Baricitinib: The Potential Future Treatment of Lupus

Baricitinib, an oral selective inhibitor of Janus kinase (JAK)1 and JAK2, has been already approved for the treatment of RA.

In a double-blind, multicenter, randomized, placebo-controlled, 24-week phase 2 study, patients were recruited from 78 centers in 11 countries. Patients who were ≥18 years of age; had a diagnosis of systemic lupus erythematosus (SLE); and had active disease involving skin or joints were eligible for the study. In all, 314 patients were randomly assigned in a ratio of 1:1:1 to receive once-daily baricitinib 2 mg, baricitinib 4 mg, or placebo for 24 weeks. The primary endpoint was the number of patients achieving resolution of arthritis or rash at week 24, as defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K).

At week 24, resolution of SLEDAI-2K arthritis or rash was achieved by 70 (67%) of 104 patients receiving baricitinib 4 mg (odds ratio [OR] vs. placebo 1·8, 95% CI 1.0–3.3; p=0.0414) and 61 (58%) of 105 patients receiving baricitinib 2 mg (OR 1.3, 0.7–2.3; p=0.39).

Adverse events were reported in 68 (65%) patients in the placebo group, 75 (71%) patients in the baricitinib 2 mg group, and 76 (73%) patients in the baricitinib 4 mg group. Serious adverse events were reported in 10 (10%) patients receiving baricitinib 4 mg, 11 (10%) receiving baricitinib 2 mg, and ve (5%) receiving placebo; no deaths were reported. Serious infections were reported in six (6%) patients with baricitinib 4 mg, two (2%) with baricitinib 2 mg, and one (1%) with placebo.

The baricitinib 4-mg dose, but not the 2-mg dose, significantly improved the signs and symptoms of active systemic lupus erythematosus in patients who were not adequately controlled despite the standard of care therapy, with a safety profile consistent with previous studies of baricitinib.

These positive findings indicate that baricitinib could be a favorable drug for systemic lupus erythematosus. However, was there also a meaningful clinical benefit? Patients started with a mean of 5·3 (SD 4·7) swollen joints and 7·7 (5·8) tender joints in the placebo group vs. 5·5 (4·2) swollen joints and 8·5 (6·2) tender joints in the baricitinib 4-mg group; after 24 weeks, the placebo group had improved by a mean of 4·6 (0·2) swollen joints and 5·6 (0·4) tender joints, whereas the baricitinib 4-mg group had improved by 4·8 (0·2) swollen joints and 6·9 (0·4) tender joints.

The initial mean Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score was 4·9 (5·7) in the placebo group and 4·0 (3·4) in the baricitinib 4-mg group, with a higher reduction at week 24 in the placebo group (–2·8, SD 0·4) compared with that in the baricitinib group (–2·3, 0·4).

In conclusion, the difference in primary outcome was mostly based on a greater reduction in the mean tender joint count in the baricitinib 4-mg group.

Reference:
Wallace DJ, Furie RA, TanakaY, et al.. Baricitinib for systemic lupus erythematosus: A double-blind, randomized, placebo-controlled, phase 2 trial. Lancet. 2018;392(10143);222–231. doi:10.1016/s0140-6736(18)31363-1.

Anifrolumab

Anifrolumab is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that targets type I IFN alpha receptor 1 (IFNAR1). It inhibits type I IFN-dependent cell signaling by binding to IFNAR1 and blocking formation of the IFN/IFNAR complex. In all, 60%–80% of adult lupus patients have an increased type I interferon gene signature, which has been shown to correlate with disease activity.

TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) program included two Phase III clinical trials. TULIP 1 and TULIP 2 evaluate the efficacy and safety of anifrolumab vs. placebo in patients with moderately to severely active auto-antibody-positive systemic lupus erythematosus (SLE) who are receiving the standard of care treatment.

TULIP 1 randomized 460 eligible patients (1:2:2) to receive a fixed-dose intravenous infusion of 150-mg anifrolumab, 300-mg anifrolumab, or placebo every 4 weeks. TULIP 2 randomized 373 eligible patients (1:1) to receive a fixed-dose intravenous infusion of 300-mg anifrolumab or placebo every 4 weeks.

The program assesses the effect of anifrolumab in reducing disease activity, as measured by the SRI4, decreasing the use of oral corticosteroids; improving skin manifestations, as measured by Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI); and reducing flares.

Dose 300-mg IV infusion/SC once a month.

Side effects: Anifrolumab is associated with minimal side effects such as upper respiratory tract infections, herpes zoster infections, and mild injection-site reactions after subcutaneous injection.

It has been announced recently (Aug 2018) that TULIP 1 Phase III trial for anifrolumab in adult patients with moderate-to-severeSLE did not meet the primary endpoint of a statistically significant reduction in disease activity in patients with SLE, as measured by the SLE Responder Index 4 (SRI4) in 12 months.

Reference:
Anifrolumab, an anti–interferon-a receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017; 69(2):376–386.

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