FDA Approves Mirdametinib for Neurofibromatosis Type 1-Associated Plexiform Neurofibromas

On February 11, 2025, the US Food and Drug Administration (FDA) approved a medicine developed by SpringWorks Therapeutics containing mirdametinib and marketed as Gomekli . This kinase inhibitor is indicated for adults and children aged 2 years and older with symptomatic NF1-associated plexiform neurofibromas (PN) that cannot be completely surgically removed.

A New Medicine for a Rare Inherited Disease

Neurofibromatosis type 1 (NF1) is a genetic disease affecting the central nervous system. It may cause symptomatic plexiform neurofibromas (PN), tumors that cannot be completely removed surgically and can create serious problems. Limited treatment options make new approaches an important clinical need.

What Are Neurofibromatosis Type 1 (NF1) and Plexiform Neurofibromas?

Neurofibromatosis type 1 (NF1) is caused by changes in the NF1 gene, specifically mutations , and is an autosomal dominant inherited disease. It causes benign tumors in nerve tissue. Café-au-lait skin spots, nerve-derived tumors, and skeletal abnormalities are common in NF1.

Plexiform neurofibromas are nerve-derived tumors, generally present from birth, that surround nerves. Although benign, they can grow aggressively, often cannot be completely removed, and may cause functional impairment over time.

Selumetinib Had Previously Received FDA Approval for Symptomatic NF1-Associated PN

Mirdametinib is not the first approved treatment for symptomatic plexiform neurofibromas (PN) associated with neurofibromatosis type 1 (NF1).

• Selumetinib (Koselugo™) was the first MEK inhibitor approved by the FDA in 2020 .
• Developed by AstraZeneca and Merck (MSD), selumetinib was approved for inoperable NF1-associated PN in children aged 2 and older.
• Mechanism: Selumetinib inhibits MEK1 and MEK2, blocking RAS/MAPK signaling and slowing tumor growth.

What Makes Mirdametinib Different?

1. Mirdametinib is the first MEK inhibitor approved for adults as well as children.
2. It may be better tolerated and is presented as a once-daily oral option.
3. It is viewed as an alternative to selumetinib with potentially fewer side effects.

In summary, it is not the first treatment approved, but is the first MEK inhibitor approved for adults and offers another option for patients with NF1.

FDA Approval Based on ReNeu

Efficacy was evaluated in ReNeu (NCT03962543), involving 114 patients: 58 adults and 56 children. Participants had PN that could not be completely removed and caused substantial morbidity.

Primary Efficacy Outcome: Overall Response Rate (ORR)

The primary measure was ORR, defined as the percentage with complete disappearance of the target PN or at least a 20% reduction in volume. Results were:

1. Adults: ORR 41% (confidence interval: 29% - 55%)
2. Children: ORR 52% (confidence interval: 38% - 65%)

Independent central review assessed responses using volumetric MRI and neurofibromatosis and schwannomatosis response criteria.

Side Effects and Safety

Common adverse reactions, occurring in ≥25%, included:

Adults:

• Rash
• Diarrhea
• Nausea
• Musculoskeletal pain
• Vomiting
• Fatigue

Children:

• Rash
• Diarrhea
• Musculoskeletal pain
• Abdominal pain
• Vomiting
• Headache
• Nail-bed infections (paronychia)
• Left ventricular dysfunction
• Nausea

The most common severe (Grade 3 or 4) laboratory abnormalities were:

• Adults: Increased creatine phosphokinase (≥2%)
• Children: Decreased neutrophils and increased creatine phosphokinase (≥2%)

Serious effects may also include left ventricular dysfunction and ocular toxicities such as retinal vein occlusion, retinal pigment epithelial detachment, and blurred vision. Depending on severity, treatment may be withheld, reduced, or permanently discontinued.

How Does Mirdametinib Work?

Mirdametinib is a small-molecule targeted therapy with MEK1 and MEK2 kinase-inhibiting activity. MEK (mitogen-activated protein kinase kinase) is an important component of RAS/MAPK signaling that regulates critical processes such as proliferation, differentiation, and cell survival.

How Mirdametinib Acts

• RAS/MAPK Pathway Activation
  • NF1 encodes neurofibromin , a tumor-suppressor protein.
  • NF1 mutations cause loss of neurofibromin function in cells.
  • This loss leads to excessive RAS protein activation and signaling.
  • Consequently, the downstream RAF-MEK-ERK pathway remains continuously active.
• Suppressing Tumor Growth Through MEK Inhibition
  • Mirdametinib acts by inhibiting MEK1 and MEK2 , which reduces ERK phosphorylation in cells.
  • Reduced ERK activity slows proliferation and suppresses tumor growth.
  • It may also cause cell-cycle arrest and apoptosis, or programmed cell death.
• Selective, Sustained MEK Blockade
  • MEK inhibitors are particularly effective for unresectable tumors such as NF1-associated plexiform neurofibromas (PN) in affected patients.
  • Mirdametinib's high selectivity and oral bioavailability may make it more effective and better tolerated than other MEK inhibitors.

Conclusion and Clinical Significance

FDA approval represents an important advance for patients with symptomatic NF1-associated PN.

The new option offers hope for reducing tumor volume and symptoms when surgery is unsuitable. However, serious side effects require close monitoring.

This approval is a major step toward better quality of life in NF1 and provides a foundation for future kinase inhibitor research.