Neurofibromatosis Type 1

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Neurofibromatosis type 1 (NF1) is a genetic disorder that affects children and adults and that manifests in a variety of symptoms including abnormal pigmentation, skeletal deformities, non-malignant and malignant tumors and neurological complications.

NF1 is characterized by mutations in the NF1 gene, which leads to over-activation of the MAPK pathway. NF1 has an estimated global birth incidence of approximately 1 in 3,000 individuals and it is estimated that nearly 100,000 people are living with NF1 in the United States. The clinical course of NF1 is heterogeneous, and people with it have an 8 to 15-year shortened lifespan compared to the general population.

What causes NF1?

NF1 is caused by mutations in the gene that controls the production of a protein called neurofibromin (neurofibromin 1). In about 50% of people with NF1, the disorder results from gene mutations that occur for unknown reasons (spontaneous mutation). In others with the disorder, NF1 is inherited.

Does NF1 progress?

Throughout their lifetime, patients with NF1 display a progression of different clinical manifestations. Almost everyone will experience a skin tumor called cutaneous neurofibroma at some point, 50-80% will exhibit a behavioral or cognitive deficit and about 30-50% of patients will develop plexiform neurofibromas (PN), which are peripheral nerve sheath tumors that cause severe disfigurement, pain and functional impairment. In rare cases, NF1-PN can transform into malignant peripheral nerve sheath tumors (MPNST), a diagnosis that has a 12-month survival rate of under 50%. NF1-PNs are most often diagnosed in the first two decades of life.

Are there treatments?

Historically, patients with NF1-PN were treated with surgical removal of the tumors. However, because NF1-PN arises from nerve cells and grows in an infiltrative pattern, it is challenging to successfully resect tumors without causing severe comorbidities, such as permanent nerve damage and disfigurement. The FDA (2020) and EMA (2021) approved a drug from the MEK inhibitor class for the treatment of children with NF1-PN.

Our investigational therapy

Mirdametinib is an oral small molecule drug designed to inhibit MEK1 and MEK2, which has been tested in several Phase 1 and Phase 2 clinical trials. The ReNeu trial, a Phase 2b, open-label, clinical trial is currently evaluating mirdametinib in children and adults with NF1-PN.

The U.S. Food and Drug Administration (FDA) and the European Commission granted Orphan Drug designation for mirdametinib for the treatment of NF1, and the FDA granted Fast Track designation for mirdametinib for the treatment of patients ≥ 2 years of age with NF1-associated inoperable plexiform neurofibromas that are progressing or causing significant morbidity.