Trofinetide Safe and Effective at Higher Dose for Fragile X, Phase 2 Trial Finds

Oral treatment with trofinetide was well tolerated and, at a higher dose, eased social avoidance, anxiety, hyperactivity and other symptoms of fragile X syndrome in adolescent and adult males, results of a Phase 2 trial show.

The study, “A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Fragile X Syndrome,” was published in the journal Pediatric Neurology.

Fragile X is caused by expansion of a CGG repeat in the FMR1 gene, which disrupts production of the FMRP protein. (C stands for cytosine and G for guanine, two of the four building blocks of DNA.)

Neuren Pharmaceuticals‘ trofinetide (NNZ-2566) is an analog of a portion of insulin-like growth factor 1 (IGF-1), a hormone that promotes normal bone and tissue growth, while also regulating nerve cell function. Besides fragile X, trofinetide is in late-stage clinical development as a possible treatment for Rett syndrome.

Preclinical work in a mouse model found that trofinetide, given over four weeks, eliminated all symptoms mimicking those seen in people with fragile X, such as hyperactivity and troubled social behavior. Neuroinflammation also stopped and brain IGF-1 levels normalized.

The multicenter and double-blind Phase 2 study (NCT01894958) tested the safety and tolerability of trofinetide in 72 males with fragile X, ages 12 to 41 (mean age, 23.5).

All  were given a placebo for the first two weeks, followed by four weeks (28 days) with either the investigative therapy at one of two doses — 35 mg/kg or 70 mg/kg — or a placebo, both taken twice daily.

No deaths or serious side effects were reported over the course of the trial. Four people withdrew before the final visit at day 56, but none due to side effects of trofinetide’s use.

The most common side effects overall were upper respiratory tract infection (occurring in 7% of participants), and diarrhea (6%).

The most frequent side effects reported in the 35 mg/kg group were diarrhea, vomiting and headache, all occurring in 8% of the patients. In the 70 mg/kg group, the most common adverse effects were diarrhea (9%) and fatigue (9%). Most effects were described as mild to moderate in severity.

Participants showed no evidence of withdrawal symptoms after discontinuing trofinetide at the end of the study.

Trofinetide also showed early evidence of clinical benefit. While no gold standard measure to assess the core symptoms of fragile X exists, researchers settled on two scales developed for the study to evaluate trofinetide’s efficacy.

Namely, the Fragile X Syndrome Rating Scale (FXSRS) and the Fragile X Syndrome Domain-Specific Concerns (FXSDSC) scale each had clinician-reported outcomes to assess the severity of  disease symptoms.

Items scored included measures of intellectual disability, repetitive behaviors, speech and language, anxiety, phobias and social withdrawal, motor performance, and cognition.

Compared to both the lower dose and the placebo, patients receiving the higher dose of trofinetide (70 mg/kg) improved their scores on both of these scales, as well as on the caregiver-completed Aberrant Behavior Checklist-Community tool adapted for fragile X (ABC-CFX). This assessment addresses common behavioral problems associated with fragile X, such as irritability, stereotypic behavior (repetitive, purposeless behavior), hyperactivity, inappropriate speech, and social avoidance.

Notably, the researchers said the analysis supported the utility of the FXSRS and FXSDSC scales, which are specific to fragile X symptoms. Finding appropriate measures for clinical trials has been a limitation in fragile X research, they added.

“These efficacy findings are notable given the short length of the treatment duration (28 days), as well as the degree of disability and symptom severity in these adolescent and adult subjects,” the researchers wrote.

“This suggests a potential for trofinetide treatment to provide clinically meaningful improvement in core FXS [fragile X syndrome] symptoms,” they added.