Wednesday, March 20, 2013

It’s not just mGluR5…there’s more than one way to fix fragile X



In case you somehow got the impression that FRAXA is only interested in mGluR5 research, or that we’ve quit funding basic research altogether, the most recent edition of the Proceedings of the National Academy of Sciences (PNAS) illustrates just why that’s not true.

Long after the seminal finding of increased mGluR-LTD in fragile X by Kim Huber and Mark Bear, FRAXA funded studies by Nobel-laureate Susumu Tonegawa investigating the role of the enzyme PAK in regulating the shape and function of dendritic spines. The results of this FRAXA-funded project demonstrated that genetic reduction of PAK could rescue most fragile X knockout “phenotypes” (the animal model equivalent of human symptoms.) This was essential proof of concept work which established PAK inhibitors as potential therapeutics for fragile X, and was the basis for a new company called Afraxis. The only problem was that no specific PAK inhibitors actually existed at that time, but Afraxis has been busy trying to find useful drugs that inhibit PAK (actually a family of enzymes, not one single enzyme.) The paper just published by Tonegawa and his collaborators from MIT, Afraxis, and universities in India and Korea, shows that a new compound which Afraxis calls FRAX486, inhibits all the PAKs in the brain at relatively low doses, and displays all the properties you’d expect of a useful drug. Most importantly, it appears to reverse most of the important animal model phenotypes with a single dose (though, presumably, daily dosing would work better as a human therapy.)

Read the whole thing: http://www.pnas.org/content/early/2013/03/14/1219383110.full.pdf+html?with-ds=yes

At this point, FRAXA has developed a large pipeline of drug candidates for the disease-modifying treatment of fragile X. We continue to fund basic research looking for more promising leads, but our main emphasis is on developing treatments based on the work we’ve already funded, which has given us plenty of candidates for therapeutics that can alter the course of fragile X. We’re excited about our partnerships with companies big and small, like Afraxis, because these partnerships are essential to bring new treatments to fragile X families in need.

Sunday, December 2, 2012

An internet friend asked for my feedback on the following article:

Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm than Good

Abstract

Antidepressant medications are the first-line treatment for people meeting current diagnostic criteria for major depressive disorder. Most antidepressants are designed to perturb the mechanisms that regulate the neurotransmitter serotonin – an evolutionarily ancient biochemical found in plants, animals, and fungi. Many adaptive processes evolved to be regulated by serotonin, including emotion, development, neuronal growth and death, platelet activation and the clotting process, attention, electrolyte balance, and reproduction. It is a principle of evolutionary medicine that the disruption of evolved adaptations will degrade biological functioning. Because serotonin regulates many adaptive processes, antidepressants could have many adverse health effects. For instance, while antidepressants are modestly effective in reducing depressive symptoms, they increase the brain’s susceptibility to future episodes after they have been discontinued. Contrary to a widely held belief in psychiatry, studies that purport to show that antidepressants promote neurogenesis are flawed because they all use a method that cannot, by itself, distinguish between neurogenesis and neuronal death. In fact, antidepressants cause neuronal damage and mature neurons to revert to an immature state, both of which may explain why antidepressants also cause neurons to undergo apoptosis (programmed death). Antidepressants can also cause developmental problems, they have adverse effects on sexual and romantic life, and they increase the risk of hyponatremia (low sodium in the blood plasma), bleeding, stroke, and death in the elderly. Our review supports the conclusion that antidepressants generally do more harm than good by disrupting a number of adaptive processes regulated by serotonin. However, there may be specific conditions for which their use is warranted (e.g., cancer, recovery from stroke). We conclude that altered informed consent practices and greater caution in the prescription of antidepressants are warranted.


