Platelet
Changes in the Rheumatoid Arthritis Clinical Development Program
Mean
Platelet Changes Over Time
In
controlled studies, for up to 16 weeks, increases in platelet counts
above 600 x 109 cells/L
occurred in 2.0 % of patients treated with baricitinib 4 mg and 1.1 %
of patients treated with placebo. No association was observed between
increased platelet counts and adverse events of a thrombotic nature.
The pattern and incidence of increases in platelet counts remained
stable at a higher value than baseline over time including in the
long term extension study. 1
5-Study
Pooled Dataset
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
2018.2
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).2
Based
on the 5-study pooled dataset, mean platelet counts
increased
early with a peak at week 2
returned
towards baseline at week 4, and
stabilized
after week 8 at levels higher than baseline with extended BARI
exposure (Figure 1).2-4
Figure
1. 5-Study Pooled Dataset Mean (SE) Platelet Levels Over Time2
Abbreviations:
BARI = baricitinib; PBO = placebo; SE = standard error Notes:
BARI 2-mg, placebo censored at rescue or dose change, and BARI 4-mg
censored at any dose change (including step-down) or rescue in
long-term extension study. Lilly-defined large clinical trial
population based reference ranges were used.
6-Study
Placebo-Controlled Dataset
The
6-study placebo-controlled dataset compared BARI 4 mg vs placebo and
included patients with RA who were randomized to BARI 4 mg (N=997) or
placebo (N=1070) from 3 phase 2 and 3 phase 3 studies. In the
majority of the studies, patients were on background therapy either
with MTX or another csDMARD. The BARI 2-mg data is derived from 4
studies in which both BARI 2 mg (N=479) and BARI 4 mg were options
during randomization.5
Reversibility
was evaluated in a subgroup of patients from the 6-Study
placebo-controlled dataset who discontinued treatment by Week 24.
Reversibility of increased platelet count was observed with the
return of mean values to baseline after treatment discontinuation
(Figure 2).3
Figure
2. Platelet Count Reversibility in a Patient Subgroup from the
6-Study Placebo-Controlled Dataset3
Notes:
Platelet counts were pooled from 6 placebo-controlled phase 2 and 3
studies, including the long-term extension study period, with data
through January 1, 2016. Reversibility was evaluated in patients who
discontinued study treatment by week 24.
Changes
in Mean Platelet Volume
Mean
Platelet Changes Over Time
The
relationship of platelet count to MPV was assessed, over 16 weeks, in
study RA-BEAM, a 52-week, randomized, placebo- and active-controlled
study of patients with moderate to severe active rheumatoid
arthritis.6
The
objective of this analysis was to determine if the observed platelet
changes were consistent with altered
platelet
synthesis
platelet
release, or
platelet
clearance.6
In
RA-BEAM, after initiation of BARI treatment
platelet
count increased at week 2, then returned toward baseline at week 4
MPV
decreased at week 2, then returned toward baseline at week 4, and
both
platelet count and MPV remained stable after week 4 through the
16-week observation period (Figure
3).6
According
to the authors, the pattern of mirrored changes for platelet count
and MPV suggests decreased platelet clearance rather than increased
platelet production. As a potential explanation, the increase in
platelet count at week 2 may represent a transient increase in
smaller and older circulating platelets, which might account for the
observed MPV decline.6
Figure
3. Change in Platelet Count and Mean Platelet Volume Over Time in
Patients from Study RA-BEAM6
Abbreviations:
BARI = baricitinib; CI = confidence interval.
Note: *
Within-group p≤.05.
Patients
With Abnormal High Platelet Values
Dataset
Descriptions
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.7
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).7
4-Study
Extended Dataset
The
extended dataset included patients with RA randomized to BARI 2 mg
(N=479, PYE=675.6, median exposure duration=257 days, maximum
exposure duration=1805 days) or BARI 4 mg (N=479, PYE=698.6, median
exposure duration=342 days, maximum exposure duration=2520 days )
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 13 February 2018 unless
otherwise specified. Data were censored at rescue or dose change.7
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
10,127
PYE,
median
exposure of 3.1 yrs,
maximum
exposure of 6.9 yrs, and
data
through 13 February 2018.7
Treatment
Emergent Abnormally High Platelet Value Analyses
Analyses
of treatment emergent high platelet counts (>ULN) across
integrated safety datasets are presented in .
2
Normal
limits were defined according to
lab
methodology
age
gender,
and
ethnicity.2
Table
1. Treatment Emergent Abnormal High Platelet Values2
|
7-Study
Placebo-Controlled Dataset, Week 24
PBO
(N=1215)
(NAR=1033)
|
7-Study
Placebo-Controlled Dataset, Week 24
BARI
2 mg
(N=479)
(NAR=420)
|
7-Study
Placebo-Controlled Dataset, Week 24
BARI
4 mg
(N=1142)
(NAR=974)
|
4-Study
Extended Dataset
BARI
2 mg
(N=479)
(NAR=421)
|
4-Study
Extended Dataset
BARI
4 mg
(N=479)
(NAR=426)
|
All
BARI RA Dataset
(N=3770)
(NAR=3296)
|
Abnormal
High, n (%)
|
98
(9.5%)
|
71
(16.9)a
|
237
(24.3)a
|
82
(19.5)
|
129
(30.3)b
|
1025
(31.1)
|
Abbreviations:
BARI = baricitinib; N = number of patients in the analysis
population; n = number of patients with the specified
abnormality; NAR = number of patients at risk for the abnormality in
each treatment group; PBO = placebo; RA = rheumatoid arthritis
Note:
For the 7-Study Placebo-ControlledDataset, the OR is versus
placebo. For the 4-Study Extended Dataset, the OR is versus BARI 2
mg.
