Apilimod is a Highly Selective PIKfyve Inhibitor

Crohn disease, psoriasis, rheumatoid arthritis, multiple sclerosis and other chronic inflammatory diseases cause widespread and severe health problems. These and other immune diseases can be considered to have a predominantly Th1 bias. Although injectable biologic treatments such as antibodies and soluble protein that block TNF-αhave provided significant clinical benefit, there is still a high unmet medical need, particularly for a safe targeted drug that can be taken orally.

The well-documented biologic functions of IL-12 are the induction of IFN-expression from T and NK cells and the differentiation of naive T cells toward a Th1-cell type. IL-12 also appears to be critical in the expansion and maintenance of the Th1 phenotype. In general, IL-23 plays a critical role in chronic inflammatory diseases. Although the inflammatory effector function of Th1 is essential for the clearance of intracellular pathogens, the excessive production of proinflammatory cytokines leads to serious tissue damage typical of organ-specific autoimmunity, including type 1 diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, and sepsis. IL-12/IL-23 appears as an attractive clinical target by a number of studies.

Apilimod (STA 5326) is a potent IL-12/IL-23 inhibitor.

For instance, Apilimod inhibits IFN-γ production induced by either IFN-γ/SAC or SAC in human PBMCs, with an IC50 of approximately 20 nM. Also it shows some inhibition against IFN-γ/SAC-induced TNF-α and ConA-induced IL-5 from human PBMCs at high concentrations, but no suppressive effect against IL-1β, IL-2, IL-4, IL-8, and IL-18 in all cultures tested.

Moreover, Apilimod (10 mg/kg, p.o.) causes a significant reduction in cell number only in the Th1 model. Also, Apilimod treatment has no effect in the Th2 setting. Apilimod (5 or 20 mg/kg, p.o.) reduces the level of IL-12 p40 in serum without altering body weight in EAU mice. Oral administration of Apilimod reduces the severity of experimental autoimmune uveoretinitis (EAU) by clinical and histopathological analysis.

Reference:

Wada Y, et al. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor. Blood. 2007 Feb 1;109(3):1156-64.

Keino H, et al. Therapeutic effect of the potent IL-12/IL-23 inhibitor STA-5326 on experimental autoimmune uveoretinitis. Arthritis Res Ther. 2008;10(5):R122.