The safety and tolerability profile of baricitinib in rheumatoid arthritis (RA) up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements were reported during the 24-week blinded period were maintained during the open-label extension (OLE). 

Rheumatoid arthritis (RA) is the most severe inflammatory disorder affecting joints severely and thus the overall quality of life of a patient. The number inflammatory markers included in the pathogenesis of RA such as interleukin 6 (IL-6), IL-12, IL-23, interferon and the γ chain cytokines including IL-2 use the Janus kinase (JAK) intracellular signaling pathway and are associated with RA. Numerous JAK inhibitors are reported to have the significant role in the RA therapy. These inhibitors work by inhibiting one or more of the 4 enzymes within the JAK family. Baricitinib is a selective inhibitor of JAK1/JAK2. A phase IIa study conducted on RA patients used baricitinib [4, 7, or 10 mg administered once daily (QD)] and showed a significant result after 12 weeks as compared to placebo. Similarly, another study conducted in Japanese patients also showed the significant efficacy of baricitinib against the RA after the 12-week treatment. The current study demonstrated the details of safety data collected during these OLE and that clinical improvement observed at week 24 were maintained or improved through week 128.

Rationale behind the research:

None of the studies reported the efficacy of baricitinib against RA for longer duration.

Therefore, the present study by Edward C. Keystone et al evaluated the details of safety data collected during these OLE and that clinical improvements observed at week 24 (maintained or improved) through week 128.

Objective:

To assess the safety and efficacy of baricitinib in patients with RA up to 128 weeks in a phase IIb study.

Study outcome measures:

• Safety assessments: Safety was monitored throughout the OLE. Assessments included treatment-emergent adverse events (TEAE), serious AE (SAE; including deaths), discontinuations due to AE, and clinical laboratory test abnormalities
• Efficacy measures: Measures of efficacy recorded through week 128 included ACR20, ACR50, ACR70, and DAS28-based on the level of high-sensitivity C-reactive protein (DAS28-CRP) or erythrocyte sedimentation rate (DAS28-ESR)-both continuous and categorical (≤ 3.2 and < 2.6) versions
• Other measures: CDAI (continuous version and ≤ 2.8 as remission), SDAI (continuous version and ≤ 3.3 as remission), and ACR/European League Against Rheumatism (EULAR) Boolean remission. Each patient’s functional ability was assessed by the Health Assessment Questionnaire–Disability Index (HAQ-DI), which is included in the ACR core set

Time period: Week 0, Week 24, Week 76, and Week 128.

Figure 1: Patient disposition diagram

Study Outcomes:

Safety:

The total exposure time to baricitinib in patients receiving at least 1 dose of the active drug during the study (including the initial 0–24 weeks) was 433.9 patient-years: 10.8 at 1 mg QD, 23.7 at 2 mg QD, 14.2 at 2 mg BID, 284.5 at 4 mg QD, and 100.7 at 8 mg QD.

Overview of adverse events (AE):

Most patients experienced at least 1 TEAE during the study. In general, no pronounced differences in the incidence of AE were seen between the doses studied, although for patients rescued during the first OLE, exposure-adjusted rates after week 24 but prior to rescue (while receiving 4 mg prior to 8 mg QD) were difficult to interpret because of the brevity of this 4- to 8-week exposure period. Importantly, TEAE occurrence did not increase in frequency with prolonged exposure, and the lowest event rates were seen during the second OLE.

Thirteen patients discontinued because of an AE during 24–76 weeks [1 anemia, 2 elevated transaminase, 1 increased creatine phosphokinase (CPK), and 4 herpes zoster in the 4-mg group; 1 basal cell carcinoma (BCC) of the skin and 1 herpes simplex in the 4/8-mg group; 1 colitis, 1 acute hepatitis B, and 1 fatal myocardial infarction in the 8-mg group]. Other than the single uncomplicated BCC, no malignancies were reported during the study. No deaths were otherwise reported during the study. During the second OLE, 3 additional patients discontinued because of an AE (1 herpes simplex in the 4/4-mg group, and 1 anemia due to suspected gastrointestinal bleeding and 1 herpes zoster in the 4:8/4-mg group).

Laboratory results:

Mean neutrophil count decreased during the double-blind period with greater declines in the 8-mg dose group. Small increase in mean neutrophil count was observed in the first OLE with small decrease in the second OLE, particularly in patients decreasing from 8 mg to 4 mg QD. Three patients experienced a Grade 3 neutropenia, and no patient experienced a Grade 4 neutropenia or discontinued because of neutropenia in the entire study. No significant change in mean lymphocyte count was observed during the double-blind period or in either OLE. Two patients experienced Grade 3 abnormalities, and no patient experienced a Grade 4 abnormality or discontinued the study because of lymphopenia. Mean platelet count increased following baricitinib treatment in a dose-dependent manner during the double-blind period, with small changes in the first and second OLE reflecting changes in baricitinib dose from 4 mg to 8 mg and from 8 mg to 4 mg QD in the first and second OLE, respectively. No clinically significant change in mean hemoglobin occurred during the OLE. Mean alanine aminotransferase (ALT) did not change in a clinically meaningful amount in the double-blind period or either OLE. Mean ALT increased in the 8-mg dose group during the first OLE.

Clinical efficacy:

In the 24-week blinded period, significantly more patients in the combined baricitinib 4- and 8-mg groups compared to placebo achieved the primary endpoint of an ACR20 response at week 125. The proportions of patients achieving an ACR20, ACR50, or ACR70 response at week 24 of the double-blind period were maintained through week 76 and week 128 of the OLE. When measured at weeks 24, 76, and 128, the percentages of patients who achieved DAS28-CRP and DAS28-ESR scores ≤3.2 and <2.6 were also maintained during the OLE, with similar consistency over time seen for remission rates as measured by ACR/EULAR (Boolean definition), CDAI (≤ 2.8), or SDAI (≤ 3.3). Improvement in HAQ-DI was similarly maintained.

The results of the present study were consistent with the prior observations gathered for shorter durations of exposure. Few of the patients were not able to continue to study due to AE. During the OLE period, few of the patients were also affected by Herpes zoster infections at incidence rates similar

to those described in association with biologic disease modifying anti-rheumatic drugs (bDMARDs) in RA. The frequency of any grade of elevated ALT or creatinine or decreased hemoglobin, neutrophils, or lymphocytes was stable during OLE period. Patients treated with baricitinib showed significant improvement after 12 weeks as compared to placebo which was maintained throughout the 24 weeks. In the present study improvement of efficacy response was seen from 24 through 76 weeks of treatment and was sustained in the second OLE period from 76 through 128 weeks of treatment.

Treatment with baricitinib for 24 weeks showed significant improvement in the disease progression in RA patients as compared to placebo. In this phase IIb study, the clinical development observed at week 24 was maintained or improved through week 128.