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Background: In a 24-week, phase 2 clinical study (NCT02708095) in patients with systemic lupus erythematosus (SLE), baricitinib (BARI), an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis and atopic dermatitis, inhibited the type l interferon gene signature, multiple other cytokine pathways, and improved disease activity (1) (2).
Objectives: To further evaluate the efficacy and safety of BARI in patients with SLE.
Methods: Patients with active SLE receiving stable background therapy were randomised 1:1:1 to BARI 2-mg, 4-mg, or placebo (PBO) once daily in two identically designed, 52-week, phase 3 randomised, PBO-controlled studies. In SLE-BRAVE-I (NCT03616912) and -II (NCT03616964), 760 and 775 patients, respectively were enrolled in a balanced manner across regions, although different countries per region participated in each study. The primary endpoint for both studies was the proportion of patients achieving an SLE Responder Index-4 (SRI-4) response at week 52. Glucocorticoid tapering was encouraged but not required per protocol.
Results: The mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) at baseline was 10.1 for both SLE-BRAVE-I and -II participants; musculoskeletal and mucocutaneous domains were the most common domains involved at baseline. In SLE-BRAVE-I, the proportion of SRI-4 responders at week 52 among patients treated with BARI 4-mg (56.7%), but not BARI 2-mg (49.8%), was significantly greater than in patients treated with PBO (45.9%, p = 0.016) (
Efficacy and safety of baricitinib in patients with SLE-BRAVE-I and -II
| SLE-BRAVE-I | SLE-BRAVE-II | |||||
|---|---|---|---|---|---|---|
| Efficacy measure | PBO (N=253) | BARI 2-mg (N=255) | BARI 4-mg (N=252) | PBO (N=256) | BARI 2-mg (N=261) | BARI 4-mg (N=258) |
| SRI-4 (W52) | 116 (45.9) | 126 (49.8) | 142 (56.7)* | 116 (45.6) | 120 (46.3) | 121 (47.1) |
| SRI-4 (W24) | 99 (39.1) | 114 (44.8) | 117 (46.5) | 98 (38.6) | 104 (40.0) | 108 (42.1) |
| Severe Flares (n, events) | 38 (15.0) | 34 (13.3) | 26 (10.3) | 26 (10.2) | 29 (11.1) | 29 (11.2) |
| HR for time to first severe flare (SFI) HR [CI] | NA | 0.8 [0.52, 1.32] | 0.65 [0.40, 1.08] | NA | 1.1 [0.65, 1.89] | 1.1 [0.67, 1.94] |
| Glucocorticoid sparing | 36 (30.8) | 31 (29.2) | 36 (34.0) | 33 (31.7) | 34 (29.8) | 36 (34.3) |
| LLDAS (W52) | 66 (26.2) | 65 (25.7) | 74 (29.7) | 59 (23.2) | 62 (24.0) | 65 (25.4) |
| Safety measure | ||||||
| TEAE | 210 (83.0) | 210 (82.4) | 208 (82.5) | 198 (77.3) | 199 (76.2) | 200 (77.5) |
| SAE | 18 (7.1) | 24 (9.4) | 26 (10.3) | 22 (8.6) | 35 (13.4) | 29 (11.2) |
Data are n (%) patients, unless otherwise indicated. BARI=baricitinib; CI=confidence interval; HR=hazard ratio compared with PBO; LLDAS=lupus low disease activity state; N=number of patients in the analysis population; n=number of patients in the specified category; PBO=placebo; TEAE=treatment-emergent adverse event; SAE=serious adverse event; W=week. *p≤0.05 vs PBO.
Conclusion: Although phase 2 data suggested BARI as a potential treatment for patients with SLE (2), the SLE-BRAVE-I and -II phase 3 study results were discordant for the primary outcome measure, with only SLE-BRAVE-I positive, making it difficult to elucidate benefit. Additional analyses are being performed to understand this discordance. No new safety signals were observed.
REFERENCES:
[1]Dörner T, Tanaka Y, et al. Lupus Sci Med. 2020;7(1).
[2]Wallace DJ, Furie RA, et al. Lancet. 2018;392(10143):222-31.
Disclosure of Interests: Eric F. Morand Speakers bureau: Astra Zeneca, Eli Lilly, Novartis, Sanofi, Consultant of: Amgen, AstraZeneca, Asahi Kasei, Biogen, BristolMyersSquibb, Capella, Eli Lilly, EMD Serono, Genentech, Glaxosmithkline, Janssen, Neovacs, Sanofi, Servier, UCB, Wolf, Grant/research support from: Janssen, AstraZeneca, BristolMyersSquibb, Eli Lilly, EMD Serono, GlaxoSmithKline, Yoshiya Tanaka Speakers bureau: Gilead, Abbvie, Behringer-Ingelheim, Eli Lilly, Mitsubishi-Tanabe, Chugai, Amgen, YL Biologics, Eisai, Astellas, Bristol-Myers, Astra-Zeneca, Consultant of: Eli Lilly, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GSK, Abbvie, Grant/research support from: Asahi-Kasei, Abbvie, Chugai, Mitsubishi-Tanabe, Eisai, Takeda, Corrona, Daiichi-Sankyo, Kowa, Behringer-Ingelheim, Richard Furie Consultant of: Eli Lilly, Edward Vital Consultant of: Eli Lilly (consultant and honoraria), Ronald van Vollenhoven Consultant of: Abbvie, Biotest, BMS, Celgene, Crescendo, Eli Lilly and Company, GSK, Janssen, Merck, Novartis, Pfizer, Roche, UCB, Vertex, Grant/research support from: Abbvie, Amgen, BMS, GSK, Pfizer, Roche, UCB, Kenneth Kalunian Consultant of: Eli Lilly, Marta Mosca Consultant of: Eli Lilly, GSK, Astra Zeneca, Thomas Dörner Speakers bureau: AbbVie, Eli Lilly, BMS, Novartis, BMS/Celgene, Janssen, Consultant of: AbbVie, Eli Lilly, BMS, Novartis, BMS/Celgene, Janssen, Daniel J. Wallace Consultant of: Amgen, Eli Lilly and Company, EMD Merck Serono, and Pfizer, Maria Silk Shareholder of: Eli Lilly, Employee of: Eli Lilly, christina dickson Shareholder of: Eli Lilly, Employee of: Eli Lilly, Inmaculada De La Torre Shareholder of: Eli Lilly, Employee of: Eli Lilly, Gabriella Meszaros Shareholder of: Eli Lilly, Employee of: Eli Lilly, Bochao Jia Shareholder of: Eli Lilly, Employee of: Eli Lilly, Brenda Crowe Shareholder of: Eli Lilly, Employee of: Eli Lilly, Michelle A Petri Consultant of: Eli Lilly