FDA Grants Priority Review to New Drug Application of Neurofibromatosis Agent Mirdametinib

According to a new announcement, the FDA has accepted and granted priority review to SpringWorks Therapeutics’ new drug application (NDA) for mirdametinib, an investigational MEK inhibitor for the treatment of adult and pediatric patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). The agency has scheduled a PDUFA action date of February 28, 2025, and stated that it does not have current plans to hold an advisory committee meeting to discuss the application.¹

In the update, the company also announced that the European Medicines Agency validated the Marketing Authorization Application (MAA) for mirdametinib for the treatment of adult and pediatric patients with NF1-PN. Both submissions for the NDA and the MAA included data from the pivotal phase 2b ReNeu trial (NCT03962543), a multicenter, open-label study that featured 114 patients with NF1 PN (58 adult and 56 pediatric) who received mirdametinib for up to 24 months.

"We look forward to working with regulatory authorities on their reviews of our applications for mirdametinib, both in the U.S. and Europe. We are also focused on sharing additional data from the phase 2b ReNeu trial at upcoming medical meetings and expect the data to be published in a peer-reviewed publication later this year. In parallel, we are advancing our preparations in anticipation of a potential launch in early 2025," Jim Cassidy, MD, PhD, chief medical officer at SpringWorks Therapeutics, told NeurologyLive^®.

Recently presented data from ReNeu at the 2024 American Society of Clinical Oncology Annual Meeting showed that treatment with mirdametinib resulted in statistically significant objective response rate (ORR) and sustained reductions in PN volume. Coupled with improvements in pain severity, pain interference, and health-related quality of life (HRQoL), results showed that the tablet therapy may be a potentially therapeutic option for patients with NF1 PN across all ages.²

Patients in the study received the investigational therapy as a capsule or dispersible tablet (2 mg/m2 BID, max 4 mg BID) without regard to food in 3 week on/1 week off 28-day cycles. Minimum clinically relevant ORR, the primary end point, was defined as at least a 23% reduction of target PN volume for adults (≥18 yrs) and 20% for pediatrics (2-17 yrs). As of the September 20, 2023, data cutoff, blinded independent central review (BICR)-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P <.001 vs null) in adults and 52% (95% CI, 38-65; P <.001 vs null) in pediatric patients treated with mirdametinib.

Top Clinical Takeaways

Mirdametinib has shown promising results in reducing tumor volume and improving the quality of life for both adult and pediatric patients with NF1-PN.
The FDA’s priority review and the European Medicines Agency's validation highlighted the drug's potential impact as a new treatment option for NF1-PN.
While mirdametinib is progressing through regulatory channels, its safety profile and observed adverse effects will be critical factors in determining its widespread adoption.

Led by Christopher L. Moertel, MD, medical director of the Pediatric Neuro-Oncology and Neurofibromatosis Programs at the University of Minnesota, median target PN volumetric best response from baseline was –41% (min: –90, max: 13) and –42% (–91, 48) in adult and pediatric patients, respectively. As of the data cutoff, median treatment duration was 22 months for each cohort and median duration of response was not reached.

Between the adult and pediatric populations, the median time to response was 7.8 (4-19) months and 7.9 (4-19) months, respectively. Both groups demonstrated statistically significant improvements after 13 cycles of treatment on pain severity, defined through Numerical Rating Scale-11, pain interference, assessed through Pain Interference Index, and key QoL (PedsQL).

In terms of safety, the most frequent treatment-emergent adverse events (TEAEs), occurring in more than 35% of patients, were dermatitis acneiform, diarrhea, nausea, and vomiting in adults. For pediatrics, diarrhea, dermatitis acneiform, and vomiting were mostly observed. In total, 16% and 25% of adult and pediatric patients, respectively, had at least grade 3 treatment-related AEs, and 22% and 9%, respectively, discontinued because of TEAEs.

“We believe that there is a significant opportunity for mirdametinib to impact the treatment landscape for NF1-PN. There are approximately 40,000 patients with NF1-PN in the U.S. today, the majority of whom are adults who currently do not have an FDA-approved therapy. We believe mirdametinib could allow many more patients to be treated, potentially filling an unmet need that currently exists and making a meaningful impact in these patients’ lives," Cassidy added.

In episode 5 of a newly published program titled “Managing Neurofibromatosis Type 1 Related Plexiform Neurofibroma in Patients of Different Ages,” Kaleb H. Yohay, MD, director of NYU Langone’s Comprehensive Neurofibromatosis Center, examined mirdametinib as an investigational treatment for NF1-PN, focusing on its potential role in managing the condition in adolescents and adults who have moved beyond pediatric care. In the clip below, he overviewed the options for NF1-PN, highlighting the benefits that mirdametinib brings.