We are focused on treating cutaneous neurofibromas (cNF) and birthmarks with a topical “soft” MEK inhibitor called NFX-179.
Previous studies have demonstrated the therapeutic potential of systemic MEK inhibitors in treating cNFs, and other tumors in NF1. In a mouse model of NF1, mice given MEK inhibitors for two months showed significant decreases in neurofibroma tumor volume. Additionally, MEK inhibitors effectively treated plexiform neurofibromas in Phase 2 human clinical trials, and in human NF1 malignant peripheral nerve sheath tumor xenograft models. Similarly, we have demonstrated systemic MEK inhibitors have therapeutic potential in birthmarks.
Despite promising data demonstrating that MEK inhibitors are efficacious in treating cNFs and birthmarks, systemic exposure to systemic MEK inhibitors commonly leads to significant adverse effects such as rash, gastrointestinal toxic effects like diarrhea, nausea and vomiting, fatigue, high blood pressure, as well as abdominal and back pain, swelling, and others.
To develop a safe and effective MEK inhibitor, we conducted a medicinal chemistry campaign to identify a proprietary “soft” (metabolically labile) MEK inhibitor. While stable in the skin, NFX-179 is engineered to be “soft” by rapidly degrading upon reaching systemic circulation. NFX-179 molecules that penetrate beyond the cNF target tissue into the bloodstream are broken into metabolites which are no longer active in contrast to “hard” MEK inhibitors which remain active in circulation over long periods of time. We have developed an esthetically pleasing and well tolerated topical formulation of NFX-179. The NFX-179 formulation has been tested on human cNF, ENS, and NS explants which have demonstrated dose-dependent suppression of p-ERK, a biomarker of Ras/Raf/MEK/ERK pathway activation that MEK inhibitors suppress. Our NFX-179 formulation can penetrate the outer layer of skin to locally deliver the MEK inhibitor while minimizing side effects caused by systemic exposure.
NFX-179 has two significant advantages over systemic MEK inhibitors: (1) a topical formulation delivers effective localized exposure to the skin for the treatment of cutaneous neurofibromas and birthmarks; (2) a “soft” MEK inhibitor is highly metabolically labile when it reaches the systemic circulation, mitigating adverse side effects caused by systemic exposure.