Phase
3 Rheumatoid Arthritis Clinical Development Program for Baricitinib
and Tofacitinib
The
phase 3 clinical development programs for BARI and tofacitinib
included patients with moderately to severely active RA who had
inadequate responses to treatment with MTX, csDMARDs, and TNF
inhibitors or who were MTX naïve. However, there were
differences in the patient populations evaluated and study designs in
these clinical development programs.1-9 Therefore,
no efficacy and safety comparative conclusions can be drawn from
indirectly comparing the results of these programs.
Descriptions
of the phase 3 RA clinical development programs for BARI and
tofacitinib are provided in Table
1, Table 2,
Table 3, and Table
4.
Methotrexate
Naïve Patients
The
phase 3 RA clinical development programs for both BARI and
tofacitinib included studies in MTX naïve patients.5,9
In
the BARI program, RA-BEGIN was conducted in patients who were DMARD
naïve and compared,
BARI
monotherapy
dose-titrated
MTX monotherapy, and
BARI
plus MTX.9
In
the tofacitinib program, ORAL Start was conducted in patients who
were MTX naïve , but 37.0% to 41.4% of the patient population
had been previously treated with nonbiologic DMARDs. ORAL Start
compared
tofacitinib
monotherapy, and
dose-titrated
MTX monotherapy.5
Thus,
the BARI phase 3 RA clinical program evaluated an additional
treatment scenario of combination BARI and MTX therapy in patients
who were DMARD naïve, not just MTX naïve.
csDMARD
Inadequate Responders
The
phase 3 RA clinical development programs for both BARI and
tofacitinib included studies in csDMARD-IR patients with ADA as a
treatment arm.3,6,8
In
the BARI program, RA-BEAM was statistically powered to make both
non-inferiority and superiority assessments between BARI and ADA for
ACR20 and superiority assessments for DAS28-hsCRP.6
In
the tofacitinib program,
ORAL
Standard was a smaller study utilizing ADA as an active control with
no type 1 error controlled statistical comparisons between
tofacitinib and ADA, and
ORAL
Strategy was a non-inferiority study with assessment superiority if
non-inferiority was met.3,8
TNF
Inhibitors Inadequate Responders
The
phase 3 RA clinical development programs for both BARI and
tofacitinib included studies in bDMARD-IR patients.1,10
In
the BARI RA-BEACON study, more than half of the patients had
previously failed more than one bDMARD.10
In
the tofacitinib ORAL Step study, only one third of the patients had
failed more than one bDMARD.1
Although
the efficacy endpoints for both RA-BEACON and ORAL Step were similar,
the BARI study population had more experience with multiple
bDMARDs including a higher proportion having received non-TNF
inhibitor bDMARDs.
Phase
3 Rheumatoid Arthritis Clinical Development Programs
Table
1. Baricitinib and Tofacitinib Phase 3 Clinical Trial Designs in
Treatment Naïve Patients5,9
|
BARI
RA-BEGIN
|
Tofacitinib
ORAL
Start
|
Patient
Population
|
DMARD
naïve
|
MTX
naïve
|
Treatment
Arms
|
BARI
4 mg mono (n=159)
|
TOFA
5 mg bid (n=373)
|
BARI
+MTX (n=215)
|
TOFA
10 mg bid (n=397)
|
MTX
mono (n=210)
|
MTX
(n=186)
|
Background
DMARDs
|
None
|
None
|
Duration
|
52
weeks
|
24
months
|
Key
Efficacy Endpoints
|
ACR20,
mTSS, SDAI ≤3.3
(week 24)
|
mTSS,
ACR70
(6 months)
|
Abbreviations:
ACR20 = American College of Rheumatology 20% improvement criteria;
ACR70 = American College of Rheumatology 70% improvement criteria;
BARI = baricitinib; bid = twice daily; DMARD = disease modifying
antirheumatic drug; mono = monotherapy; mTSS = modified total Sharp
Score; MTX = methotrexate; SDAI = Simplified Disease Activity Index.
Table
2. Baricitinib and Tofacitinib Phase 3 Active Comparator Clinical
Trial Designs3,6,8
|
BARI
RA-BEAM
|
Tofacitinib
ORAL
Standard
|
Tofacitinib
ORAL
Strategya
|
Patient
Population
|
MTX-IR
|
MTX-IR
|
MTX-IR
|
Treatment
Arms
|
BARI
4 mg (n=487)
|
TOFA
5 mg bid (n=204)
|
TOFA
5 mg bid mono (n=384)
|
TOFA
10 mg bid (n=201)
|
TOFA
5 mg plus MTX (n=376)
|
ADA
(n=330)
|
ADA
(n=204)
|
ADA
plus MTX (n=386)
|
PBO
(n=488)
|
PBO
(n=108)
|
NA
|
Background
DMARDs
|
MTX
|
MTX
|
none
or MTX
|
Duration
|
52
weeks
|
12
months
|
12
months
|
Key
Efficacy Endpoints
|
ACR20, HAQ-DI,
DAS28-CRP≤3.2
(wk
12)
mTSS
(wk
24)
|
ACR20,
DAS28-ESR <2.6 (mo 6)
HAQ-DI (mo 3)
|
ACR50,
DAS28-ESR <2.6, HAQ-DI
(mo 6)
|
Abbreviations:
ACR20 = American College of Rheumatology 20% improvement criteria;
ADA = adalimumab; BARI = baricitinib; bid = twice daily; DAS28-CRP =
28-joint Disease Activity Score based on C-reactive protein;
DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte
sedimentation rate; DMARD = disease modifying antirheumatic drug;
HAQ-DI = Health Assessment Questionnaire Disability Index; IR =
inadequate response; mono = monotherapy; mTSS = modified total Sharp
Score; MTX = methotrexate; PBO = placebo.
a
ORAL Strategy is a phase 3b/4 non-inferiority study.
Table
3. Baricitinib and Tofacitinib Phase 3 Placebo-Controlled Clinical
Trial Designs in Patients With an Inadequate Response to
csDMARDs4,7,11
|
BARI
RA-BUILD
|
Tofacitinib
ORAL
Sync
|
Tofacitinib
ORAL
Scan
|
Patient
Population
|
csDMARD
IR
|
csDMARD
IR
|
MTX
IR
|
Treatment
Arms
|
BARI
2 mg (n=229)
|
TOFA
5 mg bid (n=315)
|
TOFA
5 mg bid (n=321)
|
BARI
4 mg (n=227)
|
TOFA
10 mg bid (n=318)
|
TOFA
10 mg bid (n=316)
|
PBO
(n=228)
|
PBO
(n=159)
|
PBO
(n=160)
|
Background
DMARDs
|
csDMARDs
|
csDMARDs
|
MTX
|
Duration
|
24
weeks
|
12
months
|
24
months
|
Key
Efficacy Endpoints
|
ACR20,
SDAI ≤3.3 (wk12)
mTSS
(wk 24)
|
ACR20,
DAS28-ESR <2.6 (mo 6)
HAQ-DI
(mo 3)
|
ACR20,
mTSS, HAQ-DI (mo 3)
DAS28-ESR<2.6
(mo 6)
|
Abbreviations:
ACR20 = American College of Rheumatology 20% improvement criteria;
BARI = baricitinib; bid = twice daily; csDMARD = conventional
synthetic DMARD; DAS28-ESR = 28-joint Disease Activity Score based on
erythrocyte sedimentation rate ; DMARD = disease modifying
antirheumatic drug; HAQ-DI = Health Assessment Questionnaire
Disability Index; IR = inadequate response; mTSS = modified total
Sharp Score; MTX = methotrexate; PBO = placebo; SDAI = Simplified
Disease Activity Index.
Table
4. Baricitinib and Tofacitinib Phase 3 Clinical Trial Designs in
Patients With Inadequate Response to bDMARDs1,2,10
|
BARI
RA-BEACON
|
Tofacitinib
ORAL
Step
|
Tofacitinib
ORAL
Solo
|
Patient
Population
|
TNFi
IR
|
TNFi-IR
|
DMARD
IR (biologic or non-biologic)
|
Treatment
Arms
|
BARI
2 mg (n=174)
|
TOFA
5 mg bid (n=133)
|
TOFA
5 mg bid (n=243)
|
BARI
4 mg (n=177)
|
TOFA
10 mg bid (n=134)
|
TOFA
10 mg bid (n=245)
|
PBO
(n=176)
|
PBO
(n=132)
|
PBO
(n=122)
|
Background
DMARDs
|
csDMARDs
|
MTX
|
None
|
Duration
|
24
weeks
|
6
months
|
6
months
|
Efficacy
Endpoints
|
ACR20
HAQ-DI, DAS28-CRP, SDAI≤3.3 (wk 12)
|
ACR20,
HAQ-DI, DAS28-ESR <2.6
(mo 3)
|
ACR20,
HAQ-DI DAS28-ESR <2.6 (mo 3)
|
Abbreviations:
ACR20 = American College of Rheumatology 20% improvement criteria;
BARI = baricitinib; bid = twice daily; csDMARD = conventional
synthetic DMARD; DAS28-CRP = 28-joint Disease Activity Score based on
C-reactive protein; DAS28-ESR = 28-joint Disease Activity Score based
on erythrocyte sedimentation rate ; DMARD = disease modifying
antirheumatic drug; HAQ-DI = Health Assessment Questionnaire
Disability Index; IR = inadequate response;MTX = methotrexate; PBO =
placebo; SDAI = Simplified Disease Activity Index; TNFi =
tumor-necrosis factor inhibitor.
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Glossary
ACR20
= 20% improvement in American College of Rheumatology criteria
ADA
= adalimumab
BARI
= baricitinib
bDMARD
= biologic disease-modifying antirheumatic drug
bDMARD-IR
= inadequate resonse or intolerant to bDMARD treatment
csDMARD
= conventional synthetic disease-modifying antirheumatic drug
csDMARD-IR
= inadequate response or intolerant to csDMARD treatment
DAS28-hsCRP
= Disease Activity Score based on high-sensitivity C-reactive protein
DMARD
= disease-modifying antirheumatic drug
JAK
= Janus kinase
MTX
= methotrexate
RA =
rheumatoid arthritis
TNF
= tumor necrosis factor