Read the whole thing at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334530/

It's always interesting to read and critique articles like this, because it gives me a chance to think about the Big Picture---in fact, I think I'll expand on this and make it into an extra-long blog post. I guess this article was thought-provoking; it certainly got my juices flowing, mainly because a lot of people ask me questions related to the points made in this article, and I think it’s important to answer these questions, because it’s easy to scare people away from the medical treatment they need. Some might say I'm biased, because I prescribe drugs; however, I've also done many thousands of hours of psychotherapy, too.

As an overview, this article is typical of its genre, and can be seen as part of the ongoing psychology/psychiatry turf war. It's not really just science, but also an opinion piece from people with an ax to grind, and probably some vested interest. The article is of poor quality, and the authors clearly do not understand many of the basic neuroscience topics they are purporting to review; many of the references are review articles, not original studies, and rely heavily on their own previous review articles and on those of co-authors who clearly run in the same circles. This is OK when you're in a small field, but this is not a small field. They are using a tiny fraction of the literature to support an opinion (that antidepressants do more harm than good) which is absolutely not supported by the weight of the available evidence. They also have an annoying habit of stating something non-controversial (i.e. serotonin is in platelets) and referencing that extensively, then asserting something outrageous without any reference at all---the journal reviewers shouldn’t let them get away with this, so this speaks to the quality of the journal.

It is always true in the life sciences that there is some contradictory evidence, no matter the subject. We don't know everything, and our concept of how the brain works will be evolving for a long time to come---certainly for the rest of our lives, and then some. We cannot be paralyzed by what we don't know when there is real human suffering. Depression, anxiety disorders, and other associated conditions which are commonly (and very effectively) treated with these medications exact an enormous human toll, and if we're going to wait until we understand everything about them before we start treating, we're going to be waiting for a very long time. We do the best we can with basic neuroscience research, translational research on disease mechanisms, preclinical research in animal models, and then carefully controlled clinical trials. The science is never settled, and our understanding is always subject to review (remember that when you hear other scientific issues discussed in the popular press.)

One of their main points is that there is a carefully regulated and highly evolved homeostasis in all these systems (i.e. serotonin), and that anything that perturbs it must necessarily cause dysfunction. You could say this about any medical treatment for any condition, so I guess all of modern medicine is suspect from this point of view (with the possible exception of antibiotics, but they'd probably argue that perturbing normal flora is dangerous, too.) The point they're obviously missing is that the system is already perturbed, and that's why we have a disease state. Some of the authors have previously written that depression (and by extension, just about any mental illness) is just a normal evolutionary response; that may or may not be true, but we haven't evolved much at all (genetically speaking) as a species in the last 10,000 years, while our lifestyle has changed radically. The same is true for the extensive discussion of withdrawal and discontinuation effects in the article; while it's certainly true that many patients relapse when antidepressants are discontinued, that’s also true for virtually all medical treatments of chronic (i.e. non-infectious) diseases. When patients stop taking antihypertensives, blood pressure rebounds---often higher than ever. If an epileptic patient stops taking seizure meds, more seizures are likely. If a diabetic stops taking insulin, they’re still diabetic, and their blood sugars go up. All of this is expected, yet the authors seem to proclaim that they have discredited antidepressants with this revelation.

The surprising thing is how few patients actually relapse---if it’s done right, most people are able to discontinue their antidepressants and have something like a lasting “cure”. Of course, the devil’s in the details, and it’s often not done right. It would be nice to have more research in this area, and much is underway; in the meantime, good clinicians have figured out the best methods for successful discontinuation. My clinical pearls: treat for at least a year at the optimal dose (longer if the depression is more chronic), then decrease the dose very gradually, and do it at a time of year that’s good for the individual patient (often, Spring is the best time of year.)

