Acadia Pharmaceuticals Inc. announced that the journal Developmental Medicine and Child Neurology published interim results from the LOTUS study, a real-world observational analysis evaluating the long-term effectiveness and tolerability of DAYBUE (trofinetide) in patients with Rett syndrome receiving routine clinical care in the United States. The findings reinforce the drug's efficacy and tolerability profile over 12 months of treatment, consistent with the Phase 3 LAVENDER trial that supported FDA approval.
Study Design and Patient Population
The LOTUS study represents a caregiver-reported observational online, open-label analysis examining effectiveness and tolerability outcomes in patients prescribed DAYBUE under routine clinical care. This interim analysis included 227 people living with Rett syndrome with an age range of one to 60 years old, providing insights into real-world treatment outcomes across a broad patient population.
Behavioral Improvements and Quality of Life
The study demonstrated substantial behavioral improvements among patients receiving DAYBUE treatment. Between 71-90% of those who completed the Behavioral Improvement questionnaire (BIQ) reported at least one behavioral symptom improvement that was either new or maintained compared with before DAYBUE treatment. The BIQ was developed by Acadia specifically for this study to document caregiver observations.
Consistent with the previously reported six-month interim analysis, the most frequent caregiver-reported improvements were nonverbal communication (48-71%), alertness (44-70%), and social interaction/connectedness (33-58%), as measured by the BIQ. These findings align with improvements observed in controlled clinical trials.
Quality of life assessments showed meaningful changes, with the median change from baseline in Quality-of-Life Inventory-Disability Questionnaire (QI-Disability) total score reaching 4.6 [IQR, -0.2 to 10.2] for patients (n=33) who had both baseline and 12-month assessments.
Gastrointestinal Safety Profile
The study provided detailed insights into managing gastrointestinal symptoms in real-world settings. The incidence of diarrhea reported by caregivers varied from weeks 1 to 12 (23-50%) and months 4 to 12 (26-38%). Most reports of diarrhea were contained inside the patient's diaper, as measured by the Gastrointestinal Health Questionnaire, also developed by Acadia specifically for this study in consultation with Rett experts and caregivers.
The most commonly reported diarrhea management strategies included avoiding constipation medications, increasing fluid intake, consuming supplementary fiber, and using antidiarrheal medication. Caregivers reported normal stools over the last 3 days immediately prior to completing the GI assessment from weeks 1 to 12 (43-54%) and months 4 to 12 (55-63%).
Dosing Patterns and Treatment Duration
The study revealed important dosing patterns in real-world practice. The median dose reported at Week 1 was 36% of the target weight-banded FDA approved dose, indicating a gradual dose escalation approach. By Week 10 onwards, the median dose reached at least 80% of the labeled dose, suggesting successful dose optimization over time.
Clinical Significance for Adult Patients
"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, M.D., M.P.H., Senior Vice President, Global Head of Medical Affairs and Chief Medical Officer at Acadia Pharmaceuticals. "The data are supportive of what we've seen in DAYBUE 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."
Study Limitations and Future Directions
The researchers acknowledged several limitations of this 12-month follow-up, including the number of patients who had reached later time points, which resulted in the data being restricted to 12 months, lack of a placebo arm, missing data, lack of validation of BIQ and GI questionnaires, reliance solely on caregiver reports, the use of descriptive statistics and the online nature of this study.
Participants are being enrolled in the LOTUS study for at least 12 months from initiation of DAYBUE treatment, with the option to extend participation for an additional 12 months, potentially providing longer-term real-world evidence of the drug's effectiveness and safety profile.
About Rett Syndrome and DAYBUE
Rett syndrome is a rare, complex, neurodevelopmental disorder that occurs in approximately one of every 10,000 to 15,000 female births worldwide, affecting 6,000 to 9,000 patients in the United States. The condition is typically caused by a genetic mutation on the MECP2 gene and progresses through four stages, ultimately requiring round-the-clock care for most patients.
DAYBUE (trofinetide) is a synthetic analog of the N-terminal tripeptide of insulin-like growth factor 1, indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older. While the mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome remains unknown, animal studies have shown the drug increases branching of dendrites and synaptic plasticity signals.
