First Treatment Approved for Rare Genetic Neurologic Disorder

The FDA approved trofinetide (Daybue), the first drug to treat adult and pediatric patients age 2 and older with Rett syndrome, drugmaker Acadia Pharmaceuticals announced Friday.

“Now, for the first time after decades of clinical research, healthcare providers finally have a treatment option to address a range of core behavioral, communication, and physical symptoms for their patients living with Rett syndrome,” said Jeffrey Neul, MD, PhD, of Vanderbilt University Medical Center in Nashville, in a statement from Acadia.

Rett syndrome, a rare, debilitating, X-linked neurodevelopmental disorder, primarily affects girls and women. Birth and early development are normal, followed by slowed development, loss of purposeful hand use, slowed brain and head growth, problems walking, intellectual disability, and seizures. Symptoms often include repetitive hand movements such as hand wringing or clapping.

The disorder typically is caused by a mutation in the MECP2 gene. There are an estimated 6,000 to 9,000 cases of Rett syndrome in the U.S. and a diagnosed population of 4,500 patients.

Trofinetide is a synthetic analog of glycine-proline-glutamate, a naturally occurring tripeptide cleaved from insulin-like growth factor 1 (IGF-1). The drug was designed to treat symptoms of Rett syndrome by reducing neuroinflammation and supporting synaptic function. Its mechanism in Rett syndrome is unknown.

The FDA’s decision was based on the phase III pivotal LAVENDER trial of 187 girls and young women 5 to 20 years old with Rett syndrome. Participants had a MECP2 mutation, were past regression (they had not lost any skills in the preceding 6 months), and had a stable pattern of seizures or no seizures within 8 weeks of screening.

Overall, 93 participants were randomized to trofinetide and 94 to placebo. Treatment was given orally or by gastrostomy tube using weight-based dosing.

After 12 weeks of treatment, differences in two co-primary endpoints and a key secondary endpoint were seen with trofinetide versus placebo, Neul reported at the 2022 American Academy of Neurology meeting:

Most participants in the trofinetide group (92.5%) had a treatment-emergent adverse event, most commonly mild to moderate diarrhea or vomiting. Adverse events led to study withdrawal in 17.2% of the trofinetide-treated participants. In both groups, 3.2% of participants had serious treatment-emergent adverse events. There were no fatalities.

Both diarrhea and weight loss may occur with trofinetide, the drug label warned. Plasma concentrations of CYP3A4 substrates may be increased if given with trofinetide and can lead to serious toxicities; patients with concomitant use should be closely monitored for adverse reactions. Concomitant use of trofinetide and OATP1B1 and OATP1B3 substrates should be avoided. The drug is not recommended for patients with moderate to severe renal impairment.

Trofinetide is expected to be available in the U.S. by the end of April 2023, Acadia said.