To investigate the safety, tolerability, pharmacokinetics, and efficacy of apilimod mesylate, an oral interleukin‐12 (IL‐12)/IL‐23 inhibitor, in patients with rheumatoid arthritis (RA).

We performed a phase IIa, randomized, double‐blind, placebo‐controlled proof‐of‐concept study of apilimod, in combination with methotrexate, in 29 patients with active RA (3:1 ratio of apilimod‐treated to placebo‐treated patients) in 3 stages. Patients received apilimod 100 mg/day or placebo for 4 weeks (stage 1) or 8 weeks (stage 2). In stage 3, patients received apilimod 100 mg twice a day or placebo for 8 weeks, with an optional extension of 4 weeks. Clinical response (Disease Activity Score in 28 joints [DAS28] and American College of Rheumatology [ACR] criteria) was assessed throughout; synovial tissue samples collected at baseline and on day 29 (stages 1 and 2) or day 57 (stage 3) were stained for cellular markers and cytokines for immunohistochemistry analysis.

While only mild adverse events were observed in stages 1 and 2, in stage 3, all patients experienced headache and/or nausea. Among apilimod‐treated patients (100 mg/day), there was a small, but significant, reduction in the DAS28 on day 29 and day 57 compared with baseline. ACR20 response was reached in only 6% of patients on day 29 and 25% of patients on day 57, similar to the percentage of responders in the placebo group. Increasing the dosage (100 mg twice a day) did not improve clinical efficacy. Consistent with clinical results, apilimod did not have an effect on expression of synovial biomarkers. Of importance, we also did not observe an effect of apilimod on synovial IL‐12 and IL‐23 expression.

Our results do not support the notion that IL‐12/IL‐23 inhibition by apilimod is able to induce robust clinical improvement in RA.