Novartis has published the results of two Phase II trials of its metabotropic glutamate receptor 5 (mGluR5) inhibitor mavoglurant in Fragile X syndrome (FXS), 2 years after discontinuing development of the drug. Two Phase II trials — one in 175 adults and one in 139 adolescents — both failed to find any efficacy signal on their primary end point, the company now reports (Sci. Transl Med. 8, 321fs1; 2016).

The trial results are a disappointment, although not yet a fatal blow, for the mGluR theory of Fragile X. This theory holds that the absence of Fragile X mental retardation protein (FMRP) can cause overactivation of mGluR signalling, leading to FXS. Because FXS is the most common single-gene disorder cause of autism, mGluR might have an important role in the origins of other autism spectrum disorders.

Speaking with Nature Reviews Drug Discovery last year, Novartis and other Fragile X experts said that the field was struggling to figure out how to best test Fragile X drugs. It remains unclear which patients are most likely to benefit, and which clinical end points are most likely to capture a response (Nat. Rev. Drug Discov. 14, 151–153; 2015).

With the full results out, Novartis re-affirmed these concerns. “Challenges to translation of results in model organisms to humans for FXS thus include uncertainties around optimal patient selection, age of treatment onset, dosages and durations of treatment, differences in pharmacokinetics and pharmacodynamics, dose-limiting side effects, and biomarkers of CNS improvement,” the Novartis scientists write. “If the understanding of targeted treatment effects in FXS is to progress, and if the mGluR theory of FXS is to be fully tested, it will be necessary to design new trial paradigms to investigate effects of mGluR agents in young children and to incorporate measures of learning into the protocol.”

“The results of negative trials, while disappointing, can be crucial in refining our hypotheses and encouraging dialogue that will accelerate the process of bringing effective treatments to our patients,” write another set of authors in an accompanying article (Sci. Transl Med. 8, 321fs1; 2016).