Type 1 neurofibromatosis - Emerging treatments

Mirdametinib

Mirdametinib is an investigational oral small molecule MEK inhibitor that has been granted orphan drug status by the FDA for patients with NF1-associated plexiform neurofibromas. One phase 2 trial assessed mirdametinib in 19 patients with NF1 and a plexiform neurofibroma that was either progressive or causing significant morbidity. In total, 19 (42%) patients achieved >20% shrinkage in tumour volume at 48 weeks, and 10 (53%) had stable disease.[57]

Topical NFX-179

An investigational topical gel formulation of NFX-179, another MEK inhibitor, has been granted orphan drug status by the FDA for the treatment of cutaneous NF1. One randomised, double-blind, vehicle-controlled, parallel group phase 2a study in adults with NF1 and cutaneous neurofibromas (cNF) was completed in April 2021.[58] No treatment emergent adverse events were reported and a phase 2 dose-response study is underway to determine safety and effectiveness of two concentrations of NFX-179 gel in patients with cNF.[59]

Topical mast cell blockers

Given the well-established role of mast cells in neurofibroma growth and the preliminary trials with the orally administered mast cell blocker ketotifen, the use of a topical mast cell blocker has been considered for treating cutaneous neurofibromas, although there have been no clinical trials.

Intralesional sclerosing agents

Given the highly vascular nature of neurofibromas, the strategy of injecting a vascular sclerosing agent directly into cutaneous neurofibromas has been considered and preliminary trials are under way, although no data have been published.

Regorafenib

Regorafenib, an inhibitor of multiple protein kinases, has been approved in some countries (e.g., the US) to treat patients with advanced gastrointestinal stromal tumours (GISTs) that cannot be surgically removed, and no longer respond to imatinib and sunitinib. The approval was based upon the results of a double-blind, placebo-controlled trial of patients with metastatic or unresectable GISTs who experienced treatment failure with prior imatinib or prior sunitinib.[60]

Statins

Since 2005, when lovastatin was found to reverse learning and attention deficits in an NF1 mouse model, statins have been proposed as a potential therapeutic option for the improvement of NF1-associated cognitive deficits.[61] Although some encouraging research showed that lovastatin could improve impaired synaptic plasticity and phasic alertness in patients with NF1, a phase 3 clinical trial (n=84) found that 12 months of treatment with simvastatin did not significantly improve cognitive deficits or behavioural problems in children compared with placebo.[62][63] Currently, statins cannot be recommended for the improvement of cognitive deficits in NF1.