CHMP Endorses Mirdametinib for NF1-PN in Adults and Children

SpringWorks Therapeutics, Inc., a biopharmaceutical company dedicated to addressing severe rare diseases and cancer, recently announced a significant milestone in the treatment of neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas (PN). The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has expressed a positive opinion for the conditional marketing authorization of mirdametinib, a MEK inhibitor, for treating symptomatic, inoperable PN in both children and adults with NF1 aged 2 years and older. This decision is pending final approval from the European Commission, expected in the third quarter of 2025.

Mirdametinib, if approved, will be available in capsule and dispersible tablet forms, which can be easily dissolved in water. This advancement represents a significant step forward in providing new therapeutic options for individuals with NF1-PN, a genetic disorder affecting approximately 3 in every 10,000 people in the European Union, or about 135,000 individuals. Patients with NF1 face a 30-50% lifetime risk of developing plexiform neurofibromas, tumors that grow along the peripheral nerve sheath and may lead to severe disfigurement, pain, and functional impairment. These tumors can also transform into malignant peripheral nerve sheath tumors, posing a potentially fatal risk.

The CHMP’s recommendation follows the Marketing Authorization Application (MAA) for mirdametinib, validated by the European Medicines Agency in August 2024. This application was primarily based on the results of the Phase 2b ReNeu trial, which enrolled 114 patients, both adults and children, with NF1-PN. The trial demonstrated positive outcomes, achieving the primary endpoint of confirmed objective response rate (ORR). Specifically, adults exhibited a 41% ORR, while children showed a 52% ORR. Participants with a confirmed response experienced long-term benefits, with significant improvements in pain and quality of life reported.

Mirdametinib has already been approved in the United States for treating NF1-PN in patients aged 2 years and older and has shown a manageable safety and tolerability profile. Common side effects in adults included rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue. In children, the most common adverse events were similar but also included abdominal pain, headache, and left ventricular dysfunction.

The ReNeu trial, an open-label, single-arm, Phase 2b study, continues to explore mirdametinib's efficacy, safety, and tolerability in patients with inoperable NF1-associated PN. The trial's treatment phase is complete, with results presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. Those who completed the treatment phase can participate in an ongoing optional long-term follow-up study.

Neurofibromatosis type 1 is a rare genetic disorder caused by mutations in the NF1 gene, responsible for encoding neurofibromin, a crucial MAPK pathway suppressor. Globally, NF1 affects approximately 1 in 2,500 individuals at birth. The disorder is characterized by diverse symptoms, including abnormal pigmentation, skeletal deformities, tumor growth, and neurological complications like cognitive impairment. Patients with NF1 typically experience a reduced life expectancy compared to the general population.

With limited treatment options available, mirdametinib offers a promising alternative for managing NF1-PN. Surgical removal of these tumors is often challenging due to their infiltrative growth pattern along nerves, which can lead to permanent damage and disfigurement. Consequently, up to 85% of plexiform neurofibromas are not suitable for complete surgical resection. Mirdametinib, as an oral small molecule MEK inhibitor, represents a potential breakthrough for both pediatric and adult patients with this debilitating condition.

SpringWorks continues to focus on improving the lives of patients with severe rare diseases and cancer by developing targeted therapies. If mirdametinib receives approval from the European Commission, it will mark a significant achievement in treating NF1-associated plexiform neurofibromas, offering hope to many who currently have limited options.