Mirdametinib (MEK Inhibitor)

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Mirdametinib is an 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 (MEK inhibitor)

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.

Mirdametinib in NF1-PN

NF1 is a rare genetic disorder that arises from mutations in the NF1 gene. NF1 is a multisystem disease with clinical manifestations starting as early as infancy and spanning the entire lifetime of affected individuals. Patients with NF1 have a 30% to 50% lifetime risk of developing plexiform neurofibromas (PN), which are peripheral nerve sheath tumors that often result in severe pain, compression of critical organs, impaired physical function, severe disfigurement and decreased quality of life. Plexiform neurofibromas can transform into a devastating malignancy called malignant peripheral nerve sheath tumors (MPNST), resulting in a shortened life span.

A Phase 2 investigator-initiated trial of mirdametinib in adolescents and adults with NF1-PN showed encouraging efficacy along with a generally well-tolerated safety profile.

The Phase 2 study enrolled 19 adolescents and adults with inoperable and symptomatic or growing NF1-PNs and demonstrated objective responses in 42 percent of patients.
The most commonly reported treatment-emergent grade 2 or higher adverse events were acneiform rash, fatigue and nausea. No grade 4 or higher toxicities were reported.

SpringWorks is conducting a multi-center, open-label Phase 2b clinical trial (the ReNeu trial) to evaluate the efficacy, safety, and tolerability of mirdametinib in patients two years of age and older with an inoperable NF1-PN that is causing significant morbidity.

The U.S. Food and Drug Administration (FDA) and the European Commission granted Orphan Drug designation for mirdametinib for the treatment of NF1, and the FDA granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity.

Mirdametinib in metastatic solid tumors

MEK inhibitors hold promise for use as combination therapies for highly prevalent, genetically defined cancers owing to the critical role that the MAPK pathway plays in the growth and proliferation of many cancer types (including lung cancer, melanoma, pancreatic cancer, colorectal cancer, endometrial cancer, and ovarian cancer).

A Phase 1b/2 clinical trial is being conducted in collaboration with BeiGene to evaluate mirdametinib in combination with lifirafenib, a RAF dimer inhibitor, in patients with advanced or refractory solid tumors that harbor RAS mutations, RAF mutations, and other MAPK pathway aberrations.

In addition, under a SpringWorks-supported investigator-initiated clinical trial agreement with Memorial Sloan Kettering Cancer Center, a Phase 1b/2a study will evaluate mirdametinib in combination with fulvestrant, a selective estrogen receptor degrader, in patients with ER+ metastatic breast cancer harboring NF1 loss-of-function or other alterations of the MAPK pathway, and as a monotherapy in adult patients with advanced solid cancers harboring MEK1 or MEK2 mutations.

Read more in these key publications


Combination Therapy in MAPK Mutated Solid Tumors