They really get bogged down when talking about neurogenesis; they mistakenly assert that neurogenesis is widely considered to be the mechanism of action of antidepressants; this is one theory, but not the consensus or established view by any means, so I'm not sure why they spend so much time and effort trying to poke holes in one theory of antidepressant mechanism of action. Anyone who’s ever spent any time thinking about this has come to the conclusion that the antidepressant response is essentially an alteration of gene expression (one manifestation of which might be increased neurogenesis, but it’s hard to imagine that’s the full extent of it.) All the different monoamine manipulations caused by available antidepressants are likely just means to an end, different ways of altering gene expression in the brain. It is no accident that hormonal alterations like increased cortisol or decreased thyroid hormone, which are thought to cause some cases of depression, are also known to cause widespread alterations in gene expression. There are probably many ways to get depressed or anxious, and the available treatments are just ways that we’ve found to (partially) reverse those processes.

The authors argue that the evidence for enhanced neurogenesis with SSRIs and other antidepressants is equivocal. Since there are hundreds, even thousands, of studies demonstrating this phenomenon in many different ways (not just the one they critique) and a relative handful that show a negative result, you could call that "equivocal", but I would call it a preponderance of evidence. Remember, there is always conflicting evidence in science! They speculate that if neurogenesis is increased with antidepressants, you should see more brain tumors. This is incredibly silly, and something they just made up (no reference at all, because it just isn’t true!) Neurogenesis does not lead to neoplasia (cancer) at all---those are two entirely distinct phenomena, and anyone with any medical training would know that. If neurogenesis is increased, you would expect to see more seizures with antidepressants---and you do! All known antidepressants result in a small but significant increase in seizures in trial populations; the risk isn’t great, but it’s there, and it’s probably a direct manifestation of increased neurogenesis. The interesting thing is that antidepressants vary widely in their seizure risk, but this does not correlate with antidepressant efficacy. SSRIs are low-risk, while other drugs like maprotiline (Ludiomil) and bupropion (Wellbutrin) are clearly much higher-risk. This suggests to me that neurogenesis is a sideshow, and not the primary antidepressant mechanism, but that’s just my opinion.

The article also spends a lot of time emphasizing the point that antidepressants just don’t work as well in clinical trials as most folks might imagine, and that there have been many trials (often unpublished) where the antidepressant fails to separate from placebo, or has a very small effect size. To some extent this is true, especially for those who don’t really understand drug trials, and just how difficult they are to conduct. What happens when a clinical trial isn’t properly designed and conducted? The result is that improvement on drug is not statistically superior to placebo; note that this does not mean that the trial drug doesn’t work. It could mean that, or it could mean that the trial simply wasn’t well done, for any number of reasons. However, it is exceedingly unlikely the drug would show superior efficacy compared to placebo by chance, or because of poor methodology. So, it’s a kind of one-way street: virtually all problems (other than outright fraud) lead to a result not significantly different from placebo. Positive trial results are important, and they are accorded great significance for just this reason---they are very hard to come by, because the system is heavily biased against a positive outcome in any double-blind trial. Of course, there are limits to this. If a drug goes through 20 trials, and only one shows significant efficacy compared to placebo, then it’s probably not a very effective drug. But if a drug is in 20 clinical trials, and only 12 are positive, that’s not bad (and fairly typical in psychiatry.) That is an effective drug, and the FDA understands that. It’s also important to understand that most subjects in clinical trials are chronic, difficult, treatment resistant patients; it is rare to find drug-na├»ve subjects in any psychiatric clinical trial. So, critics of antidepressants are always fond of citing big meta-analyses, where results are pooled from all the available studies, good and bad. This invariably diminishes the effect size and increases the placebo effect compared to the more successful, well-done studies. Psychiatric research is just like any other human endeavor, some of the people doing it are incompetent, and their efforts muddy the waters for everyone else.

In the real world, we tend to see much higher response rates among the general population. For example, in my practice of young and middle-age adults in a private outpatient setting, I generally found a response rate to SSRIs for depression and anxiety disorders of about 90% in patients on their first med trial---well in excess of the usual 70% response rate in most clinical trials. These were real, life-changing responses to treatment, with no “poop-out” after a while. Placebo responses never last, so I’m confident that most of these were real therapeutic effects. My success rate in discontinuing the antidepressants in this category of patients was about 60%, using my conservative methods; the unsuccessful 40% went back on the same medication, at the same dose, and virtually always did fine until the next time they wanted to attempt drug discontinuation.

