Phase 3 Trial for Trofinetide Planned After Positive Phase 2 Results in Rett Syndrome

Ana Pena, PhD avatar

by Ana Pena, PhD |

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Investigational therapy trofinetide showed promising safety and efficacy results as a treatment for children and adolescents with Rett syndrome, according to recent data from a Phase 2 clinical trial.

A Phase 3 trial is now planned for the second half of this year to further assess the effectiveness and safety of trofinetide in females with Rett syndrome. 

Results were published in the study,“Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome,” were published in Neurology.

“These results are very encouraging because they provide strong evidence that trofinetide may be a potential treatment for Rett syndrome,” Steve Kaminsky, PhD, chief science officer of, which funded the trial together with Neuren, said in a press release

Trofinetide, also known as NNZ-2566, is a compound derived from a protein called human insulin-like growth factor 1 (IGF-1), a naturally occurring growth factor in the brain, required for its normal development and response to injury and disease.

In the brain, IGF-1 is broken down into a small protein fragment called glypromate (GPE).

Trofinetide is a modified version of GPE, designed to mimic its biological function while displaying more favorable pharmacological properties: It’s easier to store, it can be administered orally, and it remains for longer periods in the bloodstream.

IGF-1 and GPE are important in maintaining the biological balance necessary for the normal functioning of the developing brain and for responding to disease, stress, and injury in the mature brain.

Some studies have reported abnormally lower levels of IGF-1 in the brain in several conditions, particularly in Rett syndrome, fragile X syndrome, and brain injury. Restoring the levels of IGF-1 and GPE may help repair the deficits present in the brains of people affected by these disorders.

Preclinical data has shown that trofinetide can reduce inflammation, provide neuroprotection, support the development connections between nerve cells, and correct the levels of IGF-1, working to restore the brain’s natural balance.

Neuren Pharmaceuticals launched the multicenter Phase 2 trial (NCT02715115) in 2017 to assess the safety, tolerability, and effectiveness of trofinetide in children and adolescents with RTT.

The study evaluated 82 females, ages 5 to 15 years. Of these participants, 62 were randomized to receive a placebo twice a day for 14 days, followed by a placebo, plus 50, 100, or 200 mg/kg twice a day of an oral solution of trofinetide for 42 days.

After a blinded safety data review, 20 additional participants were randomized to receive the highest dose of trofinetide (200 mg/kg) or a placebo.

Efficacy was evaluated based on changes from treatment start at day 14 to the end of treatment at 56 days in core efficacy outcomes, which included clinician and caregiver assessments.

Results revealed that the highest dose of trofinetide led to clinically significant improvements for a range of core symptoms, compared with the placebo.

Significant improvements were observed in three out of five efficacy measures: the Rett Syndrome Behaviour Questionnaire (RSBQ), the Clinical Global Impression Scale-Improvement (CGI-I) and the RTT-Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC).

RSBQ is a validated rating scale in which caregivers rate the frequency of neurobehavioral symptoms. CGI-I and RTT-DSC are both clinician-completed scales; CGI-I addresses how much a patient’s illness has improved/worsened, while RTT-DSC deals with the severity of concerns identified for hand use, walking, seizures, behavior, social interaction and communication, among others.

Trofinetide was found generally safe and well-tolerated at all doses tested.

“The data reported in this study show that females treated with trofinetide experienced lessened neurobehavioral impairments including social communication deficits, anxiety-like behavior, and mood dysregulation. These are very promising data for the Rett community that is currently without any U.S. FDA-approved treatment option,” said lead author Daniel G. Glaze, MD, a professor of pediatrics and neurology at Baylor College of Medicine.

Acadia Pharmaceuticals signed a license agreement with Neuren in 2018 for the development and commercialization of trofinetide for Rett syndrome and other indications in North America.

The 12-week Phase 3 study now being planned aims to recruit about 180 females, ages 5 to 20. Half of the study participants will receive trofinetide and half will receive placebo. This will be followed by a nine-month extension study to evaluate the long-term tolerability and safety of the treatment.

Both the U.S. Food and Drug Administration and the European Medicines Agency have granted trofinetide orphan drug designation for the treatment of Rett syndrome. In addition, the FDA also gave the compound a fast track designation.