On August 28, 2024 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported that the U.S. Food and Drug Administration (FDA) has accepted the Company’s 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) (Press release, SpringWorks Therapeutics, AUG 28, 2024, View Source [SID1234646164]). The NDA was granted Priority Review and has been given a Prescription Drug User Fee Act (PDUFA) action date of February 28, 2025. In addition, the FDA has stated that it is not currently planning to hold an advisory committee meeting to discuss the application. SpringWorks also announced today that the European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for mirdametinib for the treatment of adult and pediatric patients with NF1-PN. Mirdametinib has the potential to be the first approved therapy for the treatment of adult patients and a best-in-class therapy for children with NF1-PN.
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"These significant milestones bring us closer to our goal of delivering a transformative medicine to both adults and children with NF1-PN in the U.S. and Europe," said Saqib Islam, Chief Executive Officer of SpringWorks. "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."
The FDA grants Priority Review to applications for medicines that offer, if approved, significant improvements over available options or that provide a treatment option where no adequate therapy currently exists. The FDA and the European Commission have previously granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for the treatment of 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.
"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," said Annette Bakker, Ph.D., Chief Executive Officer of the Children’s Tumor Foundation (CTF) and Board Chair of CTF Europe. "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."
Both submissions include data from the pivotal Phase 2b ReNeu trial, which evaluated mirdametinib in patients ≥ 2 years of age with NF1-associated PN causing significant morbidity. Results were presented in an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and demonstrated that mirdametinib treatment resulted in robust objective response rates confirmed by blinded independent central review, deep and durable responses, improvement in pain and health-related quality of life as well as a manageable safety profile across both the adult and pediatric cohorts.1
About the ReNeu Trial
ReNeu (NCT03962543) is an ongoing, multi-center, open-label Phase 2b trial evaluating the efficacy, safety, and tolerability of mirdametinib in patients ≥ 2 years of age with an inoperable NF1-associated PN causing significant morbidity. The study enrolled 114 patients to receive mirdametinib at a dose of 2 mg/m2 twice daily (maximum dose of 4 mg twice daily) without regard to food. Mirdametinib was administered orally in a 3-week on, 1-week off dosing schedule as either a capsule or dispersible tablet. The primary endpoint is confirmed objective response rate assessed by proportion of patients with ≥ 20% reduction in target tumor volume on consecutive scans during the 24 cycle treatment phase, as measured by MRI and assessed by blinded independent central review. Secondary endpoints include safety and tolerability, duration of response, and changes in patient reported outcomes from baseline to Cycle 13. The treatment phase of the trial is complete and results were presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. Patients who completed the treatment phase were eligible to continue receiving treatment in the optional long-term follow up portion of the study, which is ongoing.
About NF1-PN
Neurofibromatosis type 1 (NF1) is a rare genetic disorder that arises from loss-of-function variants in the NF1 gene, which encodes for neurofibromin, a key suppressor of the MAPK pathway.2,3 NF1 is the most common form of neurofibromatosis, with an estimated global birth incidence of approximately 1 in 2,500 individuals, and approximately 100,000 patients living with NF1 in the United States.4,5 The clinical course of NF1 is heterogeneous and manifests as a variety of symptoms across numerous organ systems, including abnormal skin pigmentation, skeletal deformities, tumor growth, and neurological complications such as cognitive impairment.6 Patients with NF1 have an 8 to 15-year mean reduction in their life expectancy compared to the general population.3
NF1 patients have approximately a 30-50% lifetime risk of developing plexiform neurofibromas, or PN, which are tumors that grow in an infiltrative pattern along the peripheral nerve sheath and that can cause severe disfigurement, pain and functional impairment; in rare cases, NF1-PN may be fatal.7,8 NF1-PNs are most often diagnosed in the first two decades of life.7 These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood.9,10 Surgical removal of these tumors is challenging due to the infiltrative tumor growth pattern along nerves and can lead to permanent nerve damage and disfigurement.11 MEK inhibitors have emerged as a validated class of treatment for NF1-PN.12
About Mirdametinib
Mirdametinib is a potent, oral, CNS-penetrant, allosteric small molecule MEK inhibitor in development as a monotherapy treatment for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and low-grade glioma (LGG), and as a combination therapy for the treatment of several subsets of biomarker-defined metastatic solid tumors. Mirdametinib is an investigational drug for which safety and efficacy have not been established.
Mirdametinib is designed to inhibit MEK1 and MEK2, which occupy pivotal positions in the MAPK pathway. The MAPK pathway is a key signaling network that regulates cell growth and survival and plays a central role in multiple cancers and rare diseases when genetically altered.
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 the treatment of 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.