European Commission Grants Conditional Approval of EZMEKLY for Treatment of NF1-Associated Plexiform Neurofibromas in Adults and Children
Merck, a global leader in science and technology, announced that the European Commission (EC) has granted conditional marketing authorization for EZMEKLY® (mirdametinib), a breakthrough therapy developed for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in individuals with neurofibromatosis type 1 (NF1) aged 2 years and older. This decision marks a significant milestone in the field of rare diseases, making EZMEKLY the first and only therapy approved in the European Union (EU) for both pediatric and adult patients suffering from this debilitating genetic disorder.
The marketing authorization was granted to SpringWorks Therapeutics Inc., a healthcare company that is part of Merck’s broader portfolio focused on rare diseases and precision medicine. With this approval, patients across the EU now have access to a targeted treatment option that addresses a critical unmet medical need in NF1-PN, a condition previously lacking adequate therapeutic interventions, especially for adults.
Understanding NF1 and Plexiform Neurofibromas
Neurofibromatosis type 1 (NF1) is a complex, lifelong genetic disorder that affects approximately 3 in every 10,000 individuals in the European Union, translating to around 135,000 people. NF1 is caused by mutations in the NF1 gene, which encodes neurofibromin, a protein that helps regulate cell growth. Deficiency of this protein leads to the formation of various types of tumors along the nervous system.
Among the most debilitating manifestations of NF1 are plexiform neurofibromas (PN)—large, often painful, and disfiguring tumors that grow along peripheral nerves in a highly infiltrative manner. These tumors can occur in about 30% to 50% of patients with NF1 during their lifetime. Unlike some superficial neurofibromas, plexiform neurofibromas are deep-seated and can cause significant morbidity, including pain, motor dysfunction, disfigurement, and even life-threatening complications. In some cases, PNs may undergo malignant transformation into malignant peripheral nerve sheath tumors (MPNSTs), a rare and aggressive form of cancer.
Due to the complex growth patterns of these tumors, surgical removal is often not feasible. It is estimated that up to 85% of plexiform neurofibromas are not amenable to complete surgical resection, underscoring the pressing need for effective systemic therapies.
A New Standard of Care: EZMEKLY (Mirdametinib)
EZMEKLY (mirdametinib) is a selective MEK1/2 inhibitor, designed to block a key pathway that promotes abnormal cell growth in NF1-related tumors. By targeting the mitogen-activated protein kinase (MAPK) pathway, EZMEKLY addresses the molecular basis of tumor development in NF1 patients, offering a targeted approach to treatment.
The EC’s conditional approval is primarily based on data from the ReNeu trial, a pivotal Phase 2b clinical study that demonstrated the efficacy and safety of EZMEKLY in both adult and pediatric populations. The open-label, multicenter, single-arm study enrolled 114 patients aged 2 years and older, including 58 adults and 56 children. All participants had confirmed symptomatic, inoperable PN.
Clinical Trial Results
The ReNeu trial achieved its primary endpoint, with objective response rates (ORRs) confirmed by blinded independent central review. The study showed:
- 41% ORR in adults (24 of 58 patients)
- 52% ORR in children (29 of 56 patients)
In addition to tumor shrinkage, the median best percentage change in target PN volume was:
- -41% in adults (ranging from -90% to +13%)
- -42% in children (ranging from -91% to +48%)
These reductions in tumor volume were accompanied by significant and sustained improvements in pain and quality of life, as reported by patients using validated outcome measurement tools. Among responders, 88% of adults and 90% of children maintained their tumor response for at least 12 months, while about half (50% of adults and 48% of children) had a response lasting 24 months or longer.
Safety and Tolerability
EZMEKLY demonstrated a manageable safety profile, with adverse effects consistent with MEK inhibition and generally well-tolerated across age groups.
In adult patients, the most commonly reported side effects included:
- Dermatitis acneiform (83%)
- Diarrhea (55%)
- Nausea (55%)
- Increased blood creatine phosphokinase (CPK) levels (47%)
- Musculoskeletal pain (41%)
- Vomiting (37%)
- Fatigue (36%)
In pediatric patients, the most common adverse reactions were:
- Increased blood CPK (59%)
- Diarrhea (53%)
- Dermatitis acneiform (43%)
- Musculoskeletal pain (41%)
- Abdominal pain (40%)
- Vomiting (40%)
- Headache (36%)
Importantly, the therapy is available in a tablet form that dissolves in water, making it accessible to patients—especially children—who may have difficulty swallowing pills, a key advantage over some existing medications.
A Landmark Moment for the NF1 Community
The approval of EZMEKLY has been widely hailed by the medical and patient advocacy communities.
“Patients with NF1-PN often face physical and mental health challenges and impaired quality of life given the limited treatment options available for this lifelong and debilitating disease,” said Dr. Ignacio Blanco, Chairman of the National Reference Center for Adult Patients with Neurofibromatosis at Hospital Universitari Germans Trias i Pujol in Spain. “This approval represents an important advance, especially for adults who previously did not have an approved treatment.”
“This is the kind of progress that happens when researchers, industry and organizations like ours work together with a shared focus on delivering new treatments for patients,” added Dr. Annette Bakker, CEO of the Children’s Tumor Foundation (CTF), and Dr. Dariusz Adamczewski, Director of CTF Europe.
From a corporate perspective, the decision underscores Merck’s commitment to addressing rare diseases and delivering life-changing therapies to underserved populations.
“Bringing innovation to patients living with rare tumors around the world is a clear reflection of our focus on addressing significant unmet needs,” said Jan Kirsten, Global Head of Rare Tumor Business at Merck. “With the European approval of EZMEKLY, we are taking a major step toward improving care for this underserved community.”
