Merck and SpringWorks Secure Conditional EU Approval for EZMEKLY®, the First Therapy for NF1-Associated Plexiform Neurofibromas in Both 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 for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in patients aged two years and older who have been diagnosed with neurofibromatosis type 1 (NF1). This decision marks a significant therapeutic advance, as EZMEKLY is now the first and only treatment approved in the European Union (EU) for both pediatric and adult patients living with NF1-PN.
The marketing authorization was formally granted to SpringWorks Therapeutics Inc., a biopharmaceutical company focused on advancing innovative medicines for severe rare diseases and cancers. SpringWorks, through a strategic partnership with Merck, is working to expand global access to mirdametinib, with Merck leading commercialization efforts in Europe.
Addressing a Lifelong and Debilitating Disease
Neurofibromatosis type 1 is a rare genetic condition characterized by mutations in the NF1 gene, leading to dysregulation of cell growth and tumor development along nerves. One of the most severe manifestations of this condition is the growth of plexiform neurofibromas—complex, often inoperable tumors that can cause disfigurement, functional disability, chronic pain, and life-threatening complications if they transform into malignant peripheral nerve sheath tumors (MPNSTs).
NF1 affects approximately 3 in 10,000 people in the EU, amounting to an estimated 135,000 individuals. Of these, between 30% and 50% will develop plexiform neurofibromas during their lifetime. Due to their infiltrative growth pattern along nerves, approximately 85% of PN cases are not considered suitable for complete surgical resection. This creates a pressing need for systemic therapies that can reduce tumor burden and alleviate symptoms.
A Milestone for the NF1 Community
“This European Commission approval represents a major milestone in the treatment landscape for NF1-PN,” said Dr. Ignacio Blanco, MD, PhD, Chairman of the National Reference Center for Adult Patients with Neurofibromatosis at Hospital Universitari Germans Trias i Pujol in Spain. “For adults especially—who previously had no approved treatment options—this represents a long-awaited breakthrough. The clinical data supporting EZMEKLY is compelling, showing not only tumor shrinkage but also improvements in pain and quality of life. Moreover, the availability of a dispersible tablet formulation provides a practical solution for patients who have difficulty swallowing pills and were previously excluded from treatment.”
Dr. Blanco’s sentiment was echoed by representatives from the global patient advocacy community. Annette Bakker, PhD, Chief Executive Officer of the Children’s Tumor Foundation (CTF), and Dr. Dariusz Adamczewski, Director of CTF Europe, celebrated the approval as a result of collaborative progress.
“This is the kind of transformation that can only happen when researchers, industry leaders, and advocacy organizations come together with a shared mission,” said Dr. Bakker. “EZMEKLY’s approval is not just a regulatory milestone—it’s a signal of hope for patients and families who have waited years for effective treatment options.”
Clinical Data Underpinning the Approval
The EC’s decision to grant conditional marketing authorization for EZMEKLY was based on data from the pivotal Phase 2b ReNeu clinical trial—a multi-center, open-label, single-arm study designed to evaluate the safety, efficacy, and tolerability of mirdametinib in NF1-PN patients aged two years and older.
The trial enrolled a total of 114 patients, including 58 adults and 56 pediatric patients, all of whom had symptomatic, inoperable plexiform neurofibromas. The primary endpoint was the confirmed objective response rate (ORR), as determined by blinded independent central review (BICR). A confirmed response was defined as at least a 20% reduction in target tumor volume, sustained on consecutive imaging scans.
The results were highly encouraging:
- Adults (n=58): The ORR was 41% (24 patients), with a median best percentage change in tumor volume of -41% (range: -90% to +13%).
- Children (n=56): The ORR was 52% (29 patients), with a median best percentage change in tumor volume of -42% (range: -91% to +48%).
In terms of durability, 88% of adult responders and 90% of pediatric responders maintained their response for at least 12 months. Furthermore, 50% of adult responders and 48% of pediatric responders experienced tumor reduction lasting at least 24 months—suggesting the therapy’s long-term clinical benefit.
Equally noteworthy were improvements in patient-reported outcomes. Participants experienced significant and sustained reductions in pain, alongside improvements in functional outcomes and overall quality of life, assessed through validated instruments such as the PROMIS Pain Interference Scale and Pediatric Quality of Life Inventory (PedsQL).
Safety and Tolerability
EZMEKLY demonstrated a manageable safety profile consistent with MEK inhibition. In adult patients, the most commonly reported adverse reactions were:
- Dermatitis acneiform (83%)
- Diarrhea (55%)
- Nausea (55%)
- Increased blood creatine phosphokinase (47%)
- Musculoskeletal pain (41%)
- Vomiting (37%)
- Fatigue (36%)
In pediatric patients, the most frequently observed side effects included:
- Increased blood creatine phosphokinase (59%)
- Diarrhea (53%)
- Dermatitis acneiform (43%)
- Musculoskeletal pain (41%)
- Abdominal pain (40%)
- Vomiting (40%)
- Headache (36%)
These safety outcomes affirm the therapy’s tolerability in both pediatric and adult populations, supporting its long-term use in chronic disease management.
Conditional Approval and What It Means
The EZMEKLYC’s decision to grant conditional marketing authorization reflects the urgent need for treatment in a population with no existing approved therapies. Conditional approvals are granted for therapies that address unmet medical needs, based on less comprehensive data than normally required, but where the benefits of immediate availability outweigh the risks of waiting for more conclusive evidence. Continued authorization will depend on further data confirming EZMEKLY’s benefit-risk profile.
Merck and SpringWorks are committed to meeting these post-approval obligations, including completing confirmatory studies and ongoing pharmacovigilance efforts.
Expanding Access and Impact
“With the conditional approval of EZMEKLY, we are taking a decisive step in addressing the significant unmet needs of NF1-PN patients in Europe,” said Jan Kirsten, Global Head of Rare Tumor Business at Merck’s Healthcare division. “This therapy is a meaningful advancement for a population that has long been underserved. Our next priority is to ensure rapid access to treatment across EU member states through engagement with local health authorities and reimbursement agencies.”
SpringWorks Therapeutics, which holds the global rights to mirdametinib, has previously received U.S. FDA Fast Track and Orphan Drug designations for the drug. The European approval positions the company and its partner Merck as leaders in the emerging field of rare tumor therapeutics.
The approval of EZMEKLY marks a turning point in the treatment of NF1-PN and exemplifies the value of partnerships between pharmaceutical innovators, advocacy organizations, clinicians, and regulatory bodies. For the thousands of patients and families impacted by NF1 across Europe, it offers new hope for improved health and quality of life.
As post-marketing studies continue and more real-world data become available, EZMEKLY is expected to help shape future standards of care in neurofibromatosis—and potentially inform the development of similar therapies targeting other RASopathies and genetically defined tumor syndromes.
