Introduction to clinical trials of mGluR5 antagonists for the treatment of Fragile X Syndrome

The purpose of this series of posts is to examine some human clinical trials of medications intended to improve behavior and cognition in Fragile X Syndrome.

Summaries of several of these clinical trials have already been published. For example, a review with tables of various clinical tests used during several FXS drug trials can be found in:

“The challenges of clinical trials in fragile X syndrome”,

Sébastien Jacquemont, Elizabeth Berry-Kravis, Randi Hagerman, Florian von Raison, Fabrizio Gasparini, George Apostol, Mike Ufer, Vincent Des Portes & Baltazar Gomez-Mancilla, Psychopharmacology (2014) 231:1237–1250 DOI 10.1007/s00213-013-3289-0. LINK

The intention here is to take a slightly different perspective.

First, it is interesting to note that in many articles describing the results of clinical trials, the repeated positive results of drug tests in “Fragile X” (FX) animal models are cited in a perfunctory fashion, generally without much, if any, attempt to make a detailed comparison between what was done with the animal and the human subjects.

Second, there is not much discussion of limitations in what animal models can predict about human testing involving higher order cognition. These are two of the issues we wish to address.

In these posts we will ask what might have been observed by researchers who actually provided pharmaceuticals to FX model mice, had analogous tests and drug regimes used in FXS clinical trials been given to those mice.

The reverse would also be good to consider in theory, though in many cases perhaps impractical, since clinical researchers cannot control human subjects as preclinical researchers can control other animals.

In other words, given the repeatedly significant drug effects noted in FX model mice, were there any particularly notable differences in the way the same drugs were administered and tested in human subjects that could be worth further consideration?

The approach

These presentations will attempt to provide sufficient search detail so that it should be apparent how the information discussed was found. The impetus for such posts is the primary author’s various discussions with parents of children with Fragile X Syndrome, so these posts will try to be accessible to the well-versed parent with a FXS family member. It is hoped that these posts will help bring additional ideas into consideration when testing treatments.

The first two key questions we will address in subsequent posts will be:

1) What is the structure of the clinical trials in general and the recently completed FXS clinical trials in particular?

2) What documents should we be expect to find that provide data and results for a clinical trial?

Then, we will assess data from the AFQ056 (mavoglurant) clinical trials for FXS, followed by that for Roche RO4917523 (RG7090). Issues related to data availability will also be addressed.

A separate series of posts will present comments on preclinical animal research of note to us. In particular, in order to make comparison to the human FXS clinical trials, information will be presented on FX mouse model dosing, phenotypes, and issues previously uncovered (tolerance, assay specificity, etc).