Gilenya Fails to Ease Rett Symptoms in Phase 1/2 Trial

Despite being safe, one year of treatment with Gilenya (fingolimod) in young girls with Rett syndrome failed to ease such disease symptoms as lack of communication, motor impairments, and apraxia, or the inability to perform movements previously learned, a small Phase 1/2 trial showed.

Moreover, the findings from the study, called FINGORETT (NCT02061137), show that Gilenya also failed to meet the trial’s primary goal of increasing the levels of the protein BDNF, or brain-derived neurotrophic factor.

This protein is important for nerve cell survival, but its levels are thought to be diminished in people with Rett syndrome. Earlier studies had suggested that treatment with fingolimod (FTY720) could help increase these levels, but that did not happen among the six girls in this study, data showed.

These trial findings were reported in a study, “Fingolimod in children with Rett syndrome: the FINGORETT study,” published in the Orphanet Journal of Rare Diseases.

Rett is primarily caused by a mutation in the gene coding for a protein called MeCP2. This protein normally controls the activity of several genes, including the gene that encodes BDNF.

Previous studies have shown that BDNF levels are abnormally low in animal models of Rett, and that treatment with fingolimod — sold under the brand name Gilenya, by Novartis — can help increase them. Fingolimod also was found in animal models to lead to a higher gray matter volume and to lessen Rett symptoms. Gray matter refers to brain regions mainly made up of neuron cell bodies.

As Gilenya, the oral therapy has been approved to treat relapsing forms of multiple sclerosis (MS) in children and adults. In MS patients, the medication helps reduce inflammation and nerve cell damage by preventing immune cells from exiting the lymph nodes where they are produced, which prevents them from reaching the brain and spinal cord.

Here, an international team of investigators had explored the therapeutic potential of Gilenya in a small group of children and adolescents with Rett in a Phase 1/2 trial.

The trial, conducted in collaboration with Novartis, enrolled six girls with a mean age of 11.3 years and a confirmed diagnosis of Rett. All had been treated at the University of Basel Children’s Hospital, in Switzerland.

All of the girls were monitored for six months before starting treatment with Gilenya, which was given by mouth at a daily dose of 0.25 or 0.5 mg, depending on their body weight, for one year. An additional period of six months of observations then followed.

The study’s main goals included assessing Gilenya’s safety, as well as its effects on gray matter volume, as assessed by brain MRI scans, and on BDNF levels in the blood and cerebrospinal fluid (CSF), which surrounds the brain and spinal cord.

Additional goals included assessing the effects of treatment on several measures of disease and symptom severity, including the Rett Severity Scale (RSSS), the Hand Apraxia Scale (HAS), and the Vineland Adaptive Behaviour Scale (VABS).

BDNF levels also were measured in blood samples collected from 50 children — 25 boys and 25 girls, with a mean age of 13.5 years — who did not have the disease to establish a basis for comparison.

Safety analyses showed Gilenya was safe and did not cause any serious side effects during the study.

Yet, no significant changes in BDNF levels were seen in the patients’ blood and CSF samples over the course of the study. Likewise, no significant alterations were seen over time in brain imaging measures, nor in any of the clinical scales used.

In addition, no significant differences were found in BDNF levels measured in blood samples taken from girls with Rett — mean of 25.4 nanograms per milliliter (ng/mL) — and those collected from healthy children (mean of 22.14 ng/mL) at the study’s start.

Statistical analyses also found that BDNF levels in the CSF, but not in the blood, were associated with the scores of the different measures of disease and symptom severity. High RSSS and HAS scores, indicative of higher disease severity and worse apraxia, were associated with lower BDNF levels, while high VABS scores indicative of improved social and motor skills were associated with increased BDNF levels.

According to the scientists, these findings highlight the “need to further evaluate the possible role of BDNF in the [development of Rett syndrome] and its utility as a potential, novel biomarker for [the disease].”

While trial findings indicated Gilenya was safe, “the study did not provide supportive evidence for an effect of fingolimod on clinical, laboratory, and imaging measures,” the researchers concluded.