a
P-value ≤ 0.05 and OR > 1 (missing ORs are
considered >1).
b
BARI incidence ≥10% before rounding and OR >1
(missing ORs are considered >1).
The
proportions of patients experiencing a change from ≤ 600 billion
cells/L to > 600 billion cells/L are presented in . 2
Table
2. Proportion of Patients with Platelet Value Changes from ≤ 600
billion cells/L to > 600 billion cells/L2
|
7-Study
Placebo-Controlled Dataset, Week 24
PBO
(N=1215)
(NAR=1198)
|
7-Study
Placebo-Controlled Dataset, Week 24
BARI
2 mg
(N=479)
(NAR=472)
|
7-Study
Placebo-Controlled Dataset, Week 24
BARI
4 mg
(N=1142)
(NAR=1127)
|
4-Study
Extended Dataset
BARI
2 mg
(N=479)
(NAR=473)
|
4-Study
Extended Dataset
BARI
4 mg
(N=479)
(NAR=473)
|
All
BARI RA Dataset
(N=3770)
(NAR=3716)
|
≤ 600
billion cells/L to > 600 billion cells/L
|
17
(1.4)
|
5
(1.1)a
|
27
(2.4)
|
8
(1.7)
|
19
(4.0)
|
127
(3.4)
|
Abbreviations:
BARI = baricitinib; N = number of patients in the analysis
population; n = number of patients with the specified
abnormality; NAR = number of patients at risk for the abnormality in
each treatment group; PBO = placebo; RA = rheumatoid arthritis
a
Through Week 16
Relationship
of Increased Platelets to Thrombotic Events
Thrombocytosis
and Thromboembolic Adverse Events
In
controlled studies, for up to 16 weeks, thrombocytosis (>600 x 109
cells/L) was commonly reported (≥ 1/100 to <1/10). 1
DVT
and PE are listed as uncommon in the table of adverse reactions in
the summary of product characteristics. 1
Events
of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been
reported in patients receiving baricitinib. Baricitinib should be
used with caution in patients with risk factors for DVT/PE, such as
older age, obesity, a medical history of DVT/PE, or patients
undergoing surgery and immobilisation. If clinical features of DVT/PE
occur, baricitinib treatment should be discontinued and patients
should be evaluated promptly, followed by appropriate treatment.1
The
association between thrombocytosis and adverse events of a thrombotic
nature were evaluated in patients from the All BARI RA 12-month
safety update analysis set.3
Among
the 31 patients in the All BARI RA dataset with a reported adverse
event of VTE through September 1, 2016, the proportion of patients
with high platelet levels was comparable between patients with VTE
vs those without VTE (Figure
4). No association was observed between increased platelet
counts and VTE events.3,8
Figure
4. Proportions of BARI-Treated Patients With and Without a DVT/PE
Adverse Event According to Thrombocytosis Criteria Applied at
Baseline and Post Baseline3
Abbreviations:
BARI = baricitinib; DVT/PE = deep venous thromboembolism/pulmonary
embolism.
Note: Data from the All BARI RA analysis set with data
through September 1, 2016.
References
1.
Olumiant [summary of product characteristics]. Eli Lilly Nederland
B.V., The Netherlands.
2.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3.
Kremer J, Huizinga TWJ, Chen L, et al. Analysis of neutrophils,
lymphocytes, and platelets in pooled phase 2 and phase 3 studies of
baricitinib for rheumatoid arthritis. Poster presented at: European
League Against Rheumatism (EULAR) Annual Meeting; June 14-17, 2017;
Madrid, Spain.
4.
Eli Lilly and Company. Lilly FDA Advisory Committee Meeting NDA
207924 Briefing Document.
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605062.pdf.
Accessed May 2, 2018a.
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605062.pdf
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.
Giles JT, Nurmohamed MT, Rinder HM, et al. Mean platelet volume
changes with baricitinib indicate reduced new platelet production in
baricitinib-treated rheumatoid arthritis patients. Presented at
American College of Rheumatology (ACR/ARHP) Annual Meeting; November
19-24, 2018. Chicago, IL.
7.
Genovese MC, Smolen JS, Tsutomu 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
8.
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 [published online September 15, 2018].
J Rheumatol. https://dx.doi.org/10.3899/jrheum.171361
Glossary
AD =
atopic dermatitis
BARI
= baricitinib
DVT
= deep vein thrombosis
PBO
= placebo
PE =
pulmonary embolism
RA =
rheumatoid arthritis
TE =
treatment-emergent
▼ 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.