Breakthrough Therapy Status for Neurofibromatosis Type-1 Drug

Incurable Genetic Condition Affects One in 3-4,000 People

The FDA has granted a breakthrough therapy designation to selumetinib (AstraZeneca and Merck), an investigational MEK 1/2 inhibitor. The designation is based on phase 2 data from the SPRINT trial, evaluating selumetinib in pediatric patients aged 3 years or older with inoperable neurofibromatosis type 1- (NF1) related plexiform neurofibromas (PN).

This debilitating and incurable genetic condition can cause pain, motor and airway dysfunction, bowel/bladder dysfunction, and disfigurement. People with NF1 may also experience learning difficulties, visual impairment, twisting and curvature of the spine, high blood pressure, and epilepsy.

In addition, NF1 increases the risk of developing other cancers, including malignant brain tumors and leukemia. Symptoms begin in early childhood, and can reduce life expectancy by as much as 15 years.

The NF1 gene provides instructions for producing neurofibromin, which negatively regulates the RAS/MAPK pathway, helping to control cell growth, differentiation, and survival. Gene mutations can cause dysregulation in RAS/RAF/MEK/ERK signaling, forcing cells to grow, divide, and copy themselves uncontrollably, potentially resulting in tumor growth. Selumetinib restrains the MEK enzyme in the RAS/MAPK pathway, potentially inhibiting tumor growth.

Selumetinib received an orphan drug designation from the FDA for the treatment of NF1 in February 2018 and from the European Medicines Agency in August 2018.

Source: Merck, April 1, 2019