FDA Grants Priority Review to Mirdametinib for NF1-Associated Plexiform Neurofibromas

FDA

The FDA has accepted and granted priority review to the new drug application (NDA) for mirdametinib in the treatment of adult and pediatric patients with neurofibromatosis type 1–associated plexiform neurofibromas (NF1-PN). The European Medicines Agency (EMA) has also validated the marketing authorization application for the agent in the same population, indicating that mirdametinib has the potential to be the first approved global therapy for the treatment of adults and a best-in-class therapy for children with this disease.¹

The Prescription Drug User Fee Act action date for the NDA is February 28, 2025, and the FDA does not expect to hold an advisory committee meeting to discuss the application. Both applications included data from the phase 2b ReNeu trial (NCT03962543) in which mirdametinib demonstrated objective response rates (ORRs) of 41% in adults and 52% in children at least 2 years of age with NF1-PN causing significant morbidity per blinded independent central review. Improvements in pain and health-related quality of life and a tolerable adverse effect (AE) profile were also reported with the agent in both the adult and pediatric populations.^1,2

“These significant milestones bring us closer to our goal of delivering a transformative medicine to both adults and children with NF1-PN in the US and Europe,” Saqib Islam, chief executive officer of SpringWorks, stated in a news release.¹ “People living with NF1-PN are in need of new advances and we look forward to working with the FDA and EMA during their review processes as we prepare to bring our second medicine to patients suffering from devastating diseases.”

Mirdametinib is an investigational, allosteric small molecule MEK inhibitor that previously received orphan drug designation from both the FDA and European Commission for the treatment of patients with NF1. The agent is also being fast tracked by the FDA for the treatment of patients 2 years of age or older with NF1-PN that is progressing or causing significant morbidity and has received rare pediatric disease designation for the treatment of patients with NF1.

The agent, also able to penetrate the central nervous system, is designed to inhibit MEK1 and MEK2, which are positioned within the MAPK pathway, thereby preventing cell growth and survival. In a past phase 2 trial (NCT02096471), the agent demonstrated efficacy and a manageable AE profile in adults and adolescents 16 years of age or older with NF1-PN.^1,2

ReNeu is a pivotal, multicenter, open-label, phase 2b trial evaluating the activity and safety of mirdametinib in 114 patients no younger than 2 years of age with an inoperable NF1-PN causing significant morbidity.

Eligible patients—adults at least 18 years of age and children between the ages of 2 and 17 years—received the oral agent at a dose of 2 mg/m² twice daily in a 3-week-on/1-week-off dosing schedule for 24, 28-day cycles.^1,2 Notably, the agent could be given as a capsule or dispersible tablet to aid with ease of administration. Following competition of the treatment phase, patients were allowed to continue study therapy in the optional long-term follow-up portion of the trial, which is ongoing.

The primary end point is confirmed ORR, defined by the proportion of patients who experience at least a 20% reduction in target tumor volume on consecutive MRI scans during the 24-cycle treatment phase. Secondary end points include safety and tolerability, duration of response (DOR), and changes in patient-reported outcomes from baseline to cycle 13.

Baseline demographics indicated that the median patient age was 34 years (range, 18-69) in the adult cohort and 10 years (range, 2-17) in the pediatric cohort. In both cohorts, most patients were female, had head and neck as the target location of PN, and pain as the predominant type of PN-related morbidity. The median volume of target PN was 196 mL (range, 1-3457) in the adult cohort and 99 mL (range, 5-3630) in the pediatric cohort. The respective target PN processing percentages at trial entry were 53% and 62%.

Results from the treatment phase, which has since completed, were presented at the 2024 ASCO Annual Meeting.² Within the adult population (n = 58), the median duration of treatment was 22 months and the median time to response (TTR) was 7.8 months (range, 4-19). The median DOR was not reached (NR). Moreover, 62% of adults with a confirmed response achieved a deep response quantified by over 50% reduction in tumor volume. Within the pediatric population (n = 56), the median duration of treatment was 22 months and the median TTR was 7.9 months (range, 4-19). The median DOR was NR, and 52% of children with a confirmed response achieved a deep response.

Regarding safety in the adult and pediatric populations, the most common treatment-related AEs (TRAEs) in order of frequency were dermatitis acneiform, diarrhea, nausea, vomiting, fatigue, ejection fraction decrease, blood creatinine phosphokinase increase, and paronychia.

Grade 3 or greater TRAEs were infrequent and included dermatitis acneiform (n = 5), fatigue (n = 1), and blood creatinine phosphokinase increase (n = 1) in the adult population, and blood creatinine phosphokinase increase (n = 4), dermatitis acneiform (n = 1), diarrhea (n = 1), and ejection fraction decrease (n = 1), in the pediatric population. Overall, there were 12 treatment-related discontinuations in the adult cohort and 5 in the pediatric cohort.

“Plexiform neurofibromas may sit next to or surround vital organs and can cause serious medical complications for patients. While progress has been made, there remains a pressing need for more treatment options, particularly for adults who currently have no approved therapy,” Annette Bakker, PhD, chief executive officer of the Children’s Tumor Foundation [CTF] and Board Chair of CTF Europe, added in the news release.¹ “CTF is dedicated to deploying its time, talent and funding towards accelerating the development of new treatments. We congratulate our long-term partner SpringWorks on this important milestone, and we are thrilled that patients in the United States and Europe could soon have a new therapy available to them.”

References

1. FDA grants priority review to SpringWorks Therapeutics’ new drug application for mirdametinib for the treatment of adults and children with NF1-PN. News release. SpringWorks Therapeutics, Inc. August 28, 2024. Accessed August 28, 2024. https://ir.springworkstx.com/news-releases/news-release-details/fda-grants-priority-review-springworks-therapeutics-new-drug
2. Moertel CL, Hirbe AC, Shuhaiber HH, et al. ReNeu: a pivotal phase 2b trial of mirdametinib in adults and children with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). J Clin Oncol. 2024;42(suppl 16):3016. doi:10.1200/JCO.2024.42.16_suppl.3016