FDA Initiates Rolling NDA of Mirdametinib in NF1-PN
The FDA has initiated a rolling submission for mirdametinib, an investigational MEK inhibitor, for the treatment of neurofibromatosis type 1-associated plexiform neurofibromas in pediatric and adult patients.
- Phase 2b ReNeu trial (NCT03962543) results support the efficacy of mirdametinib (formerly PD-0325901), demonstrating sustained responses and improvements in patient-reported outcomes (PROs) among treated patients.
- Blinded independent central review (BICR) assessments revealed a significant overall response rate (ORR) in pediatric and adult patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN), along with notable improvements in pain, quality of life, and physical function from baseline.
- SpringWorks Therapeutics expects the completion of the NDA submission to be in the second quarter of 2024.
The FDA has initiated a rolling submission of a new drug application (NDA) for mirdametinib, an investigational MEK inhibitor, for the treatment of pediatric and adult patients with NF1-PN.1
Findings from the phase 2b ReNeu trial (NCT03962543) support this submission as in the trial, those treated with mirdametinib had sustained responses along with enhancements in key secondary PROs.
As of the data cutoff, September 20, 2023, the BICR-assessed confirmed ORR with was 52% with mirdametinib when given to pediatric patients (n = 56) and 41% in adult patients with NF1-PN (n = 58).1,2 All patients, pediatric and adult, had statistically significant enhancements in pain, quality of life, and physical function from baseline. This was all evaluated through various PRO tools.
“There is tremendous potential for mirdametinib to address the substantial needs that exist for children and adults with NF1-PN, and the initiation of our rolling NDA submission brings us one step closer toward our goal of providing these patients with a best-in-class therapy that could make a significant impact on their lives,” Saqib Islam, chief executive officer of SpringWorks, stated in the news release.1
Also at that data cutoff, findings showed additional confirmed ORRs in 1 pediatric patient and 2 adult patients during the long-term follow-up phase of the trial, wherein patients continued to receive mirdametinib treatment. The median best percent change from baseline in target tumor volume was –42% in the pediatric cohort and –41% in the adult cohort. In both cohorts, the median duration of treatment extended to 22 months, with the median duration of response not reached in either group.2
Looking at safety, mirdametinib was generally well tolerated with most adverse effects (AEs) being grade 1 or 2. The most frequently seen AEs included rash, diarrhea, and vomiting in the pediatric cohort, and rash, diarrhea, and nausea in the adult cohort.
SpringWorks expects to complete the NDA submission in the second quarter of 2024.
“We are excited to advance the regulatory filing for our second product and look forward to working closely with the FDA on their review of our application,” said Islam.1
Molecular structure of cancer cells under microscope, realistic macro indoor part of body: ©annamaria - stock.adobe.com
About Mirdametinib
Mirdametinib is a potent, oral, allosteric small molecule inhibitor that works by targeting MEK1 and MEK2, 2 key components of the MAPK pathway. These alterations regulate cell growth and survival.
Trials of mirdametinib as a monotherapy have shown the early efficacy when given as a treatment for patients with NF1-PN and low-grade glioma. The agent has also shown promise when given in combination with other drugs for specific subsets of biomarker-defined metastatic solid tumors.
The FDA previously granted mirdametinib a rare pediatric disease designation in July 2023 for the treatment of NF1. This followed the FDA and the European Commission granting the agent orphan drug designations for the treatment of patients with NF1 in November 2018 and July 2019. Also in 2019, the FDA granted a fast track designation to mirdametinib for those aged 2 and older with NF1-PN that is progressing or causing significant morbidity.
The Phase 2b ReNeu Study
The multicenter, open-label, phase 2b ReNeu study is looking at the efficacy, safety, and tolerability of mirdametinib when given to patients aged 2 years and older with a symptomatic, inoperable NF1-associated PN causing significant morbidity. A total of 114 patients have been enrolled across the pediatric and adult cohorts at 50 sites.3
Patients must have a tumor amenable to volumetric MRI analysis, be willing to undergo a tumor biopsy prior to and following treatment if at least 18 years of age, and have adequate organ and bone marrow function.
Once enrolled, patients were given oral mirdametinib at a twice-daily dose of 2 mg/m2, with a maximum dose of 4 mg twice daily. This was given on a 3-week-on, 1-week-off dosing schedule. For pediatric patients who cannot swallow a pill, mirdametinib has a formulation as a dispersible tablet.
The primary end point of the trial was confirmed ORR and secondary end points are safety, tolerability, duration of response, and changes from baseline in PROs.
ReNeu is currently ongoing and has an estimated study completion date of May 23, 2025.