This paper also includes a rather histrionic recitation of side effects of meds, focusing on SSRIs. Of course, all medications have side effects; it’s really surprising how many side effects are reported even in placebo-treated subjects. But most people on SSRIs don’t have major side effects, and many never notice anything at all; the body does adjust, so that the reported side effects usually dissipate as treatment goes on. Here again, this is not really different from what we see with any medical treatment. The authors go into gory detail about the risks of very rare side effects like hyponatremia (I’ve never seen a single case with any antidepressant---I have seen a bunch with the anticonvulsant Tegretol), and try to demonstrate that SSRIs cause cognitive impairment (there’s no evidence of it, and it has been tested directly.) Throughout, they make the most common mistake people make in this situation: they compare the rates of various problems in depressed people treated with antidepressants to the rates seen in normal untreated people. The problem is that depression causes many of these problems, like cognitive impairment, suicide, and excessive cardiac deaths. So, it’s hard to separate the symptoms of the disease from the side effects of the treatment.

I would also note that psychotherapy is not without side effects, especially since the authors seem to have the agenda of promoting psychotherapy. Now, I trained extensively in long-term, psychodynamic psychotherapy; I’ve done lots of it, and I’m very much in favor of it, as well as newer focused psychotherapy approaches. But I’ve also seen many patients (and some personal friends) devastated by poorly done or inappropriate psychotherapy. Drug side effects are usually easy to fix---just stop the drug. The kind of damage inflicted on these folks by incompetent psychotherapists can never be undone, not to mention the financial ruin and exploitation that went along with it. Most people assume psychotherapy has no side effects because they also assume it doesn’t do anything at all. Neither assumption is true.

As a final note, there have been several long-term studies of brain volume in people with depression (and similar studies in OCD). Having depression shrinks your brain on CT or MRI, and treatment with antidepressants (doesn’t seem to matter which ones, as long as they’re clinically effective) prevents this. This is a very powerful argument against most of the pseudo-biological speculation offered in this article, yet the authors gloss over these inconvenient facts entirely. Depression is very bad for your brain; antidepressants clearly help. Are they perfect? No, but their benefits clearly greatly outweigh their risks in the vast majority of people with serious Mood Disorders and Anxiety Disorders.

