The European Commission has granted conditional approval for Ezmekly (mirdametinib), marking a significant milestone as the first therapy approved for both adults and children with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). The approval, based on a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) adopted on May 22, 2025, addresses a critical unmet medical need for patients with symptomatic, inoperable tumors.
Clinical Trial Results Drive Approval
The European Commission's decision is based on results from the ongoing ReNeu Phase 2b trial, a multi-center, open-label, single-arm study that enrolled 114 patients with NF1-PN aged 2 years or older, including 58 adults and 56 pediatric patients. The study met its primary endpoint of confirmed objective response rate (ORR), demonstrating clinically meaningful tumor reductions across both age groups.
In adults, the confirmed ORR reached 41% (24 out of 58 patients), while pediatric patients showed an even higher response rate of 52% (29 out of 56 patients). The median best percentage change in target plexiform neurofibroma volume was -41% in adults (range: -90% to 13%) and -42% in children (range: -91% to 48%).
The durability of responses proved particularly encouraging, with 88% of adults and 90% of children maintaining responses for at least 12 months. Additionally, 50% of adults and 48% of children sustained responses for at least 24 months. Both adult and pediatric patients experienced early and sustained improvements in pain and quality of life across multiple patient-reported outcome measures.
Mechanism of Action and Dosing
Ezmekly's active substance, mirdametinib, functions as a selective, non-competitive mitogen-activated protein kinase 1 and 2 (MEK 1/2) inhibitor. By inhibiting MEK, mirdametinib blocks the proliferation and survival of tumor cells in which the rapidly accelerated fibrosarcoma (RAF)-MEK-extracellular related kinase (ERK) pathway is activated.
The drug is administered orally at a dose of 2 mg/m² twice daily (maximum dose of 4 mg twice daily) in a 3-week on, 1-week off dosing schedule. Ezmekly is available in 1 mg and 2 mg hard capsules and 1 mg dispersible tablets that dissolve easily in water, providing flexibility for different patient populations.
Safety Profile and Management
Ezmekly demonstrated a manageable safety and tolerability profile across both age groups. In adults, the most common adverse reactions included dermatitis acneiform (83%), diarrhea (55%), nausea (55%), blood creatine phosphokinase increased (47%), musculoskeletal pain (41%), vomiting (37%), and fatigue (36%).
Pediatric patients experienced blood creatine phosphokinase increased (59%), diarrhea (53%), dermatitis acneiform (43%), musculoskeletal pain (41%), abdominal pain (40%), vomiting (40%), and headache (36%) as the most common adverse reactions.
The approval includes important safety considerations requiring monitoring. Ocular toxicity, including retinal vein occlusion and retinal pigment epithelial detachment, was commonly reported in adult patients. Comprehensive ophthalmological evaluations are required before treatment initiation, at regular intervals during treatment, and whenever patients report visual changes.
Additionally, asymptomatic decreases in left ventricular ejection fraction of ≥10% from baseline occurred in 17% of adult patients and 27% of pediatric patients. Regular cardiac monitoring through echocardiograms is mandated every three months during the first year of treatment.
Addressing Unmet Medical Need
Neurofibromatosis type 1 affects approximately 3 in 10,000 people in the European Union, representing an estimated 135,000 individuals. Patients with NF1 have a 30% to 50% lifetime risk of developing plexiform neurofibromas, which are tumors that grow in an infiltrative pattern along peripheral nerve sheaths and can cause severe disfigurement, pain, and functional impairment.
These tumors present significant treatment challenges, as up to approximately 85% of plexiform neurofibromas are considered not amenable to complete surgical resection due to their infiltrative growth pattern along nerves, which can lead to permanent nerve damage and disfigurement.
"Bringing innovation to patients living with rare tumors around the world is a clear reflection of our focus on addressing significant unmet needs and transforming outcomes for patients and families," said Jan Kirsten, Global Head of Rare Tumor Business at SpringWorks Therapeutics. "With the European approval of EZMEKLY, the first therapy approved for both adults and children with NF1-PN, we are taking a major step toward improving care for this underserved community."
Treatment Implementation
The full indication specifies that Ezmekly as monotherapy is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas in pediatric and adult patients with neurofibromatosis type 1 aged 2 years and above. Treatment initiation must be supervised by physicians experienced in the diagnosis and treatment of patients with NF1-related tumors.
The conditional approval reflects the European Medicines Agency's recognition of the significant unmet medical need in this rare disease population, allowing earlier patient access while additional data continue to be collected from ongoing studies.
