What to make of the clinical trial failures in fragile X

To summarize: the official results from both the adult and adolescent trials of AFQ056 for fragile X were decidedly negative. Not only was there no improvement on pre-designated outcome measures, but subjects did a bit worse on the drug than on placebo (and placebo effects were robust, but in line with other trials in developmental disorders.) However, it is important to note that trial subjects got better on the drug, just not as much better as on placebo. Extensive analysis of the trial results after the fact ("post-hoc analysis") revealed no obvious differences in clinical responses between the different drug dosage groups and placebo. Subjects with a fully methylated fragile X mutation didn't respond any better than those with a partially methylated mutation, more severely affected subjects didn't respond any better than less severely affected (or vice versa.) So, the drug simply didn't work in any way that anyone can see or measure objectively, though many families reported excellent results, and most of the subjects in the open label extension continued on the drug, apparently satisfied with the drug's effect.

Our personal experience, which may have been a bit aypical because of co-administration of minocycline, was much more positive than the official results. Even so, the great results we saw at the beginning of the trial, and then during the first few months of the open label extension, just didn't last. We think there is still some beneficial effect at this point, but we were certainly hoping for continuous improvement.

The most important point is that this isn't just a problem with outcome measures. It would be great if we could attribute this negative outcome entirely to inadequate outcome measures. It's still possible, though increasingly implausible, to claim that the drug is actually improving cognition and other important developmental outcomes which aren't captured by the outcome measures, while at the same time having little beneficial effect (and even some adverse effects) on behavior. However, that isn't what we saw at all. We saw clear improvements in mood and behavior (not to mention reflux), and our son's ABC scores plummeted (before creeping back up later.) We have not seen any major leaps forward in development, or dramatic improvements in cognitive function. Now, improved behavior and mood can make everything seem better, at least for a while, and this may be what some families were observing. When people feel better, they generally do more and expand their range of activities. But this effect won't alter developmental trajectories. In other words, it won't be truly disease-modifying unless there is a sustained effect on all major fragile X symptom domains.

Where does this leave us, then? Well, first of all, mGluR5 antagonists probably won't be a viable treatment for anything if tolerance develops to this extent, and we've seen tolerance develop to the anti-reflux effects as well as the CNS effects. It's no coincidence that so many of the mGluR5 programs around the world have failed and been discontinued. This implies that this target many not be viable for fragile X therapeutics, although it is possible that trials of higher doses of mGluR5 antagonists, perhaps in combination with other drugs, could still be effective. However, this greatly complicates the "re-purposing" strategy, since most drugs are developed with a particular dose range in mind, and most drug companies would need to go back and repeat this process specifically for fragile X. It is not likely that any company will be enthusiastic about incurring this expense in light of recent experience.

We have many more thoughts about where the fragile X research field needs to go, and we'll discuss those ideas in future posts.