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  • Writer's pictureSaeed Anwar Anuj

Trofinetide: the debut drug for Rett Syndrome

Rett syndrome

Rett syndrome is a rare and complex neurodevelopmental disorder that primarily affects females, with a prevalence rate of 1 in 10,000 to 15,000 live female births. The disorder is caused by a genetic mutation in the MECP2 gene, which is located on the X chromosome. This gene encodes a protein known as methyl-CpG binding protein 2, or MeCP2 for short. MeCP2 protein is particularly important for mature nerve cells, where it is present at high levels. It plays a vital role in 'switching off' genes in the mature nerve cells when they are required to be switched off for healthy physiological activities. MeCP2 performs this switch-like function by modifying chromatin, the complex of DNA and protein that packages DNA into chromosomes.

The onset of Rett syndrome is usually marked by a period of normal development until 6 to 18 months of age, followed by a rapid regression of abilities and skills. The symptoms of Rett syndrome vary from person to person, but some of the typical features include:

  • Loss of speech and purposeful hand use

  • Development of repetitive hand movements, e.g., wringing, clapping or tapping

  • Impaired gait and coordination

  • Seizures and abnormal EEG patterns

  • Breathing difficulties, e.g., hyperventilation, apnea, or breath-holding

  • Scoliosis and growth retardation

  • Anxiety, irritability, and mood swings

  • Sleep disturbances and gastrointestinal issues

Since Rett syndrome is a lifelong condition that requires extensive care and support from families and healthcare professionals, the absence of a specific treatment has been a significant challenge. The available management strategies were mainly palliative, targeting the symptoms and enhancing the quality of life of patients and their caregivers.

But today, things are different. A ray of hope has emerged in the form of trofinetide, the first and only treatment that addresses the underlying cause and the diverse symptoms of Rett syndrome. The Food and Drug Administration (FDA) recently approved this medication, and it's expected to be available by the end of April 2023.

Trofinetide: The first and only treatment option for Rett syndrome

There has been a number of major breakthrough in the treatment of Rett syndrome lately. The latest and perhaps the most significant to date is that the U.S. Food and Drug Administration (FDA) has approved a novel drug called trofinetide for the treatment of Rett syndrome in adult and pediatric patients two years of age and older. Trofinetide is the first and only drug approved for the treatment of Rett syndrome, offering a new hope for patients and their families.

Trofinetide is a synthetic analog of the amino-terminal tripeptide of insulin-like growth factor 1 (IGF-1), a molecule that is involved in brain development, plasticity, and repair. Trofinetide is designed to reduce neuroinflammation and support synaptic function by modulating the activity of glia, the cells that support and protect neurons in the brain.

The efficacy and safety of trofinetide for the treatment of Rett syndrome have been evaluated in several clinical trials, including the pivotal phase 3 LAVENDER study, which involved 187 female patients with Rett syndrome between the ages of 5 and 20 years. The study showed that trofinetide significantly improved the core symptoms of Rett syndrome, e.g., communication, behavior, and motor function, compared to placebo, as measured by the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression-Improvement (CGI-I) scale.

Pros of Trofinetide:

  • Addresses the underlying cause: Trofinetide is designed to target the core symptoms of Rett syndrome by addressing the underlying cause of the disorder, which is the mutation in the MECP2 gene. By modulating the activity of glia cells and improving the expression and function of the MECP2 gene and its downstream targets, trofinetide has the potential to restore the balance of gene regulation and brain connectivity that is disrupted by the mutation.

  • Improves core symptoms: Trofinetide has been shown to improve the core symptoms of Rett syndrome, e.g., communication, behavior, and motor function, as measured by the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression-Improvement (CGI-I) scale. This improvement can significantly improve the quality of life for patients with Rett syndrome and their families.

  • Limited side effects: The most common side effects of trofinetide are diarrhea and weight loss, which were mostly mild to moderate and manageable. Trofinetide was generally well tolerated and did not cause any serious adverse events.

  • Potential long-term benefits: Although further studies are needed to evaluate the long-term effects of trofinetide, initial studies suggest that it may offer sustained benefits for patients with Rett syndrome.

Cons of Trofinetide:

  • Limited availability: Trofinetide is expected to be available by the end of April 2023, and its availability may be limited due to its orphan drug status and the relatively small number of patients with Rett syndrome.

  • High cost: The cost of trofinetide is yet to be determined, but it is likely to be high due to the cost of developing and manufacturing the drug and the limited patient population. This may limit access to the drug for some patients and families.

  • Limited efficacy for some symptoms: While trofinetide has shown promising results in improving communication, behavior, and motor function, it may have limited efficacy in addressing other symptoms of Rett syndrome, e.g., breathing difficulties, scoliosis, and seizures. Additional treatments may be needed to address these symptoms.

  • Potential unknown long-term effects: As with any new drug, the long-term effects of trofinetide are not yet fully understood. Further studies are needed to evaluate the safety and efficacy of trofinetide over a longer period of time.

It is worth noting that, trofinetide is not a cure-all for Rett syndrome, and like any medication, it has its pros and cons. One advantage is that it can potentially reduce the severity of Rett syndrome symptoms, including hand stereotypies, breathing irregularities, and anxiety. Additionally, it may improve communication and social interaction in people with Rett syndrome, which can enhance their quality of life.

On the other hand, trofinetide may not be effective for all individuals with Rett syndrome, and it may cause side effects, e.g., constipation, vomiting, and headache. Furthermore, the medication is expensive, and it's unclear how much insurance will cover it.

Despite several limitations, trofinetide represents a significant breakthrough in Rett syndrome treatment and offers the first hope for addressing the underlying cause of the disorder. As further research is conducted, it's possible that additional treatment options will emerge, potentially leading to even more improvements in the lives of those with Rett syndrome.

11 March 2023

Saeed Anwar

Edmonton, Canada


  1. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature genetics. 1999 Oct;23(2):185-8.

  2. Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, Flannery R, Jaenisch R, Sur M. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proceedings of the National Academy of Sciences. 2009 Feb 10;106(6):2029-34.

  3. Neul JL, Percy AK, Benke TA, Berry-Kravis EM, Glaze DG, Peters SU, Jones NE, Youakim JM. Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome. Contemporary Clinical Trials. 2022 Mar 1;114:106704.

  4. 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.

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