Fragile X research continues to progress at a break-neck pace, and 2012 promises to be the most important year ever. Indeed, we anticipate a watershed year: no matter how things turn out, we are sure that the landscape will be very different by the end of the year. As everyone is surely aware, three different pharmaceutical companies are currently conducting clinical trials in fragile X. Two Swiss pharma giants, Novartis and Roche, are racing to get their lead mGluR5 antagonists to market for fragile X; Novartis Phase IIb/III clinical trials are underway, and should be completed this Spring. If successful, these trials could allow for approval of their drug, AFQ056, by the FDA. Roche has completed a Phase II trial, and is expected to commence Phase III shortly. The small Cambridge-based start-up, Seaside Therapeutics, has begun Phase III trials of arbaclofen (STX209) which could also allow for marketing of this drug, which enhances function of GABAb receptors.
Meanwhile, a fourth company has openly declared its intentions to develop an entirely novel class of drugs for fragile X. Afraxis, a San Diego-based startup (www.afraxis.com), has licensed the technology of PAK (p21-activated kinase) inhibition to treat fragile X from the MIT lab of Nobel Laureate (and FRAXA grantee) Dr. Susumu Tonegawa. Afraxis has announced that it has several potential drug candidates, and hopes to begin trials in the near future.
It is exciting that these new drugs are being developed for fragile X, and that the private resources of these 4 companies are being devoted to find breakthrough new treatments for our children. In this round of clinical trials, we see both incredible opportunity and tremendous risk. Simply put, if these trials are successful, enabling the marketing of new treatments for fragile X, we can expect that many more pharmaceutical companies will develop treatments for fragile X. Some of these will be similar “me-too” medications, for example, other mGluR5 antagonists or GABAb agonists. Some will be different drug classes, like GSK3 inhibitors or PDE4 (phosphodiesterase) inhibitors. We know this, because FRAXA has been funding preclinical research to demonstrate that these drug classes can be effective treatments for fragile X, and we have discussed these successful studies with many other drug companies. They are now simply waiting on the sidelines to see how the current round of trials plays out; many of them will commit to fragile X drug development immediately if these trials work. It is easy to see how the thinking goes for the “me-too” drugs: if Novartis manages to get their mGluR5 antagonist (AFQ056) officially approved for the treatment of fragile X, any other company with an mGluR5 antagonist (and there are many others) will know that there is little risk in seeking approval for this same indication. Novartis is taking a risk, since no one really knows how best to demonstrate clinical efficacy in a fragile X population, but if their trials work, any other drug company can simply use the same methods, and their mGluR5 antagonist should work just as well using the same trial methods. Follow-on companies will face much less risk, and their drugs should be just as profitable, especially given the wide range of conditions amenable to treatment with mGluR5 antagonists.
Successful trials should also spur development of other drug classes for fragile X. In many cases, these other drug classes work on the same pathways as mGluR5 antagonists, so the perceived risk in developing these therapies would be greatly reduced. In addition, the methods for proving efficacy in fragile X will be established at that point, making drug development that much simpler. These factors could make future development of advanced treatments for fragile X essentially self-sustaining. While contributions from the fragile X community have largely funded FRAXA’s research programs, which have been the driving force behind most of the translational and preclinical research, pharmaceutical industry funding could take over, if the competition to develop fragile X treatments becomes sufficiently intense. This would come as a major relief to all of us struggling to continue funding all this important research!
The problem, of course, is that the results of the current trials might not be as successful as we all hope. In that case, we might anticipate that pharmaceutical industry interest could wane, and all those companies on the sidelines will stay there. We are preparing for this possibility by continuing to look at other mechanisms of disease in fragile X, and also testing a number of available agents (lithium and minocycline are two good examples of available agents discovered by FRAXA researchers; both of them seemed unlikely at the time, but preclinical studies have shown clear evidence of disease-modifying effects, and pilot clinical trials have been quite encouraging.) Available agents with disease-modifying properties offer us a chance to fine-tune our ability to conduct clinical trials, and we are prepared to fund more clinical trials of this kind.
In addition, emphasis on other investigational drug classes (like PDE4 and GSK3, as noted above) can bring new companies into the fragile X field as their drugs fail for their primary indications. Timing is everything, and our collaborations with pharma have followed a consistent pattern: a drug being developed for a “blockbuster” indication like Alzheimer’s disease or anxiety disorders is implicated by our research as potentially effective in fragile X. We approach the company developing that drug, but the company is not interested in jeopardizing their blockbuster indication to pursue a rare-disease indication like fragile X. However, eventually, their development program runs into trouble (as most do!) and fragile X suddenly looks a lot more attractive, since we have far more preclinical evidence than is possible with virtually any other brain disorder. At this point, a serious collaboration to develop the drug for fragile X can begin in earnest.
Which way will the research take us in 2012? Only time will tell, but we are in for an interesting year. Stay tuned!