Trofinetide approved by FDA as first ever treatment for Rett syndrome

On March 10th 2023, the Food and Drug Administration (FDA) approved trofinetide in the treatment of Rett syndrome (RTT), making it the first ever drug approved that specifically treats the condition. The agent was approved for adults and children two years of age or older, after demonstrating significant symptomatic benefits in a recent Phase III trial...

RTT is a rare neurodevelopmental disorder that, until now, had no approved treatment. In most cases, RTT is caused by a mutation in the MECP2 gene, which, when it functions typically, is involved in transcriptional regulation and appears essential for nerve cell function. However, in RTT, it is suggested that the loss of MECP2 function leads to critical changes in cofactor recruitment and chromatin compaction.1 Given its numerous roles and influence on diverse biological pathways, the full impact of mutations in MECP2 remains incompletely elucidated.

Onset typically occurs around 6-18 months of age and is characterized by constant repetitive hand movements, hypotonia, and failure to reach developmental milestones, followed by a regression stage from ages 1-4 years old, where impairments develop affecting speaking, walking, eating, and breathing.2 The subsequent plateau stage then predominates for decades. As an X-linked disorder, RTT predominately affects females, with 1 in 10,000-15,000 having the condition; however, there have been rare reports in males too.2 Prior to tronfinetide’s approval, the therapeutic options for RTT were scarce, consisting only of repurposed agents tackling individual symptoms or behaviors.

Trofinetide (Daybue; Acadia Pharmaceuticals) is a novel synthetic analog of the amino-terminal tripeptide of insulin-like growth factor 1 (IGF-1), which is proposed to treat the core symptoms of RTT simultaneously, by reducing neuroinflammation and supporting synaptic function.3 Characteristic of RTT pathophysiology are synaptic and neuronal immaturities, which trofinetide is thought to have a role in overcoming. It has been shown to inhibit the production of inflammatory cytokines, inhibit the overactivation of microglia and astrocytes, and increase the ability of IGF-1 to bind to its receptors.3

The approval of trofinetide was supported by data from the 12-week, Phase III, double-blind LAVENDER study (NCT04181723).4 A total of 187 eligible females aged 5-20 years were randomized in a 1:1 ratio to receive either trofinetide or matching placebo.2 Trofinetide and the placebo comparator were administered in twice daily doses of 30-60mL (based on the subject’s weight at baseline) via the oral route or gastrostomy tube. The co-primary endpoints were change from baseline in the Rett Syndrome Behavior Questionnaire (RSBQ) total score and the Clinical Global Impression-Improvement (CGI-I) score at week 12. Various aspects of development were also assessed as secondary outcome measures.

Both the primary and secondary endpoints of the LAVANDER study were met. A statistically significant difference in change in RSBQ scores was seen at week 12 (-5.1 with trofinetide compared to -1.7 with placebo; p=0.0175).3 CGI-I scores at week 12 were also significantly lower compared to the placebo (3.5 with treatment, 5.8 with placebo; p=0.003). Trofinetide was also shown to have an impact on various aspects of development, including communication and pre-linguistic skills as assessed by the CSBS-DP infant-toddler checklist (p=0.0064).3 The most common adverse reactions in the trofinetide arm included diarrhea (81%) and vomiting (27%). This links to the 17.2% discontinuation rate, compared to 2.1% for placebo. However, these symptoms were mild to moderate in nearly all cases.3

“The positive LAVENDER study results support a potential treatment for Rett syndrome and represent an important step forward in addressing this rare and serious neurological disease”- Jeffrey L. Neul, MD, PhD, Vanderbilt University Medical Center and LAVENDER study investigator.4

Following on from this study, 95% of the participants rolled over to the 40-week open-label extension study, termed LILAC (NCT04279314). Eligible participants were then invited to participate in the ongoing LILAC-2 study (NCT04776746) to continue treatment for more than 2.5 years. In addition, the DAFFODIL trial (NCT04988867) is assessing the safety, tolerability, and pharmacokinetics of trofinetide in 15 girls aged 2-5 years.

These data demonstrate the effectiveness of trofinetide in managing numerous disease features and is, therefore, a big step in the treatment of RTT. However, as this is a symptomatic treatment and not a disease-modifying one, we are only halfway there when it comes to the potential of beating this debilitating disease. There are several other late-phase clinical trials that may provide additional options for RTT, such as blarcamesine, which has shown symptomatic improvements in a smaller study of 36 adults.5 The first-ever gene therapy trials are also underway, in the hopes of achieving disease modification in RTT (NGN-401 and TSHA-102).6,7

It is a very exciting time in the RTT field, with trofinetide being the first of hopefully many specific treatments for this disease as well as new, upcoming trials looking into a potential cure.

Written by Ashely Ellison

Reviewed by Juliet Lawrence


  1. Ehrhart F, Coort SLM, Cirillo E, et al. Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes. Orphanet J Rare Dis. Nov 2016;11(1):158.
  2. Neul JL, Percy AK, Benke TA, et al. Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome. Contemp Clin Trials. Mar 2022;114:106704.
  3. Acadia. Acadia Pharmaceuticals Announces Positive Top-line Results from the Pivotal Phase 3 Lavender Trial of Trofinetide in Rett Syndrome. [Press Release]. Dec 2021. Accessed Apr 2023.
  4. FDA. FDA approves first treatment for Rett Syndrome [Press Release]. Mar 2023. Accessed Apr 2023.
  5. Anavex Life Sciences Corp. Anavex®2-73 (Blarcamesine) AVATAR Phase 3 Trial met Primary and Secondary Efficacy Endpoints. [Press Release]. Feb 2022. Accessed Apr 2023.
  6. Neurogene. Neurogene Announces FDA Clearance of IND for NGN-401 Gene Therapy for Children with Rett Syndrome. [Press Release]. Jan 2023. Accessed Apr 2023.
  7. Taysha gene therapies. Taysha gene therapies announces initiation of clinical development of TSHA-102 in Rett syndrome. [Press Release]. Mar 2022. Accessed Apr 2023.