Thursday, September 20, 2012

2 New Arbaclofen Studies Getting Lots of Press!

Two complementary studies were just published in Science Translational Medicine, and they’ve been getting a ton of attention in the media. Since lots of people are asking about these articles, and lots of reporters are calling to get my comments (and subsequently misquoting virtually everything I tell them,) I thought I’d give my official commentary here. .................................................................................................... The first article (Henderson et al.) comes from researchers at Seaside Therapeutics, along with multiple academic collaborators around the world (including some of FRAXA’s favorite past grantees!) The authors present a series of experiments demonstrating preclinical validation of arbaclofen as a potentially disease modifying therapeutic in fragile X. This is significant, because arbaclofen entered clinical trials based on clinical observation of beneficial responses to (regular) baclofen in patients with fragile X, but without much preclinical testing in animal models of fragile X. Using a number of protocols previously established and accepted by fragile X researchers (and virtually all funded by FRAXA), this team showed that arbaclofen can rescue abnormal protein synthesis, AMPA receptor trafficking, audiogenic seizures, and dendritic spine abnormalities in the KO mouse. Thus, arbaclofen has passed a lot of the same tests that mGluR5 antagonists have passed to demonstrate potential for disease modification. While there is no single lab test which can show that a drug can cure fragile X, we think that the ability to correct a broad array of abnormalities, as shown in this study, strongly suggests that a drug strategy may be able to alter the course of fragile X (and therefore be “disease modifying”.) So, this looks really good for arbaclofen. As always, the usual caveats apply: mice aren’t humans, and the most critical aspect of translating this kind of preclinical finding into disease modifying clinical treatment is dosage. The authors of the study were careful to utilize realistic and practical doses of arbaclofen in their experiments, but it is always possible that the doses which can be tolerated by fragile X patients will not be adequate for truly disease-modifying effects (though perhaps still adequate for useful psychotropic effects.) ...................................................................................................... The second paper (Berry-Kravis et al.) presented the data from Seaside Therapeutics’ Phase II trial of arbaclofen in 63 subjects with fragile X; this seems to be the article that is getting most of the attention from the science press. It is essential to understand that Phase II clinical trials are primarily designed to demonstrate the safety and tolerability of the test drug in the target population (i.e. fragile X.) Efficacy is a secondary consideration, but criteria are specified in advance which can provide an initial demonstration of efficacy, and a Phase II trial can be quite useful for defining qualitative aspects of the drug response. In this article, it was clear that arbaclofen was quite safe and well tolerated; indeed, the low rate of side effects compared to placebo might suggest that the dose range chosen for the study was a bit too low. While this trial failed to demonstrate any advantage (statistically, or even numerically) of arbaclofen over placebo in the chosen primary outcome measure (the Irritability subscale of the Aberrant Behavior Checklist, or ABC-I) there was a definite sense from parents and the clinicians conducting the study that those on the active drug did better than those on placebo (“blinded treatment preference”.) In other words, the clinicians and the people closest to the trial subjects could tell who was on the active drug, with a moderate degree of certainty, and those subjects seemed to do better. Unfortunately, this is not the kind of outcome measure that the FDA would allow for approval of a new drug, but it is an indication that arbaclofen is doing something useful. .................................................................................................... As outlined in the article, things got much more interesting when the data were examined after the fact (“post hoc analysis”.) While the Irritability subscale of the larger ABC (the designated primary outcome measure) did not change with arbaclofen treatment, the Lethargy and Social Withdrawal (L/SW) subscale did improve slightly. Moreover, a recent re-factoring of the ABC to make it more “fragile X friendly” showed that the L/SW scale could be replaced with a slightly modified Social Avoidance subscale which was more relevant to fragile X. If the trial results were analyzed in light of this fragile X-specific re-factoring of the ABC, and if only the subjects with elevated Social Avoidance scores were included in the analysis (roughly half of the study population,) then arbaclofen appeared to lower Social Avoidance scores significantly. Additionally, subjects entering the study with elevated Social Avoidance subscale scores showed statistically significant improvement on the Clinical Global Impression Improvement scale (CGI-I), a standard assessment which is considered an acceptable outcome measure by the FDA. Unfortunately, post hoc analysis is not acceptable for FDA approval. But this kind of analysis can inform subsequent studies, and Seaside is now conducting Phase III trials of arbaclofen, using the outcome measures found in this study to be most reliable in demonstrating the therapeutic effects of arbaclofen. So, in the end, perhaps the greatest value of this clinical trial is that it will make future trials of arbaclofen (and perhaps other fragile X treatments) better, and more likely to succeed.

