EXPECTED THERAPEUTIC MECHANISM

Mammalian target of rapamycin (mTOR) plays a pivotal role in the control of immune response due to its involvement in T-cell, B-cell, monocyte, and neutrophil function. Dysfunction in mTOR pathways is known to impair the proliferation and differentiation of immune cells. Sirolimus—a mTORC1 inhibitor—has been reported to affect the proliferation and differentiation of different types of immune cells by interfering with these pathways.

SIROLIMUS’ EFFECTS IN PRIMARY IMMUNODEFICIENCIES

Primary immunodeficiency is a collective term for diseases involving genetic abnormalities somewhere in the immune system, some of which are expected to respond positively to mTOR inhibitors. It is known that abnormal activation of mTOR pathways can occur in activated PI3-Kinase delta syndrome (APDS), CTLA-4 haploinsufficiency, LRBA deficiency, IPEX syndrome, and Autoimmune lymphoproliferative syndrome (ALPS); case reports indicating sirolimus’ efficacy in such conditions have been published overseas. Several other primary immunodeficiencies characterized by mTOR pathway dysfunction are known, prompting some clinicians to advocate a unified disease concept that would encapsulate all of them.

ROADMAP TO COMMERCIALIZATION

Consultations about regulatory (PMDA) strategies for a physician-led clinical trial to assess sirolimus as a treatment for primary immunodeficiencies concluded in 2020. Planning for this trial is currently ongoing.

STATUS OF CLINICAL TRIALS

Currently in planning.