On May 26, 2021 NFlection Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on the development of targeted therapies for rare disorders driven by aberrant activation of the RAS pathway (RASopathies), reported positive results from a 28-day, Phase 2a, multicenter, randomized, double-blind, parallel-group, vehicle-controlled clinical trial investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of NFX-179 Gel in subjects with NF1 (Press release, NFlection Therapeutics, MAY 26, 2021, View Source [SID1234580652]). Topical application of NFX-179 Gel is designed to deliver a proprietary "soft" (metabolically labile) MEK inhibitor to cNF tumors to suppress the overactivation of the Ras/Raf/MEK/ERK pathway in these tumors while avoiding the systemic toxicities of orally administered MEK inhibitors, which have not been approved for this indication.

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In the trial, 48 subjects were randomized in a 1:1:1:1 ratio to receive once-daily NFX-179 Gel at 0.05%, 0.15%, or 0.5%, or placebo (vehicle), for 28 days. The primary endpoints were safety, tolerability and suppression of p-ERK, a key biomarker known to promote the growth of cNF tumors.

NFX-179 Gel was well tolerated. No serious adverse events were reported, and no adverse events were classified as related to NFX-179 Gel. All adverse events were mild to moderate and occurred at similar frequencies in the treatment and vehicle groups. Orally administered MEK inhibitors have common adverse effects of rash, diarrhea, peripheral edema and fatigue. Unlike systemic MEK inhibitors, which can cause severe acneiform rash, acneiform rash was not observed during treatment with NFX-179 Gel. Forty seven of the 48 subjects completed the trial; one subject withdrew from the trial due to COVID-19 infection.

NF1 subjects carry a mutation in the gene encoding neurofibromin 1, a tumor suppressor that suppresses the Ras/Raf/MEK/ERK pathway. The resulting overactivation of this pathway leads to increased levels of p-ERK, which drives the growth of cNF tumors. Treatment of cNF tumors with NFX-179 Gel for 28 days induced a dose-dependent suppression of p-ERK in the tumors. Compared to vehicle-treated lesions, tumors treated with 0.5% and 0.15% NFX-179 Gel showed a statistically significant suppression in p-ERK. A 47% reduction (p = 0.0001) in p-ERK was observed in tumors treated with 0.5% NFX-179 Gel, and a 26% reduction (p = 0.04) in p-ERK was observed in tumors treated with 0.15% NFX-179 Gel. The lowest dose group, 0.05% NFX-179 Gel, gave a 10% reduction of p-ERK that was not statistically different from vehicle (p = 0.4). In addition, exploratory secondary endpoints demonstrated a tumor size reduction despite limiting treatment to only 28 days. There was a 17% mean reduction in tumor volume from baseline in the 0.5% NFX-179 Gel group versus an 8% reduction in the vehicle group (p = 0.073). In a per-subject responder analysis, 22% of subjects in the 0.5% NFX-179 group had a 50% or greater mean reduction in tumor volume, versus 6% of subjects in the vehicle group (p = 0.051).

Dr. Guy Webster, Chief Medical Officer of NFlection, said, "We are very pleased with these data, which demonstrate that NFX-179 Gel is well tolerated and induces clinically meaningful levels of p-ERK suppression in cNF tumors. The strong p-ERK biomarker data, along with an unexpected early trend in cNF tumor volume reduction after only 28 days of treatment, support our hypothesis that NFX-179 Gel is an important novel therapy for NF1 patients. We look forward to progressing NFX-179 Gel to Phase 2b to determine the effect of longer treatment duration on cNF tumor regression, as well as to initiating trials testing NFX-179 Gel for the treatment of other cutaneous RASopathies."

"We are delighted that our partnership with NFlection is delivering such encouraging results," said Annette Bakker, Ph.D., President, Children’s Tumor Foundation. "It is really exciting to already observe tumor shrinkage in the 28-day Phase 2a study.

This study provides hope that the NFX-179 Gel could become a life-changing solution for the NF patients suffering with painful and often disfiguring cutaneous neurofibromas, for which no approved pharmacological therapies exist today."

About NFX-179 Gel
NFX-179 is an investigational mitogen-activated protein kinase kinase (MEK) inhibitor. NFX-179 is a "soft" (metabolically labile) drug, which, when formulated as NFX-179 Gel for topical application, is designed to concentrate at the dermal site of action but degrade in systemic circulation, thereby significantly reducing side effects compared to systemically available MEK inhibitors. NFlection is developing NFX-179 Gel for the treatment of RASopathies such as cutaneous neurofibromatosis type 1, immunosuppressant-mediated cutaneous squamous cell carcinoma, and congenital birthmarks.

About Cutaneous Neurofibromatosis Type 1
Cutaneous neurofibromas are tumors that grow from small nerves in the skin or just under the skin and appear as small or larger bumps typically beginning around the time of puberty. Individuals with NF1 commonly develop more cutaneous neurofibromas as they get older. They do not become malignant, but they may be disfiguring, itchy or painful when bumped. Despite their benign nature, they may cause significant problems (e.g., depression, isolation, etc.), and may require surgical removal.