The disease-modifying potential of this class of drugs, which block type 5 metabotropic glutamate receptors, has been incredibly well validated in animal models of fragile X. It’s actually so well validated that it’s unprecedented in the history of medicine. There really has never been another example of a small molecule fixing so many facets of a neuropsychiatric disease in multiple animal models. In part, this is because most neuropsychiatric diseases haven’t had very good animal models, at least until recently, but this just reinforces the point that fragile X is such an important model for the study of many other disorders---we have animal models that aren’t just models, they actually have fragile X. It seems like we’ve been talking about the promise of this treatment strategy forever, but it was only 2001 when the “mGluR Theory” of fragile X was conceived, and now we have 3 companies with active programs to develop their mGluR5 antagonists for fragile X (as well as the now-defunct Neuropharm, which may yet rise from the ashes.)
Novartis is the furthest along, and their compound AFQ056 just entered Phase IIb/III trials for adults and adolescents with fragile X at a large number of sites around the world (see clinicaltrials.gov for more details.) Trials in children are expected to follow soon. AFQ056 is a modern, advanced compound which appears quite safe, and also appears to be an effective treatment for complications of Parkinson’s disease (see http://www.ncbi.nlm.nih.gov/pubmed/21484867 ). It seems likely it will make it to the market for Parkinson’s, even if things don’t work out for fragile X, which is a reassuring backup plan. However, if the current round of clinical trials is successful, it could be marketed for fragile X as the first indication for any mGluR5 antagonist. The Phase II trial results with AFQ056 for fragile X have been published ( http://www.ncbi.nlm.nih.gov/pubmed/21209411 ) and much has been made of the different response to the drug in full mutation males with “full methylation” vs. full mutation males with “partial methylation” on a proprietary assay of methylation status used in this trial. However, it is important to remember that this was a relatively brief trial in a small number of subjects, so it is not surprising that the best effect was seen in the relatively pure sample of fully methylated (ie non-mosaic, for all practical purposes) subjects. Subjects in this trial received the full dose of AFQ056 for only one week; such brief treatment often results in a high placebo response rate, and that was clearly the case here. Clinical trials in psychiatry have shown over and over that the placebo effect generally wears off over 3-4 weeks, and the current phase of AFQ056 trials will dose subjects for much longer. I would expect that this longer treatment would result in statistically significant improvement in all fragile X subject groups, with decreased placebo effect. In addition, preclinical testing of mGluR5 antagonists in animal models predicts that fragile X patients would require much higher doses of these drugs for optimal effects, and that these doses would be well tolerated, so this trial may not have pushed to dose into the optimal range.
However, this raises an important issue with all the disease-modifying treatments for fragile X. How long does it take to see genuine developmental improvement, rather than simple symptomatic improvement? It stands to reason that longer trials are required to see genuine developmental effects, and that even longer trials are required to see disease modification in older subjects. As I noted in the previous post, having extensive preclinical validation gives us confidence that a particular therapeutic strategy will be disease modifying, even if this is not practical to demonstrate in a clinical trial. It may take years to see real developmental effects in 20 year olds, although clinical trials are rarely more than a few months long. Besides, drug companies aren’t required to show that they can cure fragile X, only make it measurably better. So, I’m expecting that this phase of the trials will show improvement in all subjects on AFQ056, with more severely affected subjects showing the best effect, as well as the least placebo response. But, these things are hard to predict---that’s why they do the trials!
Another Swiss pharmaceutical giant, Hoffmann-LaRoche (or just “Roche” to those of us in the know) also has an advanced mGluR5 antagonist, RO4917523, which has just completed a Phase II trial in fragile X adults. RO4917523 may actually be the most (chemically) sophisticated of all the drugs in development; it is ultra-long-acting and very potent. A tiny dose once a day is all that is required to block mGluR5 quite effectively. Results of this trial are a closely guarded secret, and no announcements have been made about future plans for RO4917523, so we are left in the dark concerning Roche’s intentions.
Seaside Therapeutics also has an mGluR5 antagonist, STX107, which was licensed from Merck. It has reportedly completed Phase I trials (normal volunteers), but has yet to be administered to any fragile X subjects. Phase II trials have yet to be announced. Seaside appears to be devoting much of its energy to the development of arbaclofen (R-baclofen, or STX209) for autism and fragile X; this will be discussed in another post.
As noted above, Neuropharm, a UK-based startup, is now out of business. The company’s fortunes rested on the near-certainty of approval of a proprietary formulation of fluoxetine (aka Prozac) for autism. However, their large, multicenter trial failed to show superiority to placebo, even though everyone still uses fluoxetine and other SSRIs for autism spectrum disorders, because they clearly do work. This serves as an important cautionary tale: trials can fail for any number of reasons! Anyway, their Phase I/II trial of fenobam was quite successful; it was only intended to show safety and tolerability, but also showed significant improvement in pre-pulse inhibition (PPI) in fragile X adults, with many anecdotal reports of behavioral improvement from a single dose. Fenobam, like Neuropharm may yet be resurrected---many companies around the world are looking at possible uses for this off-patent compound.
Many other companies have their own mGluR5 antagonists, typically developed at vast expense, and now looking for some purpose. It seems to be generally agreed that fragile X and Parkinson’s are good, proven indications for these drugs, so we anticipate that more companies will move into fragile X trials, especially if Novartis continues to have success with AFQ056.