Brief Report: A phase IIa, randomized, double‐blind, placebo‐controlled trial of apilimod mesylate, an interleukin‐12/interleukin‐23 inhibitor, in patients with rheumatoid arthritis

Abstract

Objective. 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).Methods. 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 ( Results. While only mild adverse events were observed in stages 1 and 2, in stage 3, all patients experienced headache and/or nausea. Among apilimodtreated 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. Conclusion. Our results do not support the notion that IL-12/IL-23 inhibition by apilimod is able to induce robust clinical improvement in RA.Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting synovial tissue. Activated immune cells are important in orchestrating synovial inflammation by producing several cytokines, including interleukin-12 (IL-12) and IL-23 (1). IL-12 is a heterodimeric cytokine (p70) formed by 2 subunits, p40 and p35 (2). The structure of the more recently discovered heterodimeric IL-23 is closely related to that of IL-12 and shares the p40 subunit, but IL-23 contains p19, a unique subunit (3). IL-12 acts in the initial inflammation phase by promoting differentiation of naive CD4ϩ T cells to interferon-␥-producing Th1 cells. IL-23 induces proliferation of effector memory T cells and plays a critical role in the pathogenesis of RA by inducing IL-17-producing T cells (4). Animal studies confirm this finding, as IL-23-deficient (p19 Ϫ/Ϫ ) mice and mice lacking IL-12 and IL-23 (p40 Ϫ/Ϫ ) are resistant to collagen-induced arthritis (4).Apilimod mesylate (STA-5326), an orally administered small molecule, inhibits the production of IL-12 and IL-23. It selectively prevents nuclear translocation of c-Rel, a member of the Rel/NF-B family of transcription factors, thereby reducing both p35 and p40 ClinicalTrials.gov identifier: NCT00642629.

Interleukin-23 in early disease development in rheumatoid arthritis

“…This is supported by our findings in eRA, where an inverse association was observed between the duration of symptoms prior to diagnosis and plasma levels of IL-23. Further support is found in a study by Krausz et al, in which no effect was observed in RA patients with established disease treated with anti-p40 (IL-23/IL-12) (2,15). Considering that IL-23 is important in the establishment of the autoimmune process, signs of its involvement should therefore be observed among patients in the very early phases of disease development.…”

IL-12-and IL-23 in health and disease

“…Neutralization of p40 would prevent function of both IL-23 and IL-12 but if such treatment would be of benefit to patients with RA is not known. To the best of our knowledge, ustekinumab has not been tested in RA patients, but an inhibitor of IL-12 and IL-23 signaling, apilimod mesylate, was not able to reduce proinflammatory cytokine levels or immune infiltrates in inflamed synovial tissue when administered in combination with methotrexate [67]. …”

Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications

“…The level of interest in this target can be seen from the fact that 15 different IL23R antagonists are now reported to be in clinical or pre-clinical development [182] . Recent clinical studies associated with IL-23 inhibition in arthritis include the use of apilimod mesylate, an orally administered inhibitor of IL-12/IL-23 in RA [183] . Ustekinumab and briakinumab, fully human mAbs directed against the p40, are currently in phase 2 trials.…”