Novartis trial results are in, and they're not pretty

This year's Gordon Conference just finished,and Novartis presented their results for the first time (though advisors and advocates had been given a private peak months ago.) To say that the trial results for AFQ056 were disappointing would be the understatement of the century! While the company has already announced that the adult and adolescent trials failed to meet their pre-designated endpoints, the numbers looked really bad. This wasn't a case of the drug working, but placebo effects leading to an outcome that wasn't statistically significant; in this case, the effect of the drug was statistically significant, but in the wrong direction!

So, what went wrong? The evidence for using mGluR5 antagonists in fragile X was really strong going into these trials---in fact, about as good as it ever gets. The drug itself was an advanced compound that had been studied extensively. Of course, outcome measures have been a problem, and they're definitely not good enough. However, Novartis did an exhaustive analysis of all the data, plus they even went back and looked again at subjects who were reported by clinicians and caregivers as exceptionally good responders. None of this "post hoc" analysis revealed any positive effect of the drug compared to placebo---not even a glimmer of hope in adults or adolescents (and both trials came up with very similar results, providing some degree of cross-validation). The ABC and other outcome measures used might leave much to be desired, but they weren't the reason for these trial failures. Indeed, the trials were not "failures" in any sense, except that the results were decidedly negative. Novartis conducted an excellent pair of clinical trials which showed convincingly that AFQ056 doesn't work for fragile X, as least not as administered in these trials.

Perhaps the Roche compound will show much better efficacy; it is a different drug, and somewhat different methods are being used in the Roche trials. But our personal experience may offer some insights into what is going on, and this also leads me to be a bit pessimistic about the chances for mGluR5 antagonists in general.

Our 25 year-old son was one of the last adults enrolled in the AFQ trial; I should note that he was also on minocycline during this entire time, as he has been for many years. This is thought to have potentially disease-modifying properties for fragile X, and so this may have boosted the effect of the AFQ. His other meds are valproate, topiramate, and sertraline. He also has a lot of severe gastro-esophageal reflux, which means he spits up his food a lot if he eats too fast (it seems to be reflux, which is a physical effect based in the stomach and esophagus, rather than nausea, which is a centrally mediated process controlled by the brain.) In any case, when he started the blinded phase of the trial, we saw a rapid improvement in his mood, language, social function, and basically everything else. But we only saw one "bump" up during the dose titration, which led us to think he was on the lowest dose of the drug (this was later confirmed.)

Unexpectedly, his reflux went away entirely along with all this other improvement; I should also note that this was all after the 4 week placebo run-in (we'd been tipped off about that long ago!) But this is a guy who had never in his life gone for a whole week without barfing; this was a regular, daily event for us. Our son had not one single episode of reflux for more than one month after starting on that tiny dose of AFQ! Call it a side effect, or a bonus, but it was something very objective and hard to ascribe to placebo. Indeed, mGluR5 antagonists are known to increase tone in the lower esophageal sphincter, and have been studied as treatments for reflux. The first 6 weeks or so were great---we started doing all kinds of new things, like sailing and traveling, dining out and going to lots of new places. This, I thought, was what we had been waiting for! But then the effect started to wear off, little by little. The reflux came back, though only a bit here and there.

We figured this was no big deal, that in the extension phase we'd get to a higher dose and that would work much better. Which turned out to be true! When we started the open-label extension, our son got noticeably better with each dose increase, and tolerated the full 100 mg twice a day with no side effects to speak of, except the good one (no reflux at all!) This kept up for several months, and we were very happy. We assumed that things would just keep getting better and better as long as we kept up the AFQ. However, after a while (hard to say exactly when, because I think it was very gradual), many of the old behaviors started creeping back in, as did the reflux (in fact, they seemed bound together quite tightly.) As I write this, about 9 months after starting the full dose of AFQ, I'd estimate we've lost about 70-80% of the effect of the drug. We're probably not all the way back to baseline, but we're not finding that things are getting better and better all the time.

Now, even I realize that the placebo effect is very powerful, and that we are hardly objective observers in this case. I could easily be imagining improvements in mood or behavior, or we may have treated our son differently because of our expectations, leading to better behavior. But I can't explain the reflux as anything other than a real, physical effect. He ate the same food, the same way as ever. The mGluR5 antagonist simply helped him keep it down---it's known to do that. But even that effect wore off! Tolerance developed to that physical effect at approximately the same rate as the "central" effects that were the primary objective in this case.

So, in a nutshell, the problem we've seen, and the likely reason for the trials to fail, has been the development of extensive tolerance. This is quite unexpected, it's probably something intrinsic to mGluR5 in fragile X, and something I'll discuss more in upcoming posts.