Mavoglurant disappoints in fragile X trials

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Mavoglurant findings illuminate trial path

The findings of Dr. Berry-Kravis et al. yield important lessons for clinical trial design. Rather than concluding that the negative findings prove that a treatment is ineffective or that presumed underlying pathophysiological mechanisms are invalid, trials like this one provide an opportunity to reflect on clinical trial design and implementation, as well as the underlying mechanistic motivations, and provide lessons for treatment studies of neurodevelopmental disorders in general. This trial highlights key themes to consider in clinical trials, including choice of treatment group, target engagement, selection of outcome measures, and the impact of the placebo effect.

We stand at a therapeutic frontier, with much more to learn. While the result of negative trials are disappointing, they also can be crucial for refining hypotheses and encouraging dialogue to accelerate the process of bringing effective treatments to our patients.

Dr. Shafali S. Jeste and Dr. Daniel H. Geschwind are with the University of California at Los Angeles. These comments are adapted from an accompanying editorial (Sci Transl Med. 2016 Jan 13. doi:10.1126/scitranslmed.aab4109.). The authors did not report financial disclosures.




The selective metabotropic glutamate receptor 5 (mGluR5) antagonist mavoglurant failed to improve behavioral symptoms in patients with fragile X syndrome in two phase IIb, multicenter, randomized, placebo-controlled studies.

A post hoc analysis of a prior phase II trial suggested that mavoglurant improved such symptoms in fragile X syndrome patients with completely methylated FMR1 genes, and the current trials were designed to confirm the findings in 175 adults and 139 adolescents, respectively.

But no change in maladaptive behavior, as measured using the Aberrant Behavior Checklist–Community Edition and fragile X syndrome-specific algorithm (ABC-Cfx), was seen 12 weeks after treatment with either 25, 50, or 100 mg of mavoglurant or placebo twice daily for 12 weeks, Dr. Elizabeth Berry-Kravis of Rush University Medical Center, Chicago, and her colleagues reported online Jan. 13 in Science Translational Medicine.

In completely methylated adults, the change in ABC-Cfx score at 12 weeks was similar with placebo and 25 mg mavoglurant (–11.4 and –14.3), and nearly unchanged with 50 and 100 mg of mavoglurant (1.8, -1.8). In adolescents, the corresponding changes were –9.4, –11.8, –3.4, and 8.6 (a statistically significant deterioration vs. placebo). Outcomes were similar in partially methylated adults and adolescents.

©Dr. Marian L. Miller/ ASA 3.0

Since the primary efficacy endpoint of improvement in behavioral symptoms was not met, the mGluR theory of fragile X syndrome as suggested by animal models – namely that the absence of fragile X mental retardation protein can cause overactivation of mGluR signaling, contributing to the features of the fragile X syndrome phenotype – could not be confirmed, nor could the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy, the investigators wrote (Sci Transl Med. 2016 Jan. 13. doi:10.1126/scitranslmed.aab4109).

“One of the most plausible explanations for the negative results is that the mGluR theory on which the studies were based may not be valid or may manifest itself differently in humans, compared to rodents,” they wrote, noting that a combination of targeted treatments may be needed for optimal treatment of fragile X syndrome. Further, preclinical trials suggested that treatment at a younger age and for longer durations might have a greater effect; this approach warrants evaluation in a future trial, they wrote.

This study was supported by Novartis Pharma AG. Dr. Berry-Kravis has served on the Novartis Fragile X Advisory Board and has consulted for Novartis. Other authors also served on the board and have consulted for Novartis and/or Roche, or are employed by Novartis.

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