Showing posts with label Clinical trials. Show all posts
Showing posts with label Clinical trials. Show all posts

Friday 17 September 2021

Bumetanide – Maths Test ✔✔✔ Clinical trial ✖✖✖


Memantine, Arbaclofen 
and now Bumetanide stumble in clinical trials

(also the less well known Balovaptan, which Roche dropped in 2020).

Place your bets on Suramin, anyone?


Plus ça changeplus c'est la même chose

The more things change, the more they stay the same

The first week of the school year brought two big surprises. 

Monty, aged 18 with autism, came top of the class in the math test.  This is a big win for bumetanide treatment, because 9 years ago Monty was effectively innumerate.  With a huge effort by his Assistant, he had learnt how to read and write, but even the most basic maths was beyond him.  That all changed in 2012 thanks to Professor Ben-Ari’s published research on Bumetanide in autism.

The sad news that week was that the Phase 3 clinical trial of Bumetanide for autism had been terminated early.  

Servier and Neurochlore announce the main results of the two phase 3 clinical studies assessing bumetanide in the treatment of Autism Spectrum Disorders in children and adolescents

Paris, 7 September 2021 – Servier and Neurochlore announce that no sign of effectiveness was observed in their two phase 3 clinical studies assessing bumetanide versus placebo in the treatment of Autism Spectrum Disorders (ASD) in children and adolescents. As a consequence, Servier and Neurochlore have decided, by mutual agreement, on an early termination of the two clinical studies in progress.

“The results of the phase 3 clinical studies are a major disappointment,” declares Professor Yehezkel Ben-Ari, President of Neurochlore. “Neurochlore’s teams will now analyze in detail the results of the studies and potentially explore new approaches based on artificial intelligence, which may enable us to identify sub-populations of people suffering from Autism Spectrum Disorders, for whom bumetanide could be effective.


Bumetanide also did not pass the NEMO clinical trial, as a treