Fragile X Clinical Trials: Was Tolerance the Problem?

Further thoughts on our AFQ056 experience

POSTED BY MICHAEL TRANFAGLIA MD

The recent Fragile X clinical trials sponsored by Novartis ended with a rather negative result. However, our personal experience included seeing a lot of positives in our son along the way. Could it be that there was something about our case that made a response more likely?

 

Combination Therapy (Drug Cocktails)

As mentioned previously, our son has been taking minocycline for years. I think that the combination of minocycline and AFQ056 was probably much more effective than just AFQ056 alone. The preclinical evidence for minocycline as a disease-modifying agent in fragile X is very strong, and the clinical trials done to date, though probably not rigorous enough to be considered definitive proof of efficacy, have been positive (unlike some others!)

It stands to reason that a combination of two drugs would work better, given that fragile X is a disorder that affects the brain globally. In other words, one drug might work well in one area of the brain, but not fix everything; another drug might work well in other areas or other pathways, so that the combination gives greater “coverage” and a better clinical response, especially with the rather crude outcome measures used in current clinical trials. It would be interesting to see if trial subjects on minocycline had any better pattern of response, but I doubt there were enough subjects on the combination to analyze properly (especially since many of the subjects were outside the US, where minocycline use in fragile X is much less common.

One question I’ve been asked a few times is, if there is tolerance developing to mGluR5 antagonists, why don’t the rating scales from the trials show that? Why don’t we see the scores go down, then back up? Of course, all of the above has an effect — most patients aren’t getting enough drug effect to notice in the first place. But this is also where the shortcomings of the outcome measures may come into play. The resolution of these rating scales, especially in the context of moderately large placebo responses, is simply nowhere near good enough to quantify tolerance (although, I should note that our scores did go way down, then back up a bit toward the end of the study; I believe our son’s clinician ratings also showed this.)

It’s also possible that there are sub-groups of fragile X subjects who are particularly responsive to one drug or another. We have friends who participated in both the arbaclofen trial and one of the mGluR5 trials, and some of them have had terrible experiences with one, but great effects from the other. Ideally, you’d like to be able to predict who would do better, either with a biomarker or via phenotypic features, but there’s nothing available right now to do that.

Indeed, we are caught in a bit of a Catch-22 scenario: we need to have a clinical trial success to demonstrate which outcome measures, biomarkers, and endophenotypes are most useful, but we need to have some of those things first to design successful clinical trials!

Perhaps one solution is to run pilot trials with combination treatments as a way of getting more robust and reliable effects from the drugs. This would allow for better study of outcome measures and biomarkers, and it would allow us to figure out which ones are actually drug-responsive. It may be unrealistic to expect that any one drug can move the needle far enough to be measurable, but a two drug combo may have a better chance of success.