Hemoglobin
Changes Over Time in Rheumatoid Arthritis Clinical Development
Program
The
5-study pooled dataset included patients with RA randomized to BARI 4
mg or placebo from 1 phase 2 study and 4 phase 3 studies
(RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Data includes a
long-term extension study (RA-BEYOND) with data through 13 February
2018.1
BARI
2 mg data is pooled from 3 of these studies in which both BARI 2
mg and BARI 4 mg were options during randomization (1 phase 2 study
as well as RA-BUILD and RA-BEACON).1
In 5
pooled studies including extension data through 13 February 2018,
initial mean decreases in hemoglobin observed with BARI treatment
increased
towards baseline levels starting at week 16,
corresponded
to the timing and volume of blood draws, and
mean
levels remained above baseline and relatively stable at a higher
level thereafter through 216 weeks (Figure
1).1
Figure
1. Mean Changes in Hemoglobin Over Time From 5-Study Pooled Dataset
in Rheumatoid Arthritis Studies1
Abbreviations:
BARI = baricitinib; PBO = placebo; RA = rheumatoid arthritis.
Notes:
Baricitinib 2 mg, placebo censored at rescue or dose change, and BARI
4 mg censored at any dose change (including step=down) or rescue in
RA-BEYOND.
Datasets
for Hemoglobin Values and Anemia TEAEs
7-Study
Placebo-Controlled Dataset
The
7-study pooled dataset included patients with RA randomized to BARI 4
mg (N=1142, PYE=471.8) or placebo (N=1215, PYE=450.8) from 3 phase 2
studies and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON and
RA-BALANCE). Patients in the placebo group could have been taking
background MTX or other conventional DMARDs. Evaluation time periods
included through
the
12-week placebo-controlled period in phase 2 studies
16
weeks of assigned treatment before any opportunity for rescue
therapy in phase 3 studies, and
24
weeks of assigned treatment or until rescue in phase 3 studies.2
Data
from BARI 2 mg (N=479, PYE=185.8) is derived from 4 of these studies
in which both BARI 2 mg and BARI 4 mg were options during
randomization (2 phase 2 studies as well as RA-BUILD and RA-BEACON).2
4-Study
Extended Dataset
The
extended dataset included patients with RA randomized to BARI 4 mg
(N=479, PYE=781.1) or BARI 2 mg (N=479, PYE=774.9) from 2 phase 2 and
2 phase 3 studies (RA-BUILD, RA-BEACON) and 1 long term extension
study (RA-BEYOND). The evaluation time periods included randomization
through last available observation incorporating extension data
through 01 September 2019 unless otherwise specified. Data were
censored at rescue or dose change.1
All
BARI RA Dataset
The
All BARI RA analysis set included 3770 patients with RA who received
BARI at a variety of doses from 1 phase 1, 3 phase 2, and 5 phase 3
studies (RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE). Data
includes a long-term extension study (RA-BEYOND) with
13,148
PYE,
median
exposure of 4.2 years,
maximum
exposure of 8.4 years, and
data
through 01 September 2019.3,4
Abnormal
Low Hemoglobin Values in Rheumatoid Arthritis Clinical Trials
Categorical
changes in hemoglobin values were assessed by determining the
proportion of patients who had a
TE
value below the LLN, and
TE
increase in CTCAE grade for low hemoglobin.1
7-Study
Placebo-Controlled Dataset
Abnormal
Low Hemoglobin Values
No
statistical difference in the proportion of patients with a TE
abnormal low hemoglobin value through 24 weeks of assigned treatment
or until rescue (Table 1).
Few
patients had a worsening in hemoglobin CTCAE grade from <3 to ≥3
(Table 1).
4-Study
Extended Dataset
Abnormal
Low Hemoglobin Values
The
proportion of patients with a TE abnormal low hemoglobin value was
not statistically significantly different between the BARI 4-mg and
2-mg groups (35.6% vs 33.2%).1
Few
patients had a worsening in hemoglobin CTCAE grade from <3 to ≥3
in the BARI 4-mg and 2-mg groups (0.2% vs 0.6%) (Table
1).1
All
BARI RA Dataset
Abnormal
Low Hemoglobin Values
The
proportion of patients with a TE abnormal low hemoglobin value was
1073 (40.3%).1
A
shift to CTCAE grade 3 indicates that hemoglobin levels have dropped
below 4.9 mmol/L (8.0 g/dL). There were 31 (0.8%) BARI-treated
patients in the All BARI RA dataset (N=3770) with a reported
TE decrease in hemoglobin levels to CTCAE grade ≥3.1
Table
1. Overview of CTCAE Grade Shifts in Hemoglobin From Rheumatoid
Arthritis Integrated Analysis Sets1
|
Treatment-Emergent
Abnormal Low
n/NAR (%)
|
Shift
From:
Grade <2 to Grade ≥2
n/NAR (%)
|
Shift
From:
Grade <3 to Grade ≥3
n/NAR (%)
|
7
Study Dataset through 24 weeks of assigned treatment
|
Placebo
(N=1215)
|
221/828
(26.7)
|
78/1175
(6.6)
|
2/1203
(0.2)
|
BARI
2 mg (N=479)
|
91/343
(26.5)
|
33/462
(7.1)
|
2/477
(0.4)
|
BARI
4 mg (N=1142)
|
237/772
(30.7)
|
74/1104
(6.7)
|
2/1132
(0.2)
|
Extended
4 Study Dataset with data through 13 February 2018
|
BARI
2 mg (N=479)
|
114/343
(33.2)
|
40/463
(8.6)
|
3/478
(0.6)
|
BARI
4 mg (N=479)
|
128/360
(35.6)
|
49/467
(10.5)
|
1/474
(0.2)
|
All
BARI RA Dataset with data through 13 February 2018
|
All
BARI RA (N=3770)
|
1073/2660
(40.3)
|
376/3640
(10.3)
|
31/3741
(0.8)
|
Abbreviations:
BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse
Events; NAR = number of patients at risk for specified abnormality;
RA = rheumatoid arthritis.
