Neurology & Neurosurgery

Children’s Neurologist Helps Bring First Rett Syndrome Drug to Market

Children’s of Alabama pediatric neurologists Dr. Amitha Ananth (left) and Dr. Alan Percy

In March, the U.S. Food and Drug Administration approved the first treatment for Rett syndrome, a rare neurological disease. Considered a major breakthrough, the new drug, called trofinetide, or Daybue, may never have made it to market without the groundbreaking work of Children’s of Alabama pediatric neurologist Alan Percy, M.D.

Percy is one of the leading Rett syndrome experts in the world. He diagnosed the first patient with the disease in the U.S. and led a multicenter, National Institutes of Health-funded study on its natural history. He now co-leads, with Amitha Ananth, M.D., the Children’s of Alabama/University of Alabama at Birmingham (UAB) Child Neurology Rett Syndrome Clinic, one of the largest in the country and one of just 15 centers of excellence in Rett syndrome in the country.

“The availability of this medication is a game-changer in our efforts to treat this disorder directly, rather than only treating the specific problems that may arise,” Percy said. “It is remarkable that this treatment emerged less than 40 years after Rett syndrome first became known throughout the world.”

Rett syndrome affects about one in 10,000 babies, nearly all female. Infants with the condition develop normally until about 18 months of age, when they start missing developmental milestones and even regressing in some areas. The most classic feature, according to Ananth, a pediatric neurologist at Children’s, is loss of ability to use their hands in a meaningful way. Instead, they make repetitive, purposeless movements like handwringing, squeezing, clapping, tapping or rubbing. They also can’t communicate verbally.

Ananth has begun prescribing the new treatment to her patients. Prior to its approval, physicians prescribed physical, speech and occupational therapy; medications to treat symptoms like seizures and anxiety; and monitored growth and nutrition. “But there are a lot of aspects of this condition for which we really don’t have great drug treatment,” Ananth said. For instance, many patients with the disease will hold their breath or breathe very rapidly. “That can be quite disruptive to their daily life, but we don’t have great tools to deal with it.”

The Department of Defense initially developed trofinetide to treat traumatic brain injury. It’s a novel synthetic version of a tripeptide within the insulin-like growth factor 1 molecule (IGF-1). People with Rett syndrome have altered levels of IGF-1. Data suggests trofinetide helps brain neurons grow and communicate, while potentially reducing inflammation in the brain.

Children’s and UAB hosted clinical trials for the drug which involved 187 female patients with Rett syndrome ages 5 to 20. Those who received the drug demonstrated significant improvements on caregiver and physician assessments compared to those who received a placebo.

“To actually see a statistically significant difference between the two groups in just 12 weeks is pretty remarkable,” Ananth said. However, she stressed, “this isn’t a cure. But it is different from other medications we’ve been using because it targets the overall well-being of the person as opposed to specific symptoms.”

Anecdotally, Ananth has heard from parents of patients who received the drug that their daughters are more alert and engaged, both of which are important to the success of the various therapies the girls receive. For instance, some patients can be taught to use eye-gaze communication devices since most are nonverbal and can’t use their hands to communicate. “Parents said their daughters who received the drug were using [the devices] better,” she said. One girl who, prior to the trial, spoke only two or three words has now expanded her vocabulary exponentially, Ananth said.

The drug is a liquid administered by mouth or through a gastrostomy tube. The major side effects are vomiting and diarrhea, although clinicians are finding ways to reduce their severity and better manage them.

Another clinical trial is testing the drug in children ages 2 to 5. In addition, two companies have submitted applications to the FDA to start gene therapy trials, Ananth said, and one woman in Canada has received the first such treatment. Other investigational therapies are also under way. “We may very quickly move from an era with no treatments to one with multiple treatments and combination therapies,” she said. “It’s very exciting.”

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