Experts recommend Daybue as first-line therapy for Rett syndrome
Panel endorses early treatment initiation, individualized dosing approach
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New recommendations support the use of the ready-to-use liquid formulation of trofinetide, sold as Daybue, as a first-line therapy for eligible people with Rett syndrome. A panel of 25 experts in managing the disease reached consensus on the recommendations.
The panel endorsed early treatment initiation and an individualized dosing approach to help maximize effectiveness while managing side effects and supporting treatment adherence. They also cautioned that permanent discontinuation may lead to loss of therapeutic gains, advocating instead for managing side effects through dose adjustments, dietary strategies, and short-term interventions.
“Recommendations highlight a flexible, patient‐centered approach to trofinetide use to optimize efficacy while addressing tolerability challenges and supporting adherence,” researchers wrote.
The study, “Expert Consensus on Real-World Use of Trofinetide for Rett Syndrome Using a Modified Delphi Method,” was published in the Annals of the Child Neurology Society. It was funded by Acadia Pharmaceuticals, which markets both Daybue and Daybue Stix, a powder formulation of the same active ingredient.
Daybue reduces inflammation, supports synapse health
Daybue, given twice daily as a liquid, was approved in the U.S. in 2023 as the first treatment for adults and children ages 2 and older with Rett syndrome. The therapy is thought to work by reducing inflammation and supporting the health of synapses, the connections between nerve cells, whose function is impaired in Rett.
The therapy’s approval was primarily supported by data from the Phase 3 LAVENDER clinical trial (NCT04181723), which showed that Daybue significantly eased neurobehavioral symptoms in patients ages 5 to 20. Results from two open‐label extension studies, LILAC-1 (NCT04279314) and LILAC-2 (NCT04776746), confirmed that these benefits were maintained over the long term.
Interim results from the ongoing Phase 4 LOTUS study have further supported these findings in real-world settings, showing that one year of daily treatment with Daybue was associated with improvements in behaviors such as nonverbal communication, alertness, and social interaction across patients ages 1 to 60.
As clinical experience with Daybue continues to grow, there is a need for consensus recommendations to support its streamlined and consistent use across specialized centers and general providers, the researchers wrote.
Expert panel reached consensus on all statements
To develop practical recommendations on Daybue use, a steering group of five experts with experience prescribing the therapy conducted a modified Delphi process. This approach, which relies on multiple rounds of surveys and discussion, is commonly used in health-related fields to help reach expert agreement on best practices and clinical guidelines.
The steering group developed 72 statements for rating by a panel of experts on a four-point scale (from strongly disagree to strongly agree). The statements covered six areas: first-line use, pre-treatment assessment, treatment initiation, evaluation of benefit, tolerability management, and discontinuation strategies.
After two rounds of assessments, each completed by a panel of 25 clinicians, most of whom had at least 10 years of experience treating Rett, consensus was reached across the final set of statements. Consensus was defined as at least 75% agreement.
Overall, the panel supported Daybue as a first-line therapy within the standard of care for eligible patients, with strong agreement for starting treatment early. Respondents indicated that some improvements — particularly in attention and communication — may be seen within the first month, with broader benefits, including in motor function, breathing, and sleep, emerging by about three months and maintained with continued use.
Consensus also supported the need for a thorough initial assessment of clinical severity, functional status, seizure history, bowel function, and nutritional status to guide treatment decisions and evaluate response. Given the variability of Rett syndrome’s clinical presentation, early improvements may be subtle and easily overlooked without a clear reference point.
The panel also emphasized that benefits may be delayed and emerge gradually, often becoming more apparent only after sustained treatment over several months.
[The findings support the integration of Daybue as] “a foundational component of the standard of care” [for Rett syndrome.]
A flexible, individualized dosing approach was recommended, particularly for patients with tolerability concerns. Treatment should start at lower doses and be gradually increased every one to two weeks to reduce the risk of side effects, especially diarrhea and vomiting, which remain the most common barriers to treatment adherence.
If tolerability remains a concern, the panel suggested modifying dosing schedules — for example, by dividing doses into smaller, more frequent administrations — along with slowing feeding to help reduce gastrointestinal symptoms. Short-term treatment, particularly for diarrhea, may also be used when needed.
In cases of significant tolerability issues, respondents unanimously favored dose reduction or temporary interruption followed by reinitiation at a lower dose, rather than permanent discontinuation, which may lead to loss of therapeutic gains.
The panel also supported the use of caregiver-reported diaries to help capture changes in symptoms and treatment response that may not be fully reflected in standard clinical scales.
Overall, the findings support the integration of Daybue as “a foundational component of the standard of care” for Rett syndrome, alongside supportive interventions such as occupational therapy, speech and language therapy, and physiotherapy, as well as nutritional support and assistive technologies, the researchers wrote.
Ultimately, the team emphasized that “a flexible, patient-centered approach is needed to maximize the benefits” of trofinetide, which could have the potential to improve quality of life not only for patients but also for their families and caregivers.
