Promising Vanderbilt Kennedy Center (IDDRC, UCEDD, LEND) Study on Treating Core Symptoms in Rett Syndrome Supports Further Trials

August 19, 2019

Vanderbilt Kennedy Center (IDDRC, UCEDD, LEND) Director Jeffrey Neul, M.D., Ph.D., and colleagues studied the safety and effectiveness of the drug trofinetide in female children and adolescents (age 5-15) with Rett syndrome (RTT). Findings were recently published in the journal Neurology and show promise for improving core features associated with the rare disease, supporting further trials.

RTT is a progressive neurodevelopmental disorder that is defined by apparently typical development in the first 6 months of life followed by loss of spoken language, problems with walking, loss of purposeful hand use, and distinctive repetitive, hand movements. Rett syndrome primarily affects girls and women and occurs in about 1 in 10,000 live female births.

The recent study, supported by Neuren Pharmaceuticals and, was a phase 2, double-blind, placebo-controlled trial, in which participants with RTT were given a placebo, or were given trofinetide at a low or at a high dose. They were on that experimental medicine for 6 weeks and clinicians monitored how they were doing over time, both by asking the parents how they thought their sons or daughters were doing and also by seeing the individuals in-person. Researchers used a series of questionnaires, scales, and measures to rate how well participants were doing before, during, and after on various features.

"We found that all dose levels were tolerated and generally safe," said Neul. "People who were on the highest dose of the drug showed the most improvement during that time, and when they stopped taking the medicine, improvements were lost," said Neul. "During the study, they improved in a global way and on some of the parent-reported scales, especially scales of behavioral issues. What's also very interesting is that not everyone improved on the same exact features. Each participant showed improvements, but in different ways."

Neul says that while they don't yet know why improvements vary from person to person, he suspects it is because the drug is not targeting a specific symptom, but instead is targeting how the brain is working.

"It's likely improving the functionality of the brain in people with Rett syndrome," said Neul. "If that is the case, it really emphasizes the advantage of using a clinician-rated, global impression measure. We're asking the clinician to rate how well someone is doing now as compared to when they first started. And the clinician can take the overall impression of the participant rather than just asking something like, 'How bad are the seizures now?' or 'How labored is his or her breathing now?' It seems that with this medicine, seeing different improvements in different people means we would have missed the promise of the drug therapy without that global inquiry."

The safety and effectiveness of trofinetide, as evidenced by the study findings, has supported an additional large, phase 3 trial that will take place at multiple sites across the United States later this year. Depending on those results, the drug could be moving closer to recognition from the FDA as a viable treatment for the core signs and symptoms of RTT.

"It's very exciting that we are at a new point in Rett syndrome research," said Neul. "We are thinking about evaluating drugs and therapies that could potentially be disease-modifying. They are not just treating symptoms or putting a 'Band-Aid' on a problem. They may be changing the course of the disease and how it progresses. Also, moving into a large phase 3 trial in a rare disease like Rett syndrome is remarkable. Very few drug therapies for rare diseases have gotten to the point where industry and people are willing to invest and support a large trial like we are about to see. It's a new era."

To learn more about Rett syndrome research and clinics, visit