Expected Therapeutic Mechanism

Sirolimus is thought to suppress the immune response by inhibiting the action of mammalian target of rapamycin (mTOR), a protein that regulates cell division, proliferation, and survival. mTOR forms two distinct complexes within cells in order to function: mTORC1 and mTORC2. Sirolimus binds to the cytoplasmic protein FKBP12 (FK binding protein 12), forming sirolimus–FKBP12 complexes. The drug is believed to exert its therapeutic effects via this complex, which suppresses mTORC1 by blocking mTOR from binding to its regulatory associated protein (raptor), thereby inhibiting S6K phosphorylation and weakening the PI3K/Akt/mTOR signaling pathway.

Sirolimus’ Effects in iMCD

Sirolimus is anticipated to treat cases of iMCD that respond poorly to IL-6 inhibitors effectively, as studies have indicated its efficacy in some patients (albeit few in absolute number) unresponsive to conventional therapies;¹⁾²⁾ moreover, PI3K/Akt/mTOR has been identified as the most enriched pathway in iMCD flare by plasma proteomic analysis.³⁾ In Japan, a randomized, double-blind, placebo-controlled, parallel-group, physician-led trial of sirolimus is underway for tocilizumab-resistant iMCD (clinical trial plan no. jRCT2071190029).⁴⁾

References

1) David C. Fajgenbaum, et al. J Clin Invest. 2019; 129: 4451–4463.
2) David C Fajgenbaum, et al. Blood. 2017; 130: 3593.
3) Sheila K Pierson et al. Am J Hematol. 2018; 93: 902–912.
4) Koga T, et al. Medicine. 2020; 99: e20710.