First drug for Rett syndrome tested at UAB

The drug appears to help strengthen pathways in the brain, improving the ability of neurons to communicate with each other.

Stream RETTThe drug appears to help strengthen pathways in the brain, improving the ability of neurons to communicate with each other.The United States Food and Drug Administration has approved trofinetide, marketed as Daybue, as the first treatment for Rett syndrome, a rare, genetic neurological disorder. An oral solution manufactured by Acadia Pharmaceuticals, Daybue is approved for the treatment of Rett syndrome in adults and children 2 years of age or older.

Daybue was evaluated in a randomized, double-blind, placebo-controlled, 12-week study. Researchers at the University of Alabama at Birmingham enrolled 12 study subjects in the multi-site trial. Overall, the trial enrolled 93 patients with Rett syndrome and 94 controls.  

“Daybue is not a cure for Rett syndrome,” said Alan Percy, M.D., professor of pediatric neurology at the UAB Marnix E. Heersink School of Medicine and an internationally renowned researcher and clinician in Rett syndrome. “The primary goal in caring for patients with Rett syndrome is to provide incremental improvement.”

Patients take Daybue either orally or via a gastrostomy tube. The recommended dose is based on patient weight. Daybue is taken twice daily, morning and evening. 

“The biggest concern parents or caregivers have is the inability of the patient to communicate,” Percy said. “Many engage in breath-holding behavior, and often don’t verbalize their feelings or needs. The drug seems to lead to better attention from patients and better interaction between patient and caregiver.”

Percy, who holds the Sarah Katherine Bateh Endowed Professorship for Rett Syndrome, and co-investigator Amitha Ananth, M.D., assistant professor in the Department of Pediatrics, say families and teachers reported that patients were more receptive and responded better to questions. Those on the drug were more likely to tell caregivers about aspects of daily living, such as if they were hungry or needed to go to the bathroom.

“Families are looking for any improvement in their child,” Ananth said. “This is very exciting news for families, as Daybue is the first drug to target overall well-being in a neuro-developmental disorder. This is quite a big deal to families with a child with Rett syndrome.”

Acadia Pharmaceuticals reports that trofinetide/Daybue works by reducing inflammation in the brain, stopping certain types of cells from becoming overactive and increasing the amount of a naturally occurring protein called IGF-1. 

Percy and Ananth say preliminary studies suggest the drug mediates brain development by improving pathways that neurons use to communicate with other neurons, known as synaptic connections. Basically, they say, it allows neurons to function more as they would in a healthy brain.

Rett syndrome is a rare, genetic neurological and developmental disorder that affects the way the brain develops. Patients with Rett syndrome experience a progressive loss of motor skills and language. Most babies with Rett syndrome seem to develop as expected for the first six months of life. These babies then lose skills they previously had attained at approximately 6 to 18 months of age — such as the ability to crawl, walk, communicate or use their hands. The hallmark of Rett syndrome is near constant repetitive hand movements, such as rubbing or clapping. Rett syndrome leads to severe impairments affecting nearly every aspect of life, including the ability to speak, walk, eat and breathe.

Rett syndrome is caused by mutations on the X chromosome on a gene called MECP2. Rett syndrome occurs worldwide in one of every 10,000 female births and is even rarer in boys. There are an estimated 5,000-10,000 girls with Rett syndrome in America. Most are under 20 years of age, although life expectancy is now around 50.     

“Parents are desperate for treatments that will improve their children’s lives, especially older parents who face difficulty in handling an adult child,” Ananth said.

The most common adverse reactions, occurring in at least 10 percent of Daybue-treated patients and twice the rate of placebo, included diarrhea and vomiting.