Pauline Anderson

June 22, 2015

BERLIN, Germany — A novel agent is holding out some much-needed promise for girls and women with Rett syndrome.

An exploratory phase 2, double-blind, placebo-controlled trial shows that the drug is safe, well tolerated, and effective in managing core symptoms of this rare degenerative disease.

The new results provide "initial evidence" that the drug may be an effective treatment for Rett syndrome, concluded lead author, Daniel G. Glaze, MD, Baylor College of Medicine, Houston, Texas.

Dr Glaze presented the results at the first Congress of the European Academy of Neurology (EAN).

Rett syndrome occurs in about 1 in 10,000 people. Almost all are female; 95% of patients with this disorder have a mutation in the MECP2 (methyl CpG binding protein 2) gene, which is located on the X chromosome.

The condition is characterized by an initial period of normal development followed by regression beginning at 6 to 18 months. During this regression phase, girls may lose spoken communication and normal gait. They often display features similar to autism.

Many patients with Rett syndrome have breathing problems while awake. About 70% have epilepsy. The incidence of sudden unexpected death among patients with the syndrome is higher than in the general population.

No Approved Drugs

"There is currently no approved or proven effective treatment or medication for Rett syndrome," Dr Glaze said.

The proposed new drug — glycycl-L-2-methylprolyl-L-glutamic acid — is a synthetic analogue of insulin-like growth factor-1. In knockout mice, the agent restores long-term potential, enhances dendritic growth, and improves longevity.

"In addition, this drug reduces pro-inflammatory cytokines and is neuroprotective in this respect," Dr Glaze said, adding that it also normalizes the activity and function of astrocytes.

The drug, the proposed name of which is trofinetide, is given in a liquid form. It has garnered a good safety and toleration profile in healthy human volunteers, he noted.

Moderate to Severe Disease

The current study enrolled 56 female patients, aged on average about 25 years, who met diagnostic criteria for Rett syndrome and had moderate to severe disease (4 or greater on the Clinical Global Impression Score [CGI-S]).

Participants were randomly assigned to one of three cohorts. The first included 9 patients who received placebo or 35 mg/kg of the drug twice daily for 14 days. The second group, with 18 patients, received placebo or 35 mg/kg of trofinetide twice daily for 28 days, and the third group, with 29 patients, received placebo or 70 mg/kg of the drug twice daily for 28 days.

The groups were similar in terms of age and disease severity.

The prespecified clinical benefit was defined as a change in six core measures comprising four efficacy domains. The group analysis required improvement in at least two core measures from two different efficacy domains, As well, to achieve efficacy, none of the six measures could show worsening; they would have to show no change or show improvement, said Dr Glaze.

Researchers also calculated a patient-specific efficacy score that was based on composite changes in the six measures and comparison of the mean scores between treatment and placebo groups.

Adverse Events

The study found that according to parent reports, electrocardiograms, physical examinations, and laboratory evaluations, both doses — 35 mg/kg and 70 mg/kg — were safe and well tolerated after 28 days of treatment. "There were no significant adverse side effects, dose related or time related," commented Dr Glaze.

The higher dose (70 mg/kg) exceeded the prespecified criteria for improvement: Patients taking this dose had greater improvements than placebo in Motor Behaviour Assessment; CGI-S; and a category called Caregiver Top 3 Concerns, in which caregivers were asked what they felt were the most concerning symptoms and the ones they would like most to see improved with therapy.

No prespecified clinically significant worsening occurred in any core endpoints.

"This evidence of efficacy was shown for the highest dose and was not evident for the 35-mg dose," commented Dr Glaze.

"The bottom line is that this study demonstrated that the drug is safe and well tolerated at doses of 35 and 70 mg per kg and it demonstrated that the highest dose exceeded prespecified criteria for clinical benefit," he concluded. "I suggest that these results provide initial evidence that NNZ-2566 may be an effective drug for treating Rett syndrome, and that it supports further studies."

Session co-chair Hannah Cock, MD, senior lecturer, Epilepsy Group, Centre for Clinical Neurosciences, St Georges, University of London, United Kingdom, commented that the number of patients who were recruited for the study was "impressive" considering that the condition is relatively rare.

"That reflects that they're desperate for new treatments," she said.

Dr Cock wondered about estimates of numbers needed for a phase 3 study on efficacy.

Dr Glaze reported that another phase 2 study on safety and tolerability in children would likely be undertaken next, followed by a phase 3 study in children, adolescents, and adults.

The study was funded by Neuren Pharmaceuticals and the International Rett Syndrome Foundation.

Congress of the European Academy of Neurology (EAN). Abstract 02107. Presented June 21, 2015.


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