Acadia planning to challenge CHMP’s rejection of trofinetide for Rett syndrome

Acadia Pharmaceuticals revealed that Daybue (trofinetide), the first and only approved therapy for Rett syndrome in the United States, Canada, and Israel, has received a negative opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP). Acadia, which holds North American rights to trofinetide for Rett syndrome treatment, issued a statement indicating it will request a re-examination of the CHMP’s formal refusal. The decision creates a divergence between regulators on opposite sides of the Atlantic over the clinical value of the only pharmacotherapy developed specifically for a disorder that affects approximately one in every 10,000 to 15,000 female births worldwide.

The CHMP’s rational for refusal

The CHMP did not dispute that the pivotal LAVENDER Phase III trial met its statistical endpoints. However, the committee raised concerns about the overall magnitude and durability of benefit.

According to the agency’s assessment, the treatment effect observed at 12 weeks was measurable but modest. Regulators also noted that the study’s endpoints did not capture all core symptoms of Rett syndrome, particularly motor and communication impairments. In addition, interpretation of longer-term outcomes in the open-label extension study (LILAC) was complicated by patient discontinuations over time, limiting conclusions about sustained clinical benefit.

Acadia said it will seek a re-examination of the decision, a process that allows the CHMP to reconsider the application with additional expert input.

Evidence from the LAVENDER trial

The US FDA approved trofinetide in March 2023 based on the Phase III LAVENDER trial, a randomized, double-blind, placebo-controlled study in patients aged two years and older with Rett syndrome. The trial evaluated two co-primary endpoints at week 12: the Rett Syndrome Behaviour Questionnaire (RSBQ), a caregiver-reported measure of disease symptoms, and the Clinical Global Impression–Improvement (CGI-I) scale, a clinician-rated global assessment. Both endpoints showed statistically significant improvement compared with placebo.

The safety profile was dominated by gastrointestinal adverse events. Diarrhea was the most common side effect and the leading cause of treatment discontinuation, while vomiting and decreased appetite were also reported more frequently in treated patients.

The differing conclusions reached by the US FDA and the EMA highlight contrasting regulatory approaches to evaluating clinical meaningfulness in rare diseases, where trials are constrained by small patient populations and heterogeneous symptom presentation.

Trofinetide’s development and current outlook

Trofinetide is a synthetic analog of a naturally occurring fragment of insulin-like growth factor-1 (IGF-1). Rather than targeting the underlying MECP2 gene mutation that causes Rett syndrome, the drug acts downstream by modulating neuroinflammation and supporting synaptic function.

Preclinical research suggests the compound may improve neuronal connectivity and synaptic signaling deficits associated with MeCP2 dysfunction. The drug is administered as a twice-daily oral solution.

The molecule was originally discovered by Neuren Pharmaceuticals, which licensed North American rights to Acadia in 2018 while retaining rights in other territories.

The CHMP decision means that no disease-specific therapy remains approved in Europe for Rett syndrome, where treatment continues to rely on supportive care such as physical therapy, nutritional management, and treatment of comorbidities including epilepsy.

Meanwhile, several investigational therapies are advancing through clinical development. These include gene therapies such as NGN-401 from Neurogene and TSHA-102 from Taysha Gene Therapies, as well as small-molecule approaches including blarcamesine from Anavex Life Sciences. Whether trofinetide ultimately reaches the European market will depend on the outcome of Acadia’s re-examination request and the EMA’s reassessment of the clinical evidence.