Effect of NFX-179 MEK inhibitor on cutaneous neurofibromas in persons with neurofibromatosis type 1

Abstract

This phase 2a trial investigated the efficacy of NFX-179 Topical Gel, a metabolically labile MEK inhibitor, in the treatment of cutaneous neurofibromas (cNFs) in neurofibromatosis type 1. Forty-eight participants were randomized to four treatment arms: NFX-179 Topical Gel 0.05%, 0.15%, and 0.5% or vehicle applied once daily to five target cNFs for 28 days. Treatment with NFX-179 Topical Gel resulted in a dose-dependent reduction in p-ERK levels in cNFs at day 28, with a 47% decrease in the 0.5% NFX-179 group compared to the vehicle (P = 0.0001). No local or systemic toxicities were observed during the treatment period, and systemic concentrations of NFX-179 remained below 1 ng/ml. In addition, 20% of cNFs treated with 0.5% NFX-179 Topical Gel showed a ≥50% reduction in volume compared to 6% in the vehicle group by ruler measurement with calculated volume (P = 0.021). Thus, NFX-179 Topical Gel demonstrated significant inhibition of MEK in cNF with excellent safety and potential therapeutic benefit.

Fig. 1.. Randomization and follow-up of the participants.

Participants were randomized to four treatment arms: vehicle, 0.05% NFX-179 Topical Gel, 0.15% NFX-179 Topical Gel, and 0.5% NFX-179 Topical Gel. Five target tumors were treated with NFX-179 Topical Gel or vehicle once daily during the 28-day treatment period. At day 28 (visit 5), the five Target cNF tumors were measured and then biopsied 4 hours after application for biomarker analysis.

Fig. 2.. Proportion of p-ERK to total-ERK in cNFs at day 28.

Proportion of p-ERK to total ERK in each treatment arm. Numbers in blue are relative to vehicle. 0.15% NFX-179 Topical Gel displayed a mean reduction in p-ERK:total ERK proportion of 26.2% [P = 0.036, analysis of variance (ANOVA) analysis]. cNFs treated with 0.5% NFX-179 Topical Gel displayed a mean reduction in p-ERK:total ERK proportion of 46.9% as compared with vehicle (P = 0.0001, ANOVA).

Fig. 3.. Reduction in volume of cNFs across treatment arms.

(A) Tumor level analysis: Percent reduction in cNF volume at day 28 compared with baseline in the vehicle group and 0.05, 0.15, and 0.5% Gel groups, respectively. The reduction in cNF volume in 0.5% NFX-179 Topical Gel treatment arm approached significance when compared with vehicle (P = 0.055, nonparametric ANOVA analysis). Error bars represent SE. (B) Percent of cNF tumors with a 50% or greater reduction in tumor volume. 20% of cNF tumors treated with 0.5% NFX-179 Topical Gel had a ≥50% reduction in volume versus 6% in the vehicle group (P = 0.021, ANOVA). (C) Participant level analysis: Per participant mean percent of cNFs with 50% or greater reduction in cNF volume. For each participant, the % of the treated cNF tumors with a ≥50% reduction in volume from baseline to day 28 is calculated. There is a 22% per-participant mean response in the 0.5% NFX-179 Topical Gel group versus 6% in vehicle group (P = 0.051, ANOVA). The volume of the treated cNFs was calculated on the basis of ruler measurements of longest diameter and height using a calculation of volume as a cylinder.

Fig. 4.. Correlation between percent p-ERK:total-ERK and mean change in cNF volume.

Correlation between proportion of p-ERK to total-ERK and mean change in cNF volume. (A) In the low-dose 0.05% NFX-179 Topical Gel and vehicle arms, there is no correlation between p-ERK:total ERK proportion and change in tumor volume (Spearman R = 0.0070, P = 0.9748). (B) In the combined medium/high-dose 0.15 and 0.5% NFX-179 Topical Gel treatment arms, there is a moderate correlation between p-ERK:total ERK proportion and change in tumor volume (Spearman R = 0.6228, P = 0.0026).