FDA Approval Sought for Mirdametinib in NF1-PN

Rolling submission of a new drug application (NDA) to the FDA has been initiated for the investigational MEK inhibitor mirdametinib (formerly PD-0325901) in pediatric and adult patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN), according to a press release from SpringWorks Therapeutics.¹

The NDA submission is supported by data from the phase 2b ReNeu trial (NCT03962543), in which treatment with mirdametinib generated profound and sustained responses, with notable enhancements in key secondary patient-reported outcomes (PROs). At a data cutoff of September 20, 2023, the blinded independent central review (BICR)–assessed confirmed overall response rate (ORR) with mirdametinib was 52% in pediatric patients (n = 56) and 41% in adult patients with NF1-PN (n = 58).^1,2 Moreover, both pediatric and adult patients experienced statistically significant enhancements in pain, quality of life, and physical function from baseline, as evaluated through various PRO tools.

Mirdametinib was generally well tolerated, with primarily grade 1/2 adverse effects (AEs) reported. The most commonly reported AEs were rash, diarrhea, and vomiting in the pediatric cohort, and rash, diarrhea, and nausea in the adult cohort.¹

SpringWorks expects to complete the NDA submission in the second quarter of 2024.

“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. “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.”

Mirdametinib has demonstrated early efficacy as a monotherapy for both NF1-PN and low-grade glioma, as well as in combination regimens for specific subsets of biomarker-defined metastatic solid tumors. The potent, oral, allosteric small molecule inhibitor targets MEK1 and MEK2, which are crucial components of the MAPK pathway. Alterations in this signaling network, which regulates cell growth and survival, are implicated in various oncology and rare disease indications.¹

In July 2023, the FDA granted mirdametinib rare pediatric disease designation for the treatment of NF1, which provides eligibility for a priority review voucher upon FDA approval. This designation occurred following orphan drug designations for the drug for the treatment of patients with NF1 by the FDA and the European Commission in November 2018 and July 2019, respectively.^3,4

In 2019, the FDA also granted fast track designation to mirdametinib for the treatment of patients 2 years of age or older with NF1-PN that is progressing or causing significant morbidity.³

ReNeu is a multicenter, open-label study evaluating the efficacy, safety, and tolerability of mirdametinib in patients 2 years of age and older with a symptomatic, inoperable NF1-associated PN causing significant morbidity. Other key inclusion criteria were a target tumor that is amenable to volumetric MRI analysis, willingness to undergo a tumor biopsy before and after treatment if at least 18 years of age, and adequate organ and bone marrow function.^1,5

The trial is being conducted across 50 sites in the United States and has enrolled 114 patients across pediatric and adult cohorts.¹ All patients on the study received oral mirdametinib at a twice-daily dose of 2 mg/m², with a maximum dose of 4 mg twice daily, on a 3-week-on, 1-week-off dosing schedule. Mirdametinib also has a pediatric formulation as a dispersible tablet for patients who cannot swallow a pill.

The primary end point was confirmed ORR, defined as a 20% or greater reduction in target tumor volume measured by MRI and assessed by BICR. Secondary end points include safety and tolerability, duration of response (DOR), and changes from baseline in PROs. Eligible participants may continue in a long-term follow-up phase.⁵

Additional findings at the last data cutoff demonstrated additional confirmed ORRs after cycle 24 in 1 pediatric patient and 2 adult patients in the long-term follow-up phase of the trial, where patients continue to receive mirdametinib treatment.² The median best percent change from baseline in target tumor volume was –42% in the pediatric cohort and –41% in the adult cohort. The median duration of treatment was 22 months in both the pediatric and adult cohorts, and the median DOR was not reached in either cohort.²

The study is currently ongoing, with an estimated completion date of May 23, 2025.⁵

References

1. SpringWorks Therapeutics initiates rolling submission of new drug application to the FDA for mirdametinib for the treatment of children and adults with NF1-PN. News release. SpringWorks Therapeutics. March 4, 2024. Accessed March 4, 2024. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-initiates-rolling-submission-new-drug
2. SpringWorks Therapeutics announces positive topline results from the phase 2b ReNeu trial of mirdametinib in NF1-PN. News release. SpringWorks Therapeutics. November 16, 2023. Accessed March 4, 2024. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-announces-positive-topline-results
3. SpringWorks Therapeutics announces FDA fast track designation for PD-0325901 for the treatment of a severe form of neurofibromatosis type 1. SpringWorks Therapeutics. June 3, 2019. Accessed March 4, 2024. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-announces-fda-fast-track-designation-pd
4. European Commission grants orphan drug designation for SpringWorks Therapeutics’ MEK inhibitor, mirdametinib, for the treatment of neurofibromatosis type 1. News release. SpringWorks Therapeutics. July 30, 2019. Accessed March 4, 2024. https://ir.springworkstx.com/news-releases/news-release-details/european-commission-grants-orphan-drug-designation-springworks
5. MEK inhibitor mirdametinib (PD-0325901) in patients with neurofibromatosis type 1 associated plexiform neurofibromas (ReNeu). ClinicalTrials.gov. Updated December 13, 2023. Accessed March 4, 2024. https://clinicaltrials.gov/study/NCT03962543