Friday, 26 September 2014

Autism Drugs - Horses for Courses and Safety over Assured Efficacy?

Only a few months goes by without there being an uplifting report in the media of some breakthrough drug for autism.  These reports usually relate to research on mice.

So where are the resulting approved drugs for use on humans?

There still are no drugs approved for the core symptoms of autism.  It is quite likely that in spite of all the ongoing research, the situation will not change anytime soon.

I was reading about yet another potential wonder treatment, based on research into a very old drug called Suramin.   This rather toxic drug has been shown to be effective in a particular mouse model of autism call MIA (Maternal Immune Activation).  There is some doubt as to whether the researchers have got the method of action correct, but nobody doubts the positive effect it had on some mice.

Today’s post does not look at the science of Suramin, which is, by the way, another anti-parasite drug like Ivermectin, which I looked at earlier.  The subject of this post is much more down to earth and practical.

There is a problem with all Autism Clinical Trials

It is not just me that thinks something is amiss with Autism Clinical Trials, first read what the head of Medical Research at Autism Speaks has to say.  He is talking about this in the context of Naviaux’s recent trials of Suramin on “autistic” mice:-

Paul Wang, Head of Medical Research, Autism Speaks :-

Hedging bets: “Animal models of autism, such as the maternal immune activation (MIA) model studied here by Naviaux and his colleagues, are the best tools that researchers have for examining the cellular and molecular pathophysiology of autism and for testing experimental treatments before they can be advanced to human trials.

“But, of course, none of the models can be considered valid until treatment effects in them are proven to be predictive of effects in people. In the case of the MIA mouse, the authors here candidly hedge their bets by calling it a model of both autism and schizophrenia. Meanwhile, the field of autism research wisely hedges its own bets by studying multiple treatments of the MIA mouse, including probiotics as well as antipurinergic therapy.”

Precedent lacking: “Although milestones in the initial stage of testing basic research findings for translational research continue to accumulate — from mGluR5-targeted rescue of the FMR1 knockout mouse to suramin reversal of social deficits in the MIA mouse — we appear to be making little headway on the hurdles of clinical trials. From arbaclofen to oxytocin to Trichuris suis ova, clinical trial results have been tepid at best. This should not be surprising. We have no successful precedent to guide the design of clinical trials in autism.
“How should we quantitate clinical improvement — or deterioration? How long must treatment be provided before effects are evident? At what age will each treatment be most effective: 6 years? 16 years? 6 months? Which individuals will benefit most from each treatment: those with more severe or more mild symptoms? Those with regression or not? Those with or without comorbidities? Results in Phelan-McDermid syndrome (presented by Joseph Buxbaum at the 2014 International Meeting for Autism Research) represent a rare but preliminary exception to the frustrations of clinical trials.”

Clearing the hurdles: “As basic research continues to generate more candidate treatments for autism, we need to work harder on clinical trials. Most especially, we need to identify measures of improvement that emerge early, potentially within a few weeks of treatment initiation and well before the broad functional improvement that the U.S. Food and Drug Administration is likely to require for drug approval.”

Multiple mouse models, suggests multiple human types of autism

The fact that researchers have created multiple types of mutant mice that mimic autistic behaviour does rather suggest that numerous distinct dysfunctions in humans might also result in autistic behaviour. 

In fact it is now a widely held belief, in the scientific community, that there are numerous sub-types of autism, each with its own biological dysfunction(s).

Clinical trials doomed to fail?

Since no effort is made to stratify the autistic population by sub-type, clinical trials are likely doomed to fail.  They usually just require that participants fall into the vague autism behavioral category of DSMIV, or now DSM V.

While a trial drug may indeed have a positive effect in one sub-type of autism, it may have no effect, or worse still a negative effect in other subtypes.  This is exactly what happed with Arbaclofen, and Roche pulled the plug on that one.

Horses for Courses

Perhaps a more pragmatic approach is required.  “Horses for courses”, was suggested to me the other day by that prolific autism science blogger from Sunderland.

Just accept that one Alzheimer’s drug may work for Fragile X, but be totally in-effective in broader autism.  Or maybe it only works in some people with Fragile-X?

This sound fine, but what if you do not know which “course” your horse (child) is running on?

Science may indeed have the answer in the form of something called micro RNA analysis, which is a way of looking for a large number of known genetic dysfunctions quickly and therefore relatively cheaply.  It just needs a blood sample. It is available to autism researchers today.

In the meantime we are left with that reliable old workhorse called trial and error, which does seem to work, if you do your homework.

Safety over Assured Efficacy

While clinical trials may not be able to guarantee which drugs are helpful in autism, they can tell us which are safe to use.  Fortunately many of the interesting drugs for autism are existing ones that have been in use for decades, but for other conditions.

One interesting point I noticed in the autism trials of Alzheimer’s drugs was that the drugs were very well tolerated.  Not surprisingly, older patients claim to have far more frequent side effects, since they likely have multiple ailments and may attribute their various ills to the new drug.

So what is required to treat autism is a range of drugs that are known to be safe for long term use; and then some indication of effectiveness in some people with autism.

Last year, when reading the very detailed critique of most recent clinical trials into autism, produced  by the UK’s National Institute for Health and Care Excellence (NICE), it was clear that they are looking for a level of success in clinical trials that will likely never materialize.  This was a 700 page document produced in advance of the final 40 page report.  Only the 40 page report seems to be available now.

A “one size fits all” approach will fail, because “autism” is a vague behavioral diagnosis and not a precise biological one.

Any particular drug might be effective in only 10% of what psychiatrists rather arbitrarily define as “autism”, but if your child is in that 10%, you would be delighted.

The logical way forward is blocked for most people, since they cannot access even very safe prescription drugs.  This is of course for the “greater good” of society and avoids doctors worrying about getting prosecuted for malpractice.

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