Novel Drug Offers New Hope for Rett Syndrome

Trofinetide (Acadia Pharmaceuticals) is effective in improving symptoms in girls and young women with Rett syndrome (RTT), a rare and devastating neurodevelopmental disorder, results from a phase 3 study suggest.



Dr Jeffrey Neul

“In a severe disorder like Rett syndrome that has no approved therapies and where all of our interventions are purely symptomatic, it’s very exciting to be at a point where a phase 3 trial shows benefit,” study investigator Jeffrey L. Neul, MD, PhD, director of the  Vanderbilt Kennedy Center and professor of pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, told Medscape Medical News.

The findings were presented at the American Academy of Neurology (AAN) 2022 Annual Meeting.

Rare, Devastating Condition

A neurodevelopmental disorder occurring almost exclusively in females, RTT is caused by mutations on the X chromosome on the methyl-CpG binding protein-2 ( MECP2 ) gene. The condition is rare, occurring in 1 in 10,000-15,000 female births. In the US, it affects about 6000 to 9000 individuals.

Symptoms typically present between 6 and 18 months of age, with patients experiencing a rapid decline with loss of fine motor and communication skills.

Rett syndrome is thought to be associated with severe intellectual disability, but since patients have limited ability to speak or use hand movements, they’re unable to complete standardized tests, said Neul. The condition is sometimes misdiagnosed as autism, cerebral palsy, or nonspecific developmental delay.

Trofinetide is a synthetic analog of the amino-terminal tripeptide of insulin-like growth factor-1 (IGF-1). IGF-1 in the brain is critical for both normal development and for response to injury and disease.

The drug is designed to treat the core symptoms of RTT by potentially reducing neuroinflammation and supporting synaptic function. Phase 2 studies in RTT demonstrated a clinical benefit over placebo in clinician- and caregiver-assessed efficacy measures.

The new double-blind study (LAVENDER) included 187 females with RTT, aged 5-20 years. All subjects had gone through a period of regression where they lost acquired spoken language skills, developed repetitive hand movements, and had difficulty walking or couldn’t walk at all, said Neul.

Setting a High Bar

A total of 93 participants were randomly assigned to twice-daily oral trofinetide and 94 received placebo for 12 weeks.

One co-primary endpoint was the caregiver-assessed Rett Syndrome Behavior Questionnaire (RSBQ). The RSBQ covers a wide range of clinical domains important in Rett syndrome, including behaviors, hand function, walking ability, and breathing abnormalities.

The other co-primary endpoint was the 7-point Clinical Global Impression–Improvement (CGI-I) scale, a physician assessment of worsening or improving of Rett syndrome symptoms.

Neul noted these co-primary endpoints “are a very high bar to try to meet.”

After 12 weeks, trofinetide showed a statistically significant improvement from baseline compared with placebo on both the RSBQ (least squares [LS] mean change -4.9 vs -1.7; P = .0175; Cohen’s d effect size = 0.37) and on the CGI-I (LS 3.5 vs 3.8; P = .0030; Cohen’s d effect size = 0.47).

All subscales of the domains favored the active drug, said Neul. “Not all were statistically significant, but they all directionally favored trofinetide. So it doesn’t seem to be driven by one or two of these domains. Overall, things were moving in an improved direction.”

New Hope

The key secondary endpoint was the composite score on the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist-Social (CSBS-DP-IT Social), a scale on which caregivers assess nonverbal communication. Here, the drug also outperformed placebo at 12 weeks (LS mean change -0.1 vs -1.1; P = .0064; Cohen’s d effect size = 0.43).

“The interpretation from that is that people with Rett syndrome were starting to develop better nonverbal communication skills,” said Neul.

The most common adverse events were diarrhea (80.6% with trofinetide vs 19.1% with placebo) and vomiting (26.9% with trofinetide vs 9.6% with placebo). Almost all these events were considered mild or moderate.

“Typically in Rett syndrome, most people have constipation and even severe constipation, so this actually has swung the pendulum in the other direction,” said Neul.

Serious adverse events were reported in 3.2% of participants in both the trofinetide and placebo groups. There were no fatalities.

This new research success might help pave the way for other rare neurodevelopmental disorders, where few trials have made it to phase 3, which has been discouraging for many in the field, said Neul.

“This is a good indication that there is hope we can do trials in these other disorders.”

More than 95% of participants who completed the study have opted to enter ongoing open-label trials where all patients receive trofinetide, according to Acadia Pharmaceuticals.

Trofinetide has been granted Fast Track Status and Orphan Drug Designation for Rett syndrome and Rare Pediatric Disease (RPD) designation by the US Food and Drug Administration (FDA).

The study was funded by Acadia Pharmaceuticals . Neul reports he has previously consulted for Acadia and has no financial interest in the company.

American Academy of Neurology (AAN) 2022 Annual Meeting. Abstract 004. Presented April 5, 2022.

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