Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study

Abstract

Background: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.

Methods: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3.

Results: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein.

Conclusions: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.

Trial registration number: NCT01721057; Results.

Keywords: DMARDs (synthetic); Rheumatoid Arthritis; Treatment.

Conflict of interest statement

MD has received grant/research support or consulting support from AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Novartis, Pfizer, Roche, Sanofi and UCB. PE has received grant/research support or consulting support from Abbott, AbbVie, Bristol Myers Squibb, Eli Lilly and Company, MSD, Novartis, Pfizer, Roche, Samsung, Takeda and UCB. DvdH has received grant/research support and/or consulting fees from AbbVie, Amgen, AstraZeneca, Augurex, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli Lilly and Company, Galapagos, Glaxo-Smith Kline, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi, UCB and Vertex and is director of Imaging Rheumatology bv. Y-CC has received speakers bureau fees and/or grant research support from AbbVie, Bristol Myers Squibb, Eli Lilly and Company and Pfizer. MG received research support from Eli Lilly and Company. JL, SB, SW, IdlT, CG, TR, DS and SdB are employees of Eli Lilly and Company and may own stock or stock options in Eli Lilly and Company.

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Figures

Figure 1

Patient disposition through 24 weeks. Patients who were rescued or discontinued from the study or study treatment were defined as non-responders or had their last observations before rescue or discontinuation used for analyses of subsequent time points for efficacy endpoints. Nineteen patients (8%) had baseline estimated glomerular filtration rate ≥40 and 2 and therefore received baricitinib 2 mg (despite randomisation to and analysis by assigned treatment arm of baricitinib 4 mg). LTE, long-term extension; QD, once daily.

Figure 2

Primary and secondary efficacy analyses. The percentage of patients achieving American College of Rheumatology 20% response (ACR20) is shown in (A). The vertical line at 12 weeks indicates the primary efficacy time point. The least squares mean (LSM) change from baseline in Disease Activity Score for 28 joint counts C-reactive protein (DAS28-CRP) is shown in (B). Data reported as modified last observation carried forward (mLOCF), a form of LOCF modified to use the last observation prior to rescue or discontinuation. (C) shows the LSM change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) (mLOCF) with scores ranging from 0 to 3 (higher scores indicate greater disability). Analyses of change from baseline in DAS28-CRP (mBOCF) and HAQ-DI (mBOCF) at week 12 were included in the gatekeeping strategy. The percentage of patients with Simplified Disease Activity Index (SDAI) ≤3.3 at weeks 12 and 24 is shown in (D). (E–H) show the weekly diary scores for patient-reported outcomes. (E) shows the median duration of morning joint stiffness (MJS) at time points through week 12. The LSM for severity of MJS (numeric rating scale (NRS)) is shown in (F), worst tiredness (NRS) in (G) and worst joint pain (NRS) in (H). Patients recorded these measures in an electronic daily diary. MJS duration was truncated at a maximum value of 720 min. MJS severity: 0–10 NRS; 0=no joint stiffness, 10=joint stiffness as bad as you can imagine. Worst tiredness: 0–10 NRS; 0=no tiredness, 10=as bad as you can imagine. Worst joint pain: 0–10 NRS; 0=no pain, 10=pain as bad as you can imagine. *p≤0.05, **p≤0.01, ***p≤0.001 versus placebo. †For comparisons between baricitinib 4 mg versus placebo and baricitinib 2 mg versus placebo for the gated endpoints that are statistically significant based on the gatekeeping strategy with familywise error rate strongly controlled at α=0.05 for multiple comparisons.

Figure 3

Inhibition of radiographic progression of structural joint damage at week 24. The least squares mean (LSM) change from baseline in structural joint damage evaluated using modified Total Sharp Score (mTSS), joint space narrowing and erosion score is shown in (A). (B) shows the change from baseline in structural joint damage evaluated using the cumulative percentile change in mTSS. SDC (smallest detectable change)=1.2 units. *p≤0.05, **p≤0.01, ***p≤0.001 versus placebo.