SpringWorks Therapeutics, Inc. announced positive topline results from the pivotal Phase 2b ReNeu trial evaluating mirdametinib, an investigational MEK inhibitor, in pediatric and adult patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). The ReNeu trial enrolled 114 patients in two cohorts (pediatric and adult) across 50 sites in the U.S. The primary endpoint was confirmed objective response rate (ORR), defined as >= 20% reduction in target tumor volume as measured by MRI and assessed by Blinded Independent Central Review (BICR). As of the data cutoff date of September 20, 2023, 52% (29/56) of pediatric patients and 41% (24/58) of adult patients had BICR confirmed objective responses within the 24- cycle treatment period (cycle length: 28 days).

An additional pediatric patient and two additional adult patients achieved confirmed objective responses after Cycle 24 in the long-term follow up phase of the trial, where patients continue to receive mirdametinib treatment. Median best percent change from baseline in target tumor volume was -42% and -41% in the pediatric and adult cohort, respectively. As of the data cut-off, the median duration of treatment was 22 months in both the pediatric and adult cohorts.

Median duration of response was not reached in either cohort. Pediatric and adult patients in the ReNeu trial also experienced statistically significant improvements from baseline in pain, quality of life, and physical function, as assessed across multiple patient-reported outcome tools. Mirdametinib was generally well tolerated in the ReNeu trial, with the majority of adverse events (AEs) being Grade 1 or Grade 2. The most frequently reported AEs were rash, diarrhea, and vomiting in the pediatric cohort and rash, diarrhea, and nausea in the adult cohort.

Twenty-five percent of pediatric patients and 16% of adult patients experienced a Grade 3 or higher treatment-related AE. Additional data are expected to be presented at an upcoming medical conference in the first half of 2024 and to be submitted for publication in a peer-reviewed journal. The U.S. Food and Drug Administration (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. In July 2023, FDA granted mirdametinib Rare Pediatric Disease Designation for the treatment of NF1, and as such, if approved, mirdametinib will be eligible to receive a priority review voucher. SpringWorks plans to submit a New Drug Application (NDA) for mirdametinib to the FDA in the first half of 2024.

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 two years of age and older with an inoperable NF1-associated PN causing significant morbidity. The study enrolled 114 patients to receive mirdametinib at a dose of 2 mg/m(2) twice daily (maximum dose of 4 mg twice daily) without regard to food. Mirdametinib is administered orally in a 3-week on, 1-week off dosing schedule and has a pediatric formulation (dispersible tablet) for patients who cannot swallow a pill.

The primary endpoint of the ReNeu trial is confirmed objective response rate defined as >= 20% reduction in target tumor volume as measured by MRI and assessed by blinded independent central review. Secondary endpoints include safety and tolerability, duration of response, and changes from baseline in patient reported outcomes. About NF1-PN Neurofibromatosis type 1 (NF1) is a rare genetic disorder that arises from mutations in the NF1 gene, which encodes for neurofibromin, a key suppressor of the MAPK pathway.

NF1 is the most common form of neurofibromatosis, with an estimated global birth incidence of approximately 1 in 3,000 individuals, and approximately 100,000 patients living with NF1 in the United States. The clinical course of NF1 is heterogeneous and manifests in a variety of symptoms across numerous organ systems, including abnormal pigmentation, skeletal deformities, tumor growth and neurological complications, such as cognitive impairment. Patients with NF1 have an eight to 15-year mean reduction in their life expectancy compared to the general population.

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. Patients with NF1 can also experience additional manifestations, including neurocognitive deficits and developmental delays. NF1-PNs are most often diagnosed in the first two decades of life.

These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood. 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. MEK inhibitors have emerged as a validated class of treatment for NF1- PN.

About Mirdametinib Mirdametinib is a potent, oral, 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 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 that plays a central role in multiple oncology and rare disease indications when genetically altered.