Friday, September 7, 2012

What works, and what doesn’t

At the start, it’s always hard to know what methods will work best for something as complex as the development of disease-modifying treatments for fragile X. But, we’ve always tried to let the science lead us down the right path. At this point, the results are unequivocal, and they have shaped how we are looking for the Next Great Thing in fragile X treatments. As a bit of background, it’s worth noting that there are two basic ways of approaching treatment research for any disease: rational drug discovery vs. high-throughput screening. Rational drug discovery means exploring the basic mechanism of disease and identifying specific “treatment targets” that might be expected to correct the underlying problem. Usually, the target is an enzyme (a protein which facilitates biochemical reactions in the cell) or a receptor (a protein, usually on the cell surface, which detects small amounts of a chemical messenger, such as a neurotransmitter, and reacts in various ways.) Once a potential therapeutic target is identified, small molecules (i.e. drugs) which affect the target in the desired way can be tested in animal models. It’s usually best to look for targets which need to be inhibited for a therapeutic effect, since it’s usually easier to find enzyme inhibitors or receptor antagonists (there are lots of ways to interrupt biological functions with small molecules, but fewer ways to enhance them.) High-throughput screening (HTS) means finding a simple assay, usually based on single cells or even ground up cells, but placing thousands of them in small wells in test plates, then randomly adding thousands (sometimes hundreds of thousands!) of different drugs and looking for a response (via automated equipment), without worrying about the specific mechanism of action. The hope is that many pleasant surprises could emerge from this method, that existing drugs could show unexpected therapeutic effects. The system needs to be set up properly, with some thought given to the “readout” being examined (what specific reaction you’re looking for in those miniature test tubes, like activation of one specific gene), and it is understood that many false positives (as well as false negatives) will be generated, so any “hits” from the system need to be validated later in other model systems. This is one of the standard methods that drug companies have used to look for new treatments, and it is being used increasingly in academic labs as well. A related technique, high-content screening (HCS), uses more sophisticated robotics and computers to look at more complex readouts, like dendrite shape (for an example relevant to fragile X.) Over the years, we’ve funded a lot of both kinds of research. Certainly, basic research into the mechanisms of disease is necessary early on for both approaches, and we started out by focusing on that. At a certain point, however, we were able to sponsor HTS projects, as well as projects looking at preclinical (animal model) efficacy of potential therapeutic compounds identified by the rational approach. Looking back on the results from the past 15 years, it is clear that the rational drug discovery approach has been far more productive, and that HTS has been a big disappointment. It turns out that the fragile X experience has mirrored the general experience with HTS in pharma and academia, where the overall results have simply not justified the investment. In our case, the rational approach has produced many notable successes like lithium (and other GSK3 inhibitors), ampakines, mGluR5 antagonists, minocycline, GABA (A&B) agonists, MEK and ERK inhibitors, BK channel openers, and many others---some you’ve heard a lot about, others which we’ll be talking about much more in the near future. There is now a large pipeline of new disease-modifying treatments in development for fragile X, and all of them have come from the rational drug discovery approach. Many of these therapeutic strategies have important cross-application in the treatment of other disorder (especially autism, but the list of potential applications in other brain disorders is quite long, indeed.) Why no success with HTS? Well, it is becoming apparent (at least in retrospect) that the biggest problem results from the nature of fragile X itself. For example, when scientists have tried to find a simple cell-based readout, they find that fragile X cells (stem cells, in this case) display increase proliferation. Run that through a high-throughput screen, and you get lots of “hits” which rescue this particular phenotype. The problem is that they’re all cancer drugs which are far too toxic to use in fragile X. As it turns out, the same signaling pathways which are over-active in fragile X neurons are really just re-configured versions of the signaling pathways which regulate cell growth and division in other cells. Part of the differentiation process, which makes one cell a liver cell and another, a neuron, is just a minor tweaking of these same pathways to accomplish radically different things in various parts of the body. All cells have similar building blocks, and drugs can’t always distinguish between them. So, it is very important to choose the readout of the HTS system very carefully, and with some consideration of this basic nature of fragile X pathology. We are hopeful that high-content screening may allow us to find novel agents which can rescue very specific defects found in fragile X (like abnormally developed dendrites,) but this is still an emerging technology. Again, we must go where the science leads us, and learn from these valuable experiences. While fragile X is turning out to be a different sort of problem from what we might have originally expected, we are learning ways to fix the abnormalities caused by this disorder, and better ways to look for new treatments. In the end, fragile X research and rational drug discovery will ultimately teach us a great deal about how the brain works, and about what’s wrong in a host of other disorders like autism, Alzheimer’s Disease, and schizophrenia. Even though we’ve always known this fragile X research was important work, because we care so deeply about our children’s futures, it may turn out to be even more important than we could have imagined. (double-posted here and at the official FRAXA Blog---check it out at fraxa.org/blog )