Note: Grade 2 is <10.0 and ≥8.0
g/dL. Grade 3 is <8.0 and ≥6.5 g/dL. Normal limits were defined
according to lab methodology, age, and gender. Treatment-emergent
assessments were based on postbaseline values collected at follow-up
visits during the observation period defined by each integrated
dataset.
Reported
Adverse Events of Anemia in Rheumatoid Arthritis Clinical Trials
Compared
to placebo, neither BARI dose was associated with an increased
incidence of erythropenia-related TEAEs.1
Evaluation
of TEAEs of anemia included MedDRA preferred terms, anemia and iron
deficiency anemia, from the Blood and Lymphatic System Disorders
System Organ Class.1
Percentages by treatment group and EAIR are provided below.
Exposure-adjusted
incidence rates were calculated as the number of patients with an
event per 100 patient-years of exposure time, with exposure not
censored at time of event.2
7-Study
Placebo-Controlled Dataset
Through
24 weeks of assigned treatment or until rescue, the rates of anemia
were
3.2%
(EAIR 7.8) in the BARI 4-mg group
1.9%
(EAIR 4.8) in the BARI 2-mg group, and
3.1%
(EAIR 8.4) in the placebo group.1,5
Through
24 weeks of assigned treatment or until rescue, the rates of iron
deficiency anemia were
0.2%
(EAIR 0.4) in the BARI 4-mg
0.4%
(EAIR 1.1) in the BARI 2-mg, and
0.2%
(EAIR 0.4) placebo group.1,5
4-Study
Extended Dataset
In
the 4-study extended dataset analysis, rates of anemia were
3.8%
(EAIR=2.3) in the BARI 4-mg group, and
2.9%
(EAIR=1.8) in the 2-mg group. 1
Rates
of iron deficiency anemia were
0.4%
(EAIR=0.3) in the BARI 4-mg group, and
0.6%
(EAIR=0.4) in the 2-mg group.1
Temporary
interruption due to anemia or iron deficiency anemia occurred in
2
patients in the BARI 4-mg group, and
0
patients in the BARI 2-mg group.1
Permanent
discontinuation of study treatment due to anemia or iron deficiency
anemia occurred in
2
patients in the BARI 4-mg group, and
3
patients in the BARI 2-mg group.1
All
BARI RA Dataset
In
the All BARI RA analysis
rates
of anemia were 6.1% (EAIR=1.7), and
rates
of iron deficiency anemia were 0.9% (EAIR=0.3).1
Anemia
or iron deficiency anemia led to
temporary
interruption of study treatment in 12 patients, and
permanently
discontinuation of study treatment in 17 patients.1
Role
of Janus Kinase2 in Erythropoietin Function
Erythropoietin
signals through JAK2 and inhibition of the JAK/stat pathway affects
erythropoiesis and hemoglobin.6,7
Information
From the Label
Haemoglobin
< 8 g/dL was reported in less than 1 % of patients in rheumatoid
arthritis clinical trials.8
Treatment
should not be initiated, or should be temporarily interrupted, in
patients with a haemoglobin value < 8 g/dL observed during routine
patient management. Treatment may be initiated once values have
improved above these limits.8
Haemoglobin
should be assessed before treatment initiation and thereafter
according to routine patient management.8
References
1.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
2.
Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of
baricitinib for the treatment of rheumatoid arthritis over a median
of 3 years of treatment: an updated integrated safety analysis.
Lancet Rheumatol. 2020;2(6):E347-E357.
https://doi.org/10.1016/S2665-9913(20)30032-1
3.
Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of
baricitinib for the treatment of rheumatoid arthritis up to 8.4
years: an updated integrated safety analysis [abstract]. Ann Rheum
Dis. 2020;79(suppl 1):638.
https://ard.bmj.com/content/79/Suppl_1/642.1
4.
Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of
baricitinib for the treatment of rheumatoid arthritis up to 8.4
years: an updated integrated safety analysis. Poster presented at:
European League Against Rheumatism Virtual Congress; June 3-6, 2020.
5.
Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of
baricitinib in patients with active rheumatoid arthritis with over 2
years median time in treatment. J Rheumatol. 2019;46(1):7-18.
http://dx.doi.org/10.3899/jrheum.171361
6.
Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of
JAK1 and JAK2 is efficacious in rodent models of arthritis:
preclinical characterization of INCB028050. J Immunol.
2010;184(9):5298-5307. http://dx.doi.org/10.4049/jimmunol.0902819
7.
Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the
pathogenesis and therapy of myeloproliferative disorders. Nature
Rev Cancer. 2007;7(9):673-683. http://dx.doi.org/10.1038/nrc2210
8.
Olumiant [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
Glossary
BARI
= baricitinib
CTCAE
= Common Terminology Criteria for Adverse Events
EAIR
= exposure-adjusted incidence rate
JAK
= Janus kinase
LLN
= lower limit of normal
MedDRA
= Medical Dictionary for Regulatory Activities
PYE
= patient-years of exposure
RA =
rheumatoid arthritis
TE =
treatment-emergent
TEAE
= treatment-emergent adverse event
▼ This
medicinal product is subject to additional monitoring. This will
allow quick identification of new safety information. Healthcare
professionals are asked to report any suspected adverse reactions.