analysis set to
evaluate potential subgroup interactions for
baricitinib 4 mg QD versus placebo (data on
file). This analysis set includes data from
placebo- and active-controlled phase 2 and phase 3
studies that evaluated baricitinib on a
background of csDMARD treatment in patients with
active RA. Consistent with results in the overall
patient samples from these studies, there was no
evidence suggesting an absent or unfavorable
baricitinib treatment effect (i.e., a qualitative
interaction) in any subgroup based on
demographic or disease-related characteristics
(including age, RF/ACPA- positivity, or disease
state at baseline).
Baricitinib 4 mg demonstrated higher clinical
responses compared to placebo in RA patients
with IR to methotrexate and/or csDMARD
within both the US and ROW subpopulations
despite some differences in baseline patient
characteristics. As more targeted synthetic
agents are developed to treat various rheumatic
diseases, it is crucial to establish that such
therapies maintain their efficacy and safety
profile in wide, heterogeneous patient
The authors wish to thank the patients and
their families and study personnel who
participated in these clinical trials.
Funding. This work was supported by Eli
Lilly and Company and Incyte Corporation.
The article processing charges were funded by
Eli Lilly and Company. All authors had full
access to all of the data in this study and take
complete responsibility for the integrity of the
data and accuracy of the data analysis.
Medical Writing and/or Editorial Assistance
and Statistical Assistance. Lori Kornberg, PhD
and Meredith Fraser, MFA, who are full-time
employees of Syneos Health (Raleigh, NC),
provided writing support and editorial support.
Jinglin Zhong, MS (IQVIA, Morrisville, NC)
assisted with the statistical analyses.
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole, and have given their
approval for this version to be published.
Disclosures. AF Wells reports research sup
port and consulting fees from Eli Lilly and
Company. M Greenwald reports that her
institution has ongoing research grants from Eli Lilly
and Company. JD Bradley is an employee of Eli
Lilly and Company and owns stock. V Arora is
an employee of Eli Lilly and Company and
owns stock. CE Kartman is an employee of Eli
Lilly and Company and owns stock. J Alam was
an employee of Eli Lilly and Company at the
time that this work was conducted.
Compliance with Ethics Guidelines. Both
studies were conducted in accordance with
ethical principles of the Declaration of Helsinki
and Good Clinical Practice guidelines and
approved by ethical review boards for each
center. All patients provided written informed
consent before enrolment.
Data Availability. Lilly provides access to
relevant anonymized patient level data from
studies on approved medicines and indications
as defined by the sponsor specific information
on clinicalstudydatarequest.com. For details on
submitting a request see the instructions
provided at clinicalstudydatarequest.com.
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International
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