LOTUS study: Trofinetide data show Rett syndrome symptom improvement | Image Credit: © ARBA - © ARBA - stock.adobe.com.

Trofinetide (Daybue; Acadia Pharmaceuticals) treatment among 277 people living with Rett syndrome led to caregiver-reported improvements in symptoms, from behavioral symptoms to improvements in nonverbal communication, alertness, and social interactions, according to interim data newly published in the Developmental Medicine and Child Neurology journal.^1,2

According to a press release from Acadia, the interim data published is from the ongoing, caregiver-reported observational, online, and open-label LOTUS study. LOTUS is evaluating effectiveness and tolerability outcomes in patients with Rett syndrome who are prescribed trofinetide in those under routine clinical care in the United States. In addition to improvements in Rett syndrome symptoms, early insights into managing gastrointestinal (GI) symptoms were also reported.¹

Trofinetide was approved by the FDA on March 13, 2023, for patients aged 2 years and older with Rett syndrome.³

Trofinetide data from the LOTUS study

The interim analysis included 227 individuals aged 1 to 60 years living with Rett syndrome who were followed for up to 12 months. Caregivers completed study-specific instruments developed by Acadia in consultation with Rett experts, including the Behavioral Improvement Questionnaire (BIQ) and the Gastrointestinal (GI) Health Questionnaire.

Across BIQ responses, 71% to 90% of caregivers noted at least one new or maintained behavioral improvement following treatment. The most frequently reported improvements involved nonverbal communication (48% – 71%), alertness (44% – 70%), and social connectedness (33% – 58%). Among the subset of patients with 12-month Quality-of-Life Inventory-Disability Questionnaire data (n = 33), the median change from baseline was 4.6 points (IQR, −0.2 to 10.2).

Managing Gastrointestinal Symptoms
Caregivers reported diarrhea in 23% to 50% of patients between weeks 1 and 12 and in 26% to 38% from months 4 to 12. Most episodes were contained in diapers. Strategies used to address diarrhea included avoiding constipation medications, increasing fluid intake, adding dietary fiber, and using antidiarrheals. Normal stools in the 3 days prior to assessment were reported in 43% to 54% of patients during weeks 1 to 12 and 55% to 63% during months 4 to 12.

Median dosing reached 36% of the FDA-approved target dose at Week 1 and rose to at least 80% by Week 10.

“These findings from LOTUS help deepen our understanding of the potential outcomes associated with long-term treatment of DAYBUE in the real-world setting,” said Ponni Subbiah, MD, MPH, senior vice president, global head of Medical Affairs and Chief Medical Officer, in a statement. “The data are supportive of what we’ve seen in [trofinetide] clinical trials and offer new scientific insights to clinicians that improvements in Rett syndrome signs and symptoms are possible among a broadly inclusive sample of Rett patients. It’s particularly gratifying to document improvements in adult patients, knowing that they may have waited decades without knowing if a treatment would become available within their lifetime.”

Discussing trofinetide data, FDA approval for Rett syndrome with Alan Percy, MD⁴

In a previous interview with Contemporary Pediatrics, Alan Percy, MD, Professor of Pediatrics, Neurology, Neurobiology, Genetics, and Psychology at the University of Alabama, Birmingham, discussed the groundbreaking nature of the treatment, noting, this was the first product that was ever has been developed and approved by the FDA for direct treatment of the signs or symptoms of Rett syndrome. Other medications we use are for symptomatic care, but nothing has been available previously to direct at the basic underpinnings of Rett syndrome."

WATCH: The pediatrician's role in prescribing trofinetide for Rett syndrome

Efficacy and tolerability among patients prescribed trofinetide for as long as 12 months were consistent with the phase 3 LAVENDER trial that supported FDA approval and the open label LILAC, LILAC-2 and DAFFODIL studies, for which Percy was a lead author.^1,4

LAVENDER, a double-blind, placebo-controlled study that lasted 12 weeks, utilized the Rett Syndrome Behavioral Questionnaire (RSBQ) and the Clinical Global Impression of Improvement (CGI-I) as primary endpoints to measure the treatment's effectiveness. "What is quite remarkable is at the end of the first pivotal trial, 12 weeks both the RSBQ and the CGI-I showed improvement," said Percy.⁴

Click here for more on the phase 3 LILAC-1 and LILAC-2 studies.

References:

1. Real world data from LOTUS study evaluating long-term efficacy and tolerability outcomes of Daybue (trofinetide) in patients with Rett syndrome published in developmental medicine and child neurology. Acadia Pharmaceuticals. Press release. September 12, 2025. Accessed September 15, 2025. https://acadia.com/en-us/media/news-releases/real-world-data-lotus-study-evaluating-long-term-efficacy-and
2. Cosand L, Mayman H, Downs J, Abler V. Real-world benefits and tolerability of trofinetide for the treatment of Rett syndrome: The LOTUS study. Developmental Medicine & Child Neurology. Published online September 11, 2025. Accessed September 15, 2025. https://onlinelibrary.wiley.com/doi/10.1111/dmcn.16482
3. Krewson C. FDA approves trofinetide for treatment of Rett syndrome. Contemporary Pediatrics. Published March 13, 2023. Accessed September 15, 2025. https://www.contemporarypediatrics.com/view/fda-approves-trofinetide-for-treatment-of-rett-syndrome
4. Fitch J. Discussing trofinetide data, FDA approval for Rett syndrome with Alan Percy, MD. Contemporary Pediatrics. Published September 4, 2024. Accessed September 15, 2025. https://www.contemporarypediatrics.com/view/trofinetide-data-fda-approval-rett-syndrome-alan-percy-md