AstraZeneca found a winning indication for Koselugo (selumetinib), the first drug to be approved by the US Food and Drug Administration (FDA) for neurofibromatosis type 1 (NF1), a genetic disorder that causes benign tumor growth in nerves. Koselugo is approved for pediatric patients 2 years of age and older with symptomatic, inoperable plexiform neurofibromas — nerve sheaths tumors — which can grow anywhere in the body, including the spine and organs. Koselugo is a small molecule that targets the kinase MEK, which phosphorylates mitogen-activated protein kinase (MAPK). The drug’s approval rests on the back of a phase 2 trial conducted at the US National Cancer Institute. Trial results showed a partial response in all 50 patients and an overall response rate of 66%, most responses lasting 12 months or longer.
NF1 is caused by germline mutations in the NF1 tumor suppressor gene and affects 1 in 3,000 people. It is characterized by elevated RAS–MAPK signaling. Koselugo is an oral selective inhibitor of MEKs 1 and 2 and the fourth MEK inhibitor approved overall (the other indications are melanoma and non-small-cell lung cancer). The FDA previously granted AstraZeneca an Orphan Drug designation for Koselugo in pediatric NF1, as well as Priority Review and Breakthrough Therapy designations. The drug has been tested in clinical trials for at least 13 tumor types.
Mutations in the NF1 gene are known drivers in multiple cancers. AstraZeneca still has Koselugo in phase 1 testing in combination with Imfinzi (durvalumab) for solid tumors and in phase 2 testing in combination with Tagrisso (osimertinib) for advanced non-small-cell lung cancer expressing the epidermal growth factor receptor. The company tested Koselugo with docetaxel as a second-line treatment for KRAS-positive NSCLC, but the combination failed to meet its primary endpoint of progression-free survival in a phase 3 trial.
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First drug approved for neurofibromas is a MEK inhibitor. Nat Biotechnol 38, 513 (2020). https://doi.org/10.1038/s41587-020-0530-3