Mirdametinib (Gomekli) wins FDA approval, bringing relief to NF‐1 patients with surgically inoperable plexiform neurofibromatosis worldwide

Neurofibromatosis type 1 (NF-1) is an autosomal dominant, complex multi-system disorder that primarily affects the skin and nervous system. It is characterized by mutations in the NF1 gene on chromosome 17, leading to abnormal production of neurofibromin protein. Common symptoms include café au lait spots, Lisch nodules, neurofibromas, plexiform neurofibromas, scoliosis, vision disorders, and learning and mental disabilities 1. Managing NF-1 can be challenging because it is a lifelong disorder in which chronic pain is a prominent feature; consequently, opioids are prescribed and somnolence is frequently reported. Surgical interventions to remove tumors can also result in long-term physical impairments 2. In recent years, new treatments like Selumetinib (Koselugo) have been approved. However, its effectiveness is mainly limited to children, and it can cause adverse effects like vomiting, raised creatinine phosphokinase, dry skin, and diarrhea 3. A new development is the U.S. Food and Drug Administration's (FDA) approval on February 11, 2025 of mirdametinib (Gomekli), a mitogen-activated protein kinase kinase (MEK) inhibitor, for the treatment of adults and pediatric patients aged 2 years and older with NF-1-associated surgically inoperable plexiform neurofibromas. 4. Loss of neurofibromin protein in NF-1 patients causes Ras signaling dysregulation. This results in MEK hyperactivation, driving uncontrolled cell growth and tumor formation. Mirdametinib, a specific noncompetitive MEK inhibitor (MEKi), blocks MEK activity, reducing hyperactivation of Ras and shrinkage of surgically inoperable plexiform neurofibromatosis. A Phase II trial assessed the safety and efficacy of mirdametinib in adolescents and adults of age ≥ 16 years with NF1-related plexiform neurofibromas. The results showed that mirdametinib is well-tolerated and effective, with a 42% partial response rate and at least 20% tumor shrinkage by volume 5. The ReNeu trial, a pivotal Phase IIb study, evaluated the efficacy of mirdametinib in 114 patients. The results demonstrated a substantial confirmed objective response rate, durable reductions in plexiform neurofibromas volume, and clinically meaningful improvements in pain and health-related quality of life 6. Crucially, mirdametinib stands out as a treatment distinct from traditional approaches like selumetinib, as it has been proved to be effective in the treatment for both children and adults. Although mirdametinib represents a breakthrough for plexiform neurofibromas in NF-1, it carries a broad side-effect profile. Most commonly, cutaneous toxicities, including acneiform rash, eczema, seborrheic dermatitis, paronychia, and xerosis, have been reported 7, along with fatigue, profound changes in bile acid metabolism leading to nausea, vomiting, diarrhea 8, as well as MEKi-associated retinopathy 9. Mirdametinib is specifically designed for the treatment of NF-1 pediatric and adult patients, aged 2 years and above, who are affected by surgically inoperable plexiform neurofibromas. In a study, mirdametinib has been shown to amplify the effectiveness of radiotherapy in treating tumors associated with NF1 deficiency, particularly in low-grade gliomas and, to lesser extent, high-grade gliomas 10. Furthermore, a groundbreaking study reveals that mirdametinib can disrupt and weaken fear memories when combined with memory destabilization techniques. This breakthrough suggests that mirdametinib holds potential as a novel treatment for posttraumatic stress disorders 11. Another study revealed that mirdametinib shows promise in developing new treatments for acute kidney injury in patients undergoing chemotherapy with cisplatin 12. Memuna J. Zeb: Protocol development, manuscript writing, and final editing. The author has nothing to report. The author declares no conflict of interest. The author has nothing to report. The author has nothing to report.