Trofinetide Leads to Real-World Improvements in Rett Syndrome Symptoms, LOTUS Study Finds

Subgroup data presented from the ongoing phase 4 LOTUS trial, a prospective study of individuals with Rett syndrome (RTT) on trofinetide (Daybue; Acadia), revealed that treatment with the medication led to real-world improvements in a number of RTT-related behavioral symptoms among both pediatric and adult patients.¹

Presented at the 2025 Child Neurology Society (CNS) Annual Meeting, held October 8-11 in Charlotte, North Carolina, the subgroup analysis focused on the 12-month follow-up of pediatric (0-17 years of age; n = 117) and adult (≥18 years of age; n = 74) patients within the LOTUS trial. Led by Louise Cosand, PhD, medical director in rare disease at Acadia Pharmaceuticals, the assessments used included the Behavioral Improvement Questionnaire (BIQ), the Quality-of-Life Inventory-Disability (QI-Disability) Questionnaire, and the Gastrointestinal Health Questionnaire.

Because of ongoing enrollment, the data reported from the analysis included those who’ve been on trofinetide for 9 months. Here, results showed that treatment with the medication led to improvements in nonverbal communication (pediatric: 53-64%; adult: 41-58%), alertness (pediatric: 50-69%; adult: 33-65%), and social interaction/connectedness (pediatric: 36-58%; adult: 26-48%).

After 8 weeks, the median dose was at least 86.0% and 70.0% of target weight-branded label dose for pediatric and adult patients, respectively, up from the 45.0% and 41.0% documented at week 1. Among both pediatric and adult patients, QI-Disability total scores indicated improvements in quality of life. In terms of safety, it was noted that most reports of diarrhea, the most common side effect of trofinetide, were contained inside the patient’s diapers.

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Trofinetide, a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 designed to potentially reduce neuroinflammation and supporting synaptic function, became the first and only approved therapy for RTT in March 2023. Data from the phase 3 LAVENDER trial (NCT04181723), a 187-patient cohort, was the basis for the approval.²

In LAVENDAR, treatment with trofinetide led to statistically significant improvements in the co-primary efficacy end points: change from baseline in Rett Syndrome Behaviour Questionnaire (RSBQ) total score (P = .018) and the Clinical Global Impression-Improvement (CGI-I) scale score (P = .003) at week 12. On the RSBQ caregiver assessment, participants treated with trofinetide had a score change from baseline to week 12 of –5.1, compared with –1.7 for those given placebo (P = .0175; effect size = 0.37).

Following LAVENDAR, patients were eligible to enter LILAC-2, an open-label study further testing the therapeutic benefits of trofinetide. Patients received a weight-based dose of the medication, twice daily orally or by gastrostomy tube, with the main goal being safety. Findings presented at the 2023 American Epilepsy Society Annual Meeting revealed that patients on the medication showed continued improved symptoms for up to 32 months, with no new safety signals identified.

In LILAC-2, efficacy analyses showed sustained improvement in RSBQ and CGI-I scores. From the LAVENDER baseline to week 104 of LILAC-2, mean RSBQ changes were –9.8 for prior trofinetide patients, –13.8 for prior placebo, and –11.8 overall. Mean CGI-I scores at week 12 of LILAC-2 were 3.2, 3.0, and 3.1, respectively, indicating continued clinical benefit.³

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REFERENCES
1. Cosand L, Downs J. Real-world benefits and tolerability of trofinetide for the treatment of pediatric and adult patients with Rett syndrome: the LOTUS study. Presented at: 2025 Child Neurology Society Annual Meeting; Oct 8-11. Abstract 190.
2. Acadia Pharmaceuticals Announces U.S. FDA Approval of DAYBUE™ (trofinetide) for the Treatment of Rett Syndrome in Adult and Pediatric Patients Two Years of Age and Older News Release. Acadia Pharmaceuticals. March 10, 2023. Accessed October 10, 2025. https://acadia.com/media/news-releases/acadia-pharmaceuticals-announces-u-s-fda-approval-of-daybue-trofinetide-for-the-treatment-of-rett-syndrome-in-adult-and-pediatric-patients-two-years-of-age-and-older/
3. Percy AK, Neul JL, Benke TA, et al. Trofinetide for the treatment of Rett syndrome: long-term safety and efficacy results from the open-label LILAC-2 study. Presented at: AES 2023; December 1-5; Orlando, FL.