Tuesday, October 11, 2011

Update on new treatments for fragile X---Part 4: MMP-9 inhibitors

In 2007, Iryna and Doug Ethell of UC Riverside made the seminal finding of excessive activation of the enzyme Matrix Metalloproteinase-9 (MMP-9) in fragile X. They showed that excessive MMP-9 activity maintained dendritic spines in an immature state, and that this contributed to the behavioral abnormalities seen in the fmr1 KO mouse. Most importantly, they showed that the known inhibitor of MMP-9, the available antibiotic minocycline, could rescue all the abnormalities they found in the mouse model. This made minocycline an attractive off-the-shelf treatment for fragile X. Shortly thereafter, I started experimenting with the judicious off-label prescription of minocycline in a small number of carefully selected patients; the results were impressive, to say the least! Indeed, the effect of minocycline was too good, and too rapid to be solely the result of normalized developmental trajectory. Minocycline appears to have an early psychotropic effect which is independent of its fragile X-specific mechanism; this has been utilized in several studies of minocycline as a treatment for schizophrenia and obsessive-compulsive disorder (which leads to the intriguing possibility that minocycline could be an excellent treatment for autism spectrum disorders in general.) Keep in mind that, in the mice, treatment was a very long-term affair---the equivalent of years in human terms.

After conferring with Carlo Paribello, of the Fragile X Research Foundation of Canada, we quickly began organizing a clinical trial. This first trial was an open trial, designed to examine the pattern of responses in high and low dose minocycline treated subjects. The trial achieved excellent results, with substantial decreases in aberrant behaviors over 8 weeks of treatment. Long-term follow-up of these subjects was also done, and results of that phase of the trial are now being analyzed. Very few side effects were seen in either high or low dose groups, and the therapeutic effect seemed similar (though the number of subjects could not discriminate subtle differences.) This is not unexpected, since studies by surgeons have shown that typical antibiotic doses of minocycline (100 mg/d) inhibit MMP-9 levels by 50-75%. That is just about exactly what we want. One unexpected result from the study was that ¼ of all the subjects followed for a year had an increase in Anti-Nuclear Antibodies (ANA), a rather non-specific indicator of autoimmune reactions. None of these subjects had any actual symptoms, though serious autoimmune reactions to minocycline are seen (fortunately, only rarely.) We’re still not entirely sure what to make of this finding, as it’s not known just what percentage of people in the general population develop elevated ANA levels with chronic minocycline treatment. However, it could be a useful indication of impending autoimmune problems, and may be worth checking as a screening test. Interestingly, none of the patients that I treat directly have developed this kind of reaction to minocycline, though I have talked to a number of parents around the country who have encountered this problem.

A larger, placebo controlled trial is under way at the MIND Institute to follow up on these initial findings, and we look forward to these results. In the meantime, another bit of confirmatory evidence came from the lab of Kendal Broadie at Vanderbilt. His group has published results showing dramatic rescue of fragile X fruit fly abnormalities with minocycline---all the more impressive because the fly model is essentially a knockout of 3 genes (fmr1, fxr1, and fxr2.) This group also showed that genetic reduction of the fly equivalent of MMP-9 yielded similar results; this is significant, because minocycline does several different things, but MMP-9 inhibition does seem to be the active ingredient.

So, we have an excellent off-the-shelf treatment in the form of minocycline, a cheap generic medication with a long history and fairly benign safety profile. But some people, perhaps as many as ¼, have trouble taking it, and it’s not recommended for kids under 8 because of dental discoloration (which is not directly related to MMP-9 inhibition.) We at FRAXA are continuing to explore more specific alternatives to minocycline; there is interest in pharmaceutical companies in drugs which can inhibit MMP-9 specifically without some of the other effects of minocycline. However, this is a niche market, and only a few companies have active programs in this area, so it may be a while before we find anything better than minocycline in this area.

Monday, June 27, 2011

Update on new treatments for fragile X---Part 3: GSK3 inhibitors

After mGluR5 antagonists, the drug class with the most extensive validation as a disease-modifying treatment for fragile X is one called GSK3 inhibitors. Glycogen Synthase Kinase 3 is a ubiquitous enzyme present in a number of signaling pathways throughout the body (a problem which we will re-visit later.) GSK3 beta is the specific version which is excessively active in fragile X (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707186/?tool=pubmed ), and studies in fragile X mouse, fly, zebrafish, and neural stem cells all show that reducing GSK3 activity, either genetically or with chemical inhibitors, can rescue a very wide range of fragile X phenotypes (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838793/?tool=pubmed ). FRAXA invested heavily in funding the study of GSK3-based treatment strategies following the original finding that MAP1b was one of the critical overexpressed proteins in fragile X (http://www.ncbi.nlm.nih.gov/pubmed/11733059). Since it is known that activation of MAP1b occurs via GSK3, it was recognized early on that inhibition of GSK3 could be therapeutic for fragile X. Subsequent evidence has shown this to be correct, and perhaps even an underestimate. GSK3 inhibitors appear to have as much therapeutic potential as mGluR5 antagonists, though they may not be quite as well tolerated.

While virtually every major pharmaceutical company in the world is working on improved GSK3 inhibitors for a number of different indications, there is an available drug which is an excellent GSK3 inhibitor. This drug is lithium. Ironically, even though lithium has a reputation for being rather toxic, it may turn out to be less toxic than any of the newer, “cleaner” GSK3 inhibitors in development. Indeed, most of these development programs are in trouble because of toxicity and off-target effects. It is because of the ubiquitousness of GSK3 that these side effects may be unavoidable (in fact, in this light, lithium looks pretty good!), but there are efforts to develop brain-specific GSK3 inhibitors which leave the rest of the body untouched.

Millions of people around the world have been treated safely and effectively with lithium for psychiatric disorders (especially Bipolar Disorder, a.k.a. Manic-Depressive Illness.) However, lithium has fallen out of favor with psychiatrists who now have many other options for treating psychiatric disorders, especially in the form of heavily promoted, brand name drugs like Zyprexa and Depakote. Lithium is a cheap generic, and no one is promoting it. It is also hard to prescribe, and no doctors other than psychiatrists have any experience using it. But lithium does appear to be therapeutic for fragile X, showing disease-modifying properties in animal models (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102293/?tool=pubmed and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810609/?tool=pubmed and http://www.ncbi.nlm.nih.gov/pubmed/21078304 and http://www.ncbi.nlm.nih.gov/pubmed/20705090, among others) and excellent results in a pilot clinical trial in fragile X patients ( http://www.ncbi.nlm.nih.gov/pubmed/18698192 ).

However, it is fair to say that lithium has not become a common treatment for fragile X, probably because it is widely perceived as a dangerous drug (whether this is correct or not, the perception certainly influences acceptance of the treatment by patients, families, and physicians.) Further trials are clearly warranted, however. A larger, controlled trial of lithium in fragile X subjects is a high priority for FRAXA. There is also the possibility of identifying available agents which can enhance the effectiveness of lithium (http://www.fraxa.org/researchTeam.aspx?id=659 ), and perhaps allow for lower dosing. This might eliminate the need for blood testing to determine lithium levels, one of the more unpleasant aspects of lithium treatment for patients and families. It is surprising to me that more psychiatrists are not prescribing lithium for their fragile X patients, especially in case where the psychiatric presentation alone (i.e. aggression or mood lability) might justify a trial of lithium. It may simply be that doctors today have so many choices, it’s easy to avoid lithium.

Monday, June 20, 2011

mGluR5 antagonists for fragile X

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.