Olumiant® (Baricitinib)

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Baricitinib: Comparison of Baricitinib and Tofacitinib Phase 3 Rheumatoid Arthritis Clinical Development Programs

Both baricitinib and tofacitinib conducted phase 3 rheumatoid arthritis clinical development programs.

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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.

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

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.

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.

aORAL Strategy is a phase 3b/4 non-inferiority study.

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.

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.

References

1Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomized phase 3 trial. Lancet. 2013;381(9865):451-460. http://dx.doi.org/10.1016/S0140-6736(12)61424-X

2Fleischmann R, Kremer J, Crush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495-507. http://dx.doi.org/10.1056/NEJMoa1109071

3Fleischmann R, Mysler E, Hall S, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head randomised controlled trial. Lancet. 2017;390(10093):457-468. https://dx.doi.org/10.1016/S0140-6736(17)31618-5

4Kremer J, Li ZG, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013:159(4):253-261. http://dx.doi.org/10.7326/0003-4819-159-4-201308200-00006

5Lee EB, Fleischmann R, Hall S et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377-2386. http://dx.doi.org/10.1056/NEJMoa1310476

6Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652-662. http://dx.doi.org/10.1056/NEJMoa1608345

7Van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65(3):559-570. http://dx.doi.org/10.1002/art.37816

8Van Vollenhaven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508-519. http://dx.doi.org/10.1056/NEJMoa1112072

9Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 2017;69(3):506-517. http://dx.doi.org/10.1002/art.39953

10Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243-1252. http://dx.doi.org/10.1056/NEJMoa1507247

11Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2016. epub ahead of print. http://dx.doi.org/10.1136/annrheumdis-2016-210094

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

Fecha de la última revisión: 2019 M04 19


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