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While the first medical treatment for neurofibromatosis (NF) was recently , many further options are on the horizon.

"You see a massive acceleration of research and development," said Annette Bakker, PhD, president of the Children's Tumor Foundation, a nonprofit focused on NF research and education. Ten companies are now working on novel NF treatments with some 67 studies underway, she noted.

For this rare group of genetic tumor-causing conditions, the U.S. Army Medical Research and Materiel Command built the to help organize clinical trials across the types of NF. The Children's Tumor Foundation, along with its European arm, developed the to do the same.

These efforts are starting to have an impact.

NFlection Therapeutics recently positive topline results from a randomized, double-blind, phase IIb clinical trial for a novel topical MEK inhibitor, NFX‑179 gel, as a treatment for cutaneous neurofibromas in people with NF type 1 (NF1). These rubbery bumps or lumps, on or just under the skin, affect nearly all people with NF1 but have no approved medical treatments.

During the 6‑month study, double-blind randomization to the higher concentration of NFX‑179 gel tested (1.5%) shrank cutaneous neurofibromas significantly more than did the vehicle control. A press release noted that this benefit "was highly correlated with patient-reported meaningful improvements" despite plasma drug concentrations "orders of magnitude lower than those typically observed for oral MEK inhibitors."

Such an attempt to use MEK inhibitors topically was "long overdue," said Roger Packer, MD, of the Gilbert Family Neurofibromatosis Institute at Children's National Hospital in Washington, D.C., who noted the potential safety advantage over systemic treatment.

While details are yet to be reported from that trial and both the risks and benefits need to be proven in phase III research, the agent stirs hope for reducing the number and size of cutaneous neurofibromas and their burden on the patient, Packer said.

Bakker noted that NFX‑179 gel is now entering phase III study, as is another novel MEK inhibitor, mirdametinib.

from the phase IIb ReNeu trial were recently announced for mirdametinib -- an investigational oral, allosteric, small molecule MEK inhibitor in development as monotherapy for NF1-associated plexiform neurofibromas. In the trial, 52% of children and 41% of adults had at least a 20% target tumor volume reduction, with additional patients reaching that threshold for confirmed objective response during longer-term treatment. Pain, quality of life, and physical function also improved from baseline. FDA approval will be sought in 2024, according to drug developer SpringWorks.

Since the approval of the first drug for NF in 2020, the MEK inhibitor selumetinib (Koselugo), a number of other MEK inhibitors are in various stages of clinical trials for NF, Packer noted. That includes a granule formulation of selumetinib to overcome the limitations of its current availability only as capsules, "which makes it difficult for little babies to take it and young children."

Trials are also comparing selumetinib to more standard chemotherapies for low-grade gliomas that affect some 20% of children with NF.

"The question is, are MEK inhibitors better in these children as regards to other things like not only controlling the growth, but will more children regain vision if treated with MEK inhibitors than chemotherapy?" Packer noted.

Another question is long-term side effects, as MEK inhibition can affect mechanisms that are very critical in normal child development, Packer noted. "Are you just going to have it activate later in life when maybe a patient would tolerate the tumor less?"

The umbrella for platform trials includes an NF1 arm getting underway that is prioritizing cutaneous neurofibromas, low-grade gliomas (including optic pathway gliomas), and plexiform neurofibromas.

For NF type 2-related schwannomatosis (NF2-related SWN, formerly known as NF2), a more rare form of the condition, a preclinical pipeline coordination effort by the Children's Tumor Foundation led to a platform trial "factory" for clinical research.

With a master protocol, "all the site agreements are pre-negotiated and pre-signed, so companies can just come in and plug in their drug as they go on," Bakker explained. "What we have been doing is really facilitating drug discovery."

The platform trial has subtrials testing the non-small cell lung cancer drug brigatinib (Alunbrig; an ALK inhibitor) and breast cancer drug neratinib (Nerlynx; a pan HER inhibitor). Initial tumor response rates appeared for meningiomas and non-vestibular schwannoma with brigatinib.

Other phase II research includes selumetinib for all NF2 tumors, aspirin for vestibular schwannoma, and novel nerve growth factor monoclonal antibody for schwannomatosis-related pain. The novel HDAC inhibitor is in combined phase II/III study for NF2-mutated meningiomas. Early-phase clinical research is underway for or with novel Hippo-pathway inhibitor VT3989.

In plexiform disease, phase II has also been reached by imatinib and trametinib (Mekinist) as well as a novel MEK inhibitor HL-085 (tunlametinib).

Cognitive impacts common in NF have been targeted with phase II research with lovastatin, N-acetylcysteine, and lamotrigine (Lamictal).

"I think the future is bright," Packer concluded. "We've spent many years trying to define the problems; now we just have to find better answers for some of them. But I think we've made a lot of progress, and there's a lot of hope that we'll make a lot more progress with the right resources in the very near future."

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