Open-Label LILAC-2 Data Demonstrates Trofinetide’s Long-Term Treatment Benefit in Rett Syndrome


Over a 32-week treatment period, patients on trofinetide continued to show improvements on the primary efficacy outcomes of Rett Syndrome Behavior Questionnaire and Clinical Global Impression-Improvement total scores.

Alan Percy, MD, a professor of pediatrics, neurology, neurobiology, genetics, and psychology at the University of Alabama at Birmingham

Alan Percy, MD

New open-label data from the LILAC-2 study (NCT047767746) presented at the 2023 American Epilepsy Society (AES) annual meeting, held December 1-5, in Orlando, Florida, demonstrated the long-term treatment impacts of trofinetide (Daybue; Acadia Pharmacueticals) in patients with Rett syndrome. All told, patients showed continued improved symptoms for up to 32 months, with no new safety signals observed.

Led by Alan Percy, MD, a professor of pediatrics, neurology, neurobiology, genetics, and psychology at the University of Alabama at Birmingham, the open-label extension (OLE) study included 77 females aged 5-22 with Rett syndrome who completed the LAVENDAR (NCT04181723) and LILAC (NCT04279314) studies. Trofinetide was given following weight-based dosing twice daily (morning and evening, ≥8 hours apart) orally or by gastrostomy tube, with the main goal of safety.

At baseline, the mean age of the cohort was 12.0 (SD, 4.38) years with a mean Rett Syndrome Behavior Questionnaire (RSBQ) total score of 36.4 (SD, 12.68). Across the 32-month study period, 20.8% of patients discontinued, with reasons that included adverse events (AEs; 6.5%), death (5.2%; n = 4), lack of efficacy (3.9%; n = 3), noncompliance with study drug (2.6%; n = 2), and other (2.6%; n = 2). Cardiac arrest (n = 1), gastric ulcer hemorrhage (n = 1), sudden unexplained death in epilepsy (n = 1) and vomiting and aspiration (n =1) were causes of death; however, none were connected to the study drug.

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The mean duration of exposure to trofinetide for LILAC-2 participants was 811.1 (SE, 23.16) and 692.3 (SE, 33.20) days for those treated with trofinetide and placebo in LAVENDER, respectively. The duration of exposure to trofinetide was 755.6 (SE, 20.83) days in the LILAC-2 total group. In total, 72 patients (93.5%) reported at least 1 AE, with diarrhea (53.2%), COVID-19 (27.3%), vomiting (19.5%), pyrexia (16.9%) as the most commonly reported symptoms. Over the study period, there were 23 patients (29.9%) who reported serious AEs, 9 of whom ended up withdrawing treatment.

In terms of efficacy, treatment with trofinetide resulted in improved RSBQ and Clinical Global Impression-Improvement (CGI-I) scores. Overall, the mean change in RSBQ total score from the LAVENDER baseline to week 104 of LILAC-2 was –9.8 (SE, 3.38) and –13.8 (SE, 3.61) for those treated with trofinetide and placebo, respectively, in LAVENDER. The score in the LILAC-2 total group was –11.8 (SE, 2.45). Furthermore, from the LILAC baseline to week 12 of LILAC-2, investigators reported mean GCI-I scores of 3.2 (SE, 0.14) for patients on continued trofinetide and 3.0 (SE, 0.15) for those on placebo in LAVENDER. The score in the LILAC-2 total group was 3.1 (SE, 0.10).

Trofinetide, a novel synthetic analog of the amino-terminal tripeptide of IGF-1, became the first approved therapy for patients with Rett syndrome earlier this year, with data from LAVENDER supporting its approval. In LAVENDER, patients on the therapy demonstrated statistically significant improvements on the co-primary end points of RSBQ total score (P = .018) and CGI-I scale score (P = .003) vs placebo after 12 weeks of treatment. Those participating in LAVENDER had the option to receive trofinetide in the planned extension studies, with 95% of partiicpants electing to continue in the LILAC OLE.2

Following the approval of trofinetide, NeurologyLive® launched a special Mind Moments podcast episode with Jeffrey L. Neul, MD, PhD, lead investigator of the phase 3 LAVENDER study. Neul, the Annette Schaffer Eskind Chair and director of the Vanderbilt Kennedy Center, discussed the supportive data that led to its approval and the significance of the first drug for the Rett syndrome community.

Click here for more coverage of AES 2023.

1. 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.
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 December 6, 2023.
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