SpringWorks Therapeutics' new drug application (NDA) for mirdametinib, a MEK inhibitor, has been granted priority review by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of February 28, 2025, and indicated that it is not currently planning to hold an advisory committee meeting to discuss the application. This decision underscores the potential of mirdametinib to address a significant unmet need in NF1-PN treatment. The European Medicines Agency (EMA) has also validated the Marketing Authorization Application (MAA) for mirdametinib for the same indication.
Clinical Data from the ReNeu Trial
The NDA and MAA submissions are supported by data from the pivotal Phase 2b ReNeu trial (NCT03962543), a multi-center, open-label study. The trial enrolled 114 patients aged 2 years and older with NF1-associated PN causing significant morbidity. Patients received mirdametinib at a dose of 2 mg/m² twice daily (maximum dose of 4 mg twice daily) on a 3-week on, 1-week off schedule. Mirdametinib was administered orally as either a capsule or dispersible tablet.
Results from the ReNeu trial, presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated a confirmed objective response rate (ORR) assessed by blinded independent central review (BICR). The primary endpoint was the proportion of patients with a ≥ 20% reduction in target tumor volume on consecutive scans during the 24-cycle treatment phase, as measured by MRI. Secondary endpoints included safety and tolerability, duration of response, and changes in patient-reported outcomes from baseline to Cycle 13.
Christopher L. Moertel, MD, of the University of Minnesota, reported that the median target PN volumetric best response from baseline was -41% in adults and -42% in pediatric patients. The median time to response was 7.8 months in adults and 7.9 months in pediatric patients. Both groups showed statistically significant improvements in pain severity, pain interference, and quality of life after 13 cycles of treatment.
Safety and Tolerability
The most frequent treatment-emergent adverse events (TEAEs) in adults were dermatitis acneiform, diarrhea, nausea, and vomiting. In pediatric patients, the most common TEAEs were diarrhea, dermatitis acneiform, and vomiting. Grade 3 or higher treatment-related adverse events occurred in 16% of adult patients and 25% of pediatric patients. Discontinuations due to TEAEs were reported in 22% of adults and 9% of pediatric patients.
Addressing Unmet Needs in NF1-PN
Neurofibromatosis type 1 (NF1) is a rare genetic disorder affecting approximately 1 in 2,500 individuals globally, with about 100,000 patients in the United States. NF1 is caused by loss-of-function variants in the NF1 gene, which encodes neurofibromin, a key suppressor of the MAPK pathway. Patients with NF1 have a 30-50% lifetime risk of developing plexiform neurofibromas (PN), tumors that can cause disfigurement, pain, and functional impairment. The current treatment landscape for NF1-PN is limited, particularly for adults, highlighting the need for new therapeutic options.
Annette Bakker, Ph.D., CEO of the Children’s Tumor Foundation (CTF), emphasized the need for more treatment options, especially for adults, noting that plexiform neurofibromas can cause serious medical complications. She congratulated SpringWorks on this milestone, expressing hope that patients in the U.S. and Europe could soon have a new therapy available.
Mirdametinib: A Potential New Standard of Care
Mirdametinib is a potent, oral, CNS-penetrant, allosteric small molecule MEK inhibitor. It is designed to inhibit MEK1 and MEK2, key components of the MAPK pathway, which regulates cell growth and survival. The FDA and the European Commission have granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity, and Rare Pediatric Disease designation for the treatment of NF1.
Saqib Islam, CEO of SpringWorks, stated that these milestones bring the company closer to delivering a transformative medicine to adults and children with NF1-PN in the U.S. and Europe. He looks forward to working with the FDA and EMA during their review processes as they prepare to bring their second medicine to patients suffering from devastating diseases.
