Acadia Pharmaceuticals plans to challenge the negative opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use regarding trofinetide for patients with Rett syndrome aged two and older.
Acadia Pharmaceuticals Inc.has announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has formally adopted a negative opinion on the company’s Marketing Authorization Application (MAA) for trofinetide for the treatment of Rett syndrome in patients aged two years and older. The decision represents a significant regulatory hurdle for the company’s efforts to expand access to the therapy across the European Union. However, Acadia has confirmed that it intends to request a formal re-examination of the opinion, signaling its commitment to pursuing approval for the treatment in Europe.
CHMP Opinion and Grounds for Refusal
The CHMP’s negative recommendation follows its review of data submitted in support of trofinetide, including results from the pivotal Phase 3 LAVENDER™ trial. While the study successfully met its co-primary and key secondary endpoints, the CHMP cited several concerns that ultimately led to its refusal recommendation.
According to Acadia, the CHMP viewed the magnitude of treatment effect observed with trofinetide after 12 weeks as limited, despite being statistically measurable and clinically meaningful in the context of a complex neurodevelopmental disorder such as Rett syndrome. Additionally, the committee expressed concerns that the clinical trial did not fully capture all core symptoms associated with Rett syndrome, a multifaceted condition characterized by a wide range of neurological and developmental impairments.
Another factor highlighted in the CHMP’s assessment was the evaluation of longer-term outcomes. The committee noted that patient discontinuations over time may have influenced the interpretation of extended efficacy and safety data. These discontinuations, which are not uncommon in long-term studies involving rare and severe disorders, were viewed as potentially impacting the robustness of long-term conclusions.
Acadia stated that it has carefully reviewed the CHMP’s grounds for refusal and considers the feedback valuable as it prepares its re-examination request. The company believes that further dialogue with European regulators may help address outstanding questions and clarify aspects of the clinical data that support trofinetide’s benefit-risk profile.
Company Response and Commitment to Patients
Catherine Owen Adams, Chief Executive Officer of Acadia, expressed disappointment with the CHMP’s recommendation but reaffirmed the company’s confidence in trofinetide’s therapeutic value.
She emphasized that trofinetide has demonstrated meaningful benefits for individuals living with Rett syndrome and noted the strong engagement and positive feedback from patients, caregivers, and clinicians within the Rett community. According to Adams, this real-world experience reinforces Acadia’s belief that the therapy represents an important advancement for a population with profound unmet medical needs.
The company underscored its intention to work constructively with European regulators during the re-examination process. This formal procedure allows applicants to request a renewed review of a CHMP opinion, during which additional analyses, clarifications, or data interpretations may be considered.
Caregiver Perspective
The reaction within the Rett community reflects both disappointment and hope. Markus Schulze, a caregiver and member of the Rett Syndrome Society Nordrhein-Westfalen in Germany, shared his perspective on the importance of access to new treatment options.
He highlighted the daily challenges faced by individuals living with Rett syndrome and the families who support them. For caregivers, therapies that offer even incremental improvements in communication, motor function, or quality of life can represent meaningful progress. Schulze expressed hope that trofinetide will ultimately receive approval in the European Union, enabling broader access for patients across member states.
Trofinetide’s Current Regulatory Status
Despite the setback in Europe, trofinetide has achieved regulatory success in other regions. The therapy is approved in the United States, Canada, and Israel, where it is recognized as the first and only approved treatment specifically indicated for Rett syndrome. These approvals marked a milestone in the management of a disorder that, until recently, had no disease-specific pharmacological options.
Trofinetide is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor 1 (IGF-1). In preclinical studies, it has been shown to enhance dendritic branching and support synaptic plasticity signals. Because Rett syndrome is associated with impaired synaptic communication and reduced brain plasticity, therapies targeting these mechanisms are considered scientifically promising.
Understanding Rett Syndrome
Rett syndrome is a rare and complex neurodevelopmental disorder that primarily affects females, occurring in approximately one in every 10,000 to 15,000 live female births worldwide. The condition is typically caused by mutations in the MECP2 gene, which plays a critical role in regulating gene expression in the brain.
Children with Rett syndrome often experience an initial period of apparently normal development during the first six to 18 months of life. This early stability is followed by developmental stagnation and regression. During the regression phase, affected children lose previously acquired skills, including purposeful hand use and spoken communication. Repetitive hand movements—such as hand wringing or clapping—commonly emerge, along with gait abnormalities and impaired motor coordination.
After this regression period, individuals may enter a plateau phase, during which cognitive interest may show slight improvement. However, severe motor impairments typically persist. As patients age, they may experience progressive motor deterioration, often requiring lifelong, intensive, round-the-clock care.
The burden of Rett syndrome extends beyond motor and communication challenges. Many individuals experience seizures, breathing irregularities, gastrointestinal complications, and scoliosis. Given the broad spectrum of symptoms and the lifelong nature of the condition, therapeutic development has historically been challenging.
Acadia’s Broader Mission and Pipeline
Acadia’s pursuit of trofinetide in Europe aligns with its broader mission to address unmet needs in neurological and rare diseases. The company’s commercial portfolio includes FDA-approved treatments for Parkinson’s disease psychosis and Rett syndrome in the United States. Beyond its marketed therapies, Acadia maintains a pipeline of mid- to late-stage development programs targeting Alzheimer’s disease psychosis and Lewy body dementia psychosis, as well as earlier-stage programs for additional underserved conditions.
The company positions itself as focused on translating scientific discoveries into meaningful therapies for patients who often have limited options. Its ongoing engagement with regulators across global markets reflects a strategy aimed at expanding access to innovative treatments where significant unmet needs remain.
Next Steps
The re-examination process with the CHMP will be a critical next step for Acadia’s European ambitions for trofinetide. During this phase, the company will have the opportunity to address the committee’s concerns, potentially provide further analyses of clinical data, and clarify interpretations regarding treatment effect magnitude and long-term outcomes.
While the timeline for re-examination has not been specified, such reviews typically involve additional scientific dialogue before a final opinion is issued. For patients and families in Europe, the outcome will determine whether trofinetide becomes available as a treatment option within the EU.
Despite the regulatory setback, Acadia remains publicly committed to advancing trofinetide and to supporting the Rett syndrome community. The company’s leadership maintains that the therapy represents a meaningful step forward in addressing the complex challenges of this rare neurodevelopmental disorder, and it intends to continue working toward broader global access.
