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

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 Patients^5,9

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 Designs^3,6,8

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 csDMARDs^4,7,11

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 bDMARDs^1,2,10

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

1. Burmester 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

2. Fleischmann 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

3. Fleischmann 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

4. Kremer 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

5. Lee 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

6. Taylor 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

7. Van 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

8. Van 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

9. Fleischmann 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

10. Genovese 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

11. Dougados 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