Thursday, July 24, 2014

More on fragile X and MMP-9

Just in case we're all getting despondent about the prospects for fragile X treatment, it's worth remembering that there are many potential disease-modifying strategies---it's not just mGluR5! Another major article from the Ethell lab at UC Riverside has shown the therapeutic potential of drugs that inhibit MMP-9. A nice lay description of the new paper is here and the abstract of the article is here.

This latest work shows that human fragile X tissues have elevated levels of the extracellular enzyme MMP-9, as well as an increase in the active fraction of that protein (like most enzymes, MMP-9 can exist in an inactive form which can be switched on rapidly; this kind of regulation is important in most biological pathways.)

The Ethell lab also showed that genetic reduction of MMP-9 rescues most fragile X phenotypes in the mouse model. Previous work had shown that inhibition of MMP-9 with minocycline also had similar effects, but minocycline has many different actions. These experiments demonstrate conclusively that MMP-9 inhibition is the active ingredient. This is important, because pharma companies are working on drugs which inhibit MMP-9 without the antibiotic effects. They also showed that inhibition of this extracellular enzyme can normalize the activity of many of the intracellular signaling pathways (i.e. mTOR) that have been the focus of so much fragile X research. And, perhaps most interesting of all, they showed that genetic reduction of MMP-9 rescues the macro-orchidism phenotype in fragile X, something which has been relatively resistant to rescue with other therapeutic strategies. Since MMP-9 is a gelatinase, we have previously hypothesized that excessive MMP-9 activity in fragile X was responsible for the well-described lax connective tissue; confirmation that MMP-9 activity is indeed elevated in human fragile X tissue lends support for this idea, though this phenotype is difficult to measure in mice, so rescue effects were not assessed in this study.

All in all, this latest article adds to the growing body of evidence that MMP-9 dysregulation is a critical part of the pathology of fragile X, and MMP-9 should be considered a major treatment target for fragile X.

Saturday, July 19, 2014

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.