Expected Therapeutic Mechanism

Neurofibromatosis type 1 (NF1) is a disease that presents with systemic neurofibromas in association with brown spots (“café au lait spots”) and various skeletal and vascular abnormalities. This condition results from defects in the NF1 gene that cause constitutive activation of Ras proteins and subsequently of the RAS–MAPK and PI3K–AKT–mTOR pathways. Loss of heterozygosity in NF1 gene in Schwann cells in conjunction with abnormal microenvironment are important factors that contribute to tumorigenesis in NF1. mTORC1 is thought to play a role in the regulation of tumor microenvironment in NF1, as the protein is involved in autophagy, immunoregulation, and numerous other processes in addition to tumor growth, similar to the RAS–MAPK pathway. Accordingly, sirolimus—an mTORC1 inhibitor— should inhibit both tumor growth and microenvironment perturbation in NF1, thereby inhibiting neurofibroma formation.
Since sirolimus does not readily migrate from the blood to the skin, local administration—i.e., as a topical agent, which is absorbed well by skin yet resistant to entering the bloodstream—is expected to be safer and more effective in treating NF1 skin tumors than internal dosage forms.

Sirolimus’ Effects in NF1

A double-blind study was conducted from 2015 to 2017 to assess sirolimus’ effectiveness in treating NF1 skin tumors, in which subjects were administered a topical preparation at one of two concentrations (0.2%, 0.4%) or a placebo. Sirolimus suppressed tumor growth in a dose-dependent manner when evaluated by volume reduction on CT. In addition, tumor diameter as measured by ruler was significantly different between the 0.2% and 0.4% treatment arms.
Encouraged by these results, a physician-led phase 3 trial involving four Japanese centers was started in 2018, which is currently in progress. No results have yet been released.