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The investigational drug trofinetide showed modest benefit in girls and young women with Rett syndrome, the phase III study showed.

After 12 weeks of treatment, significant differences in two co-primary endpoints and a key secondary endpoint were seen with trofinetide versus placebo, reported Jeffrey Neul, MD, PhD, of Vanderbilt University in Nashville, in a clinical trials plenary session at the American Academy of Neurology annual meeting.

On the Rett Syndrome Behavior Questionnaire () 45-item caregiver-completed scale -- a co-primary endpoint that reflects caregiver assessment of Rett syndrome symptoms -- scores dropped by 5.1 points for trofinetide and 1.7 points for placebo (P=0.0175, Cohen d=0.37) from baseline to week 12.

On the other co-primary endpoint, the clinician-rated Clinical Global Impression of Improvement () scale, scores were 3.5 for trofinetide and 3.8 for placebo (P=0.0030, Cohen d=0.47) at week 12. Scores on the CGI-I scale range from 1 (very much improved) to 7 (very much worse).

On the secondary endpoint -- the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist-Social ( Social) composite score of 13 items rated by caregivers -- change at week 12 was -0.1 for trofinetide and -1.1 for placebo (P=0.0064, Cohen d=0.43).

"Rett syndrome is a significant, severe, rare, debilitating, X-linked neurodevelopmental disorder, which currently is approached in an entirely symptomatic way, so there is no approved treatment," Neul said. "There are about 6,000 to 9,000 identified cases in the United States, but this is very likely an underrepresentation."

Rett syndrome primarily and women. The disorder is characterized by normal birth and early development followed by slowed development, loss of purposeful use of hands, slowed brain and head growth, problems walking, intellectual disability, and seizures. Most Rett syndrome cases are caused by a mutation in the MECP2 gene.

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.

In MECP2-, IGF-1 treatment improved symptoms. A of trofinetide in children and adolescents with Rett syndrome showed improvement over placebo in functionally important dimensions.

The phase III LAVENDER study evaluated the efficacy and safety of trofinetide in 187 girls and young women with Rett syndrome. Participants had a disease-causing mutation in the MECP2 gene, 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. Treatment was given orally or by gastrostomy tube using weight-based dosing.

In total, 93 participants were randomized to trofinetide and 94 to placebo. Mean age in each group was 11. The groups were balanced for baseline disease severity on the Clinical Global Impression of Severity () scale and for key comorbidities including constipation and seizure.

Improvements were seen in all subscales of the RSBQ with trofinetide. "This represents that the overall effect on RSBQ was not driven by one or two of the domains, but seemed to be a more generalized pattern of improvement," Neul said.

On both RSBQ and CGI-I scores, all age groups -- 5 to 11, 12 to 16, and 17 to 20 -- showed benefit with trofinetide.

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.

The FDA has granted and orphan drug designation to trofinetide for Rett syndrome. The drug also received a rare pediatric disease designation from the agency.

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