Trofinetide is the first medication specifically approved by the United States Food and Drug Administration (FDA) for Rett syndrome, a complex neurological disorder. Its approval offers a dedicated therapeutic option, providing new hope for patients and their families.
What is Trofinetide and What Does It Treat?
Trofinetide is a synthetic analog of glycine-proline-glutamate (GPE), a tripeptide found naturally in the brain. It treats Rett syndrome in adult and pediatric patients aged two years and older. Rett syndrome is a rare, severe neurodevelopmental disorder primarily affecting girls, typically manifesting after 6 to 18 months of normal development. The disorder causes a progressive loss of acquired communication skills and purposeful hand use, often leading to repetitive hand movements. Individuals experience developmental regression, including problems with walking, intellectual disability, and communication difficulties.
How Does Trofinetide Work?
The exact mechanism of action for trofinetide in treating Rett syndrome is not fully understood, but it is believed to involve multiple pathways. As a derivative of glycine-proline-glutamate (GPE), which is a product of insulin-like growth factor 1 (IGF-1) cleavage, trofinetide is thought to mimic GPE’s neuroprotective properties. It is hypothesized to work by modulating synaptic function, which is the communication between brain cells. Trofinetide also appears to reduce neuroinflammation, a process where the brain’s immune cells become overactive. Furthermore, it is thought to promote neuronal maturation and enhance neuroplasticity, the brain’s ability to reorganize and form new connections. These combined actions may contribute to alleviating symptoms of Rett syndrome by protecting neurons, improving communication pathways, and potentially enhancing motor skills and behavioral aspects.
Clinical Efficacy and Safety Profile
The approval of trofinetide was largely based on findings from the pivotal Phase 3 LAVENDER study, a 12-week, randomized, double-blind, placebo-controlled trial involving 187 female patients with Rett syndrome aged 5 to 20 years. This study evaluated the drug’s effectiveness using co-primary efficacy endpoints: the Rett Syndrome Behavior Questionnaire (RSBQ) total score and the Clinical Global Impression-Improvement (CCGI-I) scale. Trofinetide demonstrated a statistically significant improvement compared to placebo on both these measures, indicating a reduction in the severity of Rett syndrome symptoms.
While trofinetide offers symptomatic improvement, it is not a cure for Rett syndrome. Common side effects reported during clinical trials included diarrhea, which occurred in 81% of patients, and vomiting, affecting 27%. Other frequently observed adverse events included fever, anxiety, decreased appetite, and weight loss. Diarrhea was the most common reason for treatment withdrawal in long-term studies. Patients and caregivers are advised to manage diarrhea, potentially with antidiarrheal medication, and to monitor for dehydration or significant weight loss.
Administration and Patient Access
Trofinetide, marketed under the brand name Daybue, is administered orally as a solution. It is taken twice daily, once in the morning and once in the evening, and can be consumed with or without food. The recommended dosage is based on the patient’s body weight, and a physician determines the precise amount. The medication can be given orally or through a gastrostomy (G) tube. Patient eligibility typically requires a confirmed clinical diagnosis of typical Rett syndrome and the presence of a MECP2 gene mutation. Pharmaceutical companies often provide support programs, such as Acadia Connect, to assist patients with personal assistance, financial resources, and prescription support.