FDA Approves Acadia's Trofinetide for Rett Syndrome


The therapy, marketed as Daybue, is the first therapy indicated for Rett syndrome with supporting data from the pivotal phase 3 LAVENDER study.

Jeffrey L. Neul, MD, PhD, Annette Schaffer Eskind Chair and director, Vanderbilt Kennedy Center; professor of pediatrics, Vanderbilt University Medical Center

Jeffrey L. Neul, MD, PhD

The FDA has approved trofinetide (Daybue; Acadia Pharmaceuticals) for the treatment of Rett syndrome in adult and pediatric patients 2 years of age and older. This treatment, a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 designed to potentially reduce neuroinflammation and supporting synaptic function, is the first and only approved therapy for Rett syndrome, signifying a major breakthrough.1

The supporting data from the pivotal phase 3 LAVENDER study (NCT04181723) demonstrated statistically significant improvement compared with placebo on both co-primary efficacy end points, as measured by the 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.

“Rett syndrome is a profoundly debilitating and complex, rare, neurodevelopmental disorder that presents differently across patients and can lead to an array of unpredictable symptoms throughout the course of a patient’s life,” lead investigator Jeffrey L. Neul, MD, PhD, Annette Schaffer Eskind Chair and director of the Vanderbilt Kennedy Center, and professor of pediatrics at Vanderbilt University Medical Center, said in a statement.1 “Now, for the first time after decades of clinical research, healthcare providers finally have a treatment option to address a range of core behavioral, communication and physical symptoms for their patients living with Rett syndrome.”

The phase 3 study included a total of 187 female patients with Rett syndrome between the ages of 5 and 20 years evaluated over a 12-week period. 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). Looking at the CGI-I, those treated with trofinetide had a mean score of 3.5 at week 12 compared with those receiving placebo, who had a mean score of 3.8 (P = .0030; effect size = 0.47). 

Participants discontinued treatment for a variety of treatment emergent adverse events, with 17.2% discontinuing in the trofinetide group versus 2.1% in the placebo group. Diarrhea was among the most common adverse events, reported by 80.6% of patients in the treatment group versus 19.1% in the placebo group. Vomiting was also reported, affecting 26.9% of patients in the treatment group versus 9.6% in the placebo group. Serious adverse events were reported in a combined 3.2% of patients in both groups. Those who participated in the study also had the option to receive trofinetide in planned extension studies, with 95% of participants electing to continue in the LILAC open-label extension study.

In September 2022, the FDA accepted the NDA for the agent and used data from phase 3 of the study, which assessed the agent in 187 girls and women with Rett syndrome.2 Previously in 2015, trofinetide was granted fast track status, as well as orphan drug designation, for treatment of Rett syndrome.

“This is a historic day for the Rett syndrome community and a meaningful moment for the patients and caregivers who have eagerly awaited the arrival of an approved treatment for this condition,” said Melissa Kennedy, chief executive officer of the International Rett Syndrome Foundation, in a statement.1 “Rett syndrome is a complicated, devastating disease that affects not only the individual patient, but whole families. With today’s FDA decision, those impacted by Rett have a promising new treatment option that has demonstrated benefit across a variety of Rett symptoms, including those that impact the daily lives of those living with Rett and their loved ones.”

In December 2021, Acadia Pharmaceuticals announced positive topline results from the phase 3 LAVENDER clinical trial3 The agent met its coprimary efficacy end points in demonstrating statistically significant improvement in the RSBQ and the CGI-I, comparison with placebo. The trial also met its key secondary end point by demonstrating statistically significant improvement in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist–Social composite score over placebo from baseline to week 12. Those receiving trofinetide had a mean change of –0.1 compared with those receiving placebo, who had a mean change of –1.1 (P = .0064; effect size = 0.43).3

In March 2019, findings from a phase 2 study showed that the 200 mg/kg dose of trofinetide displayed a clinically meaningful and statistically significant benefit for a trio of syndrome-specific efficacy measurements in pediatric patients with Rett syndrome.4 Of the 5 measurements recorded in the trial, the Neuren product showed a benefit on a pair of clinician assessments and a caregiver evaluation. All told, significant results were observed on the RSBQ (P = .042), the CGI-I (P = .029), and the Rett Syndrome Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC; P = .025).

"Today marks an important milestone for the Rett community and Acadia. As the first FDA-approved drug for the treatment of Rett syndrome, DAYBUE now offers the potential to make meaningful differences in the lives of patients and their families who have lacked options to treat the diverse and debilitating array of symptoms caused by Rett syndrome,” said Steve Davis, Acadia’s chief executive officer said in a statement.1 "We are grateful to all of the Rett syndrome patients, caregivers, clinical investigators and our employees who have contributed to making today a reality and look forward to getting DAYBUE to patients as quickly as possible.”

Currently, trofinetide is also being assessed in another phase 2/3 trial, DAFFODIL (NCT04988867), in 15 girls aged 2 to 5 years, with primary outcomes of safety and tolerability, as well as measures of whole blood concentration, terminal half-life, and peak drug concentration.

"This is a monumental step forward in the care of patients with Rett Syndrome. This provides hope to every patient and their family. I am excited to watch the evolution of the next phase of Rett Syndrome as we rewrite the natural history of this disorder. Our work is not yet done though, not until we have a cure," Robin Ryther, MD, PhD, director of the Rett Spectrum Clinic at Washington University School of Medicine told NeurologyLive®.

1. 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 March 11, 2023. 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/
2. Acadia Pharmaceuticals Announces Trofinetide New Drug Application for the Treatment of Rett Syndrome has been Accepted for Filing and Review by U.S. FDA. News release. Acadia Pharmaceuticals. September 12, 2022. Accessed March 2, 2023. https://acadia.com/media/news-releases/acadia-pharmaceuticals-announces-trofinetide-new-drug-application-for-the-treatment-of-rett-syndrome-has-been-accepted-for-filing-and-review-by-u-s-fda/
3. Acadia Pharmaceuticals announces positive topline results from the pivotal phase 3 Lavender trial of trofinetide in Rett syndrome. News release. Acadia Pharmaceuticals. December 6, 2021. Accessed March 2, 2023. https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-positive-top-line-results-1
4. Positive Phase 2 Study Results of Trofinetide in Pediatric Rett Syndrome Published in Neurology, the Medical Journal of the American Academy of Neurology [press release]. San Diego, CA; Cincinnati, OH; Melbourne, Australia: ACADIA Pharmaceuticals Inc.; Neuren Pharmaceuticals Limited; Rettsyndrome.org; Published March 27, 2018. Accessed March 2, 2023.
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