Mavoglurant Safe, Well-tolerated Long-term in Adolescents and Adults with Fragile X Syndrome, Studies Show

Mavoglurant is safe and well-tolerated in the long-term to treat adolescents and adults who have fragile X symptoms. The investigational compound also is associated with positive efficacy results, according to results from two clinical studies.

The research with those findings, “Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents,” was published in the journal Scientific Reports.

Fragile X, the most common genetic cause of autism, is characterized by a mutation in the FMR1 gene, which disrupts the production of the FMRP protein. FMRP regulates protein production at the synapse —  the site where neurons communicate — via a type of glutamate receptors called metabotropic glutamate receptors (mGluRs), among other targets. Glutamate is the main excitatory neurotransmitter in the central nervous system, which includes the brain and the spinal cord.

Loss of FMRP causes abnormal cell communication, which is believed to underlie the behavioral and cognitive symptoms of fragile X. Preclinical studies have shown that Novartis’ mavoglurant, a selective mGluR5 blocker, restores normal architecture of dendritic spines (small neuronal protrusions participating in synapses) and social behavior in a mouse model of fragile X.

A Phase 2a trial (NCT00718341) that recruited 30 male fragile X patients suggested efficacy of mavoglurant in patients with a fully methylated (the addition of methyl chemical groups that can “turn off” genes) FMR1 gene, thereby supporting larger-scale development.

Despite good safety and tolerability results, the efficacy of mavoglurant was not superior to that of placebo in two 12-week Phase 2b trials in adolescent (NCT01357239) and adult fragile X patients (NCT01253629). Results of the Clinical Global Impression – Improvement (CGI-I) scale (which measures symptom severity, treatment response and effectiveness) did not show a benefit in mavoglurant treatment. That led to its discontinuation in 2014. Among the reasons for this lack of effectiveness, the team mentioned the relatively brief intervention period.

Two Novartis-sponsored open-label, extension studies in adolescents (NCT01433354) and adults (NCT01348087) with fragile X were initiated to ensure that the trials’ participants had continued access to mavoglurant. These studies also enabled further evaluation of the treatment’s safety and effectiveness over a longer treatment period. Both ran from 2011 to 2014.

Each extension study was planned to last 24 months or until mavoglurant would become available in the market, whichever occurred later. Extension of treatment beyond 24 months was possible, if required.

A total of 119 adolescent (age 12-19 years) and 148 adult (age 18-45 years) fragile X patients received up to 100 mg mavoglurant twice daily for up to 34 months. The initial dose was 25 mg, which could be increased at weekly intervals until the patients reached their highest tolerated dose. Concomitant medication to treat co-morbid behavioral symptoms was allowed. (A comorbidity refers to the presence of one or more additional disorders.)

Safety assessments included reports of adverse events (AEs) and serious AEs (SAEs), standard clinical laboratory measures, electrocardiograms (ECGs), regular physical examination, and assessment of vital signs, body height, weight, and pregnancy status.

The modified, 55-item Aberrant Behavior Checklist – Community edition Fragile X Syndrome specific algorithm (ABC-C_FX) scale was used to evaluate behavior. Also, the Clinical Global Impression — Severity (CGI-S) scale was employed to measure baseline illness severity, while CGI-I addressed global changes in symptoms. The team further used the caregiver-rated Repetitive Behavior Scale – Revised, and the Social Responsiveness Scale to assess autistic spectrum symptoms.

Both studies were terminated prematurely due to lack of proven efficacy in the core Phase 2b studies. Mean exposure time to mavoglurant was 513.2 days in the study with adolescents, and 538.3 days in the trial with adults. Ninety-one adolescents (76.5%) and 135 adults (91.2%) received the intended mavoglurant 100 mg twice-daily dose for one or more days. More than 69% of patients received this dose from day 22 onward in both trials.

Treatment with mavoglurant was well-tolerated with no new safety signal. Most adolescents (92.4%) and adults (93.2%) reported at least one AE, with nasopharyngitis (29.4% in adolescents, 18.2% in adults), insomnia (21.0%/15.5%), aggression (16.0%/15.5%) and upper respiratory tract infection (14.3%/16.2%) being the most common. Most AEs were mild or moderate in both studies, and were more common in patients on the 100 mg twice-daily dose.

Four adolescents (3.4%) and seven adults (4.7%) experienced a SAE, with cases of aggression, visual hallucinations and liver enzyme elevations considered possibly related to mavoglurant. The data further show that 5% of adults and 16.9% of adolescents discontinued treatment due to adverse events such as psychiatric disorders (4.2% in adolescents/12.2% in adults) and nervous system disorders including dizziness, speech disorder, headache, incoherent/poor quality sleep, and psychomotor hyperactivity (2.5%/4.1%).

Gradual and consistent improvements of behavioral symptoms were observed, which were superior to those in placebo-treated patients in the core studies. At 12 weeks, clinicians rated more than 75% of patients in both studies as showing an improvement in their global FXS symptoms. The patients’ repetitive behavior and social interactions also showed gradual improvements from baseline.

However, “these positive trends should be interpreted with caution given that the studies do not have a control group and thus cannot make comparative assessment of efficacy,” researchers cautioned.

Overall, “these two extension studies confirm the long-term safety of mavoglurant in FXS [fragile X],” they wrote. Further investigations are needed to determine whether the benefits seen in preclinical studies translate to humans, the team added.

Of note, four of the study’s authors are employees of Novartis. Three others served on the Novartis Fragile X Advisory Board, and four consulted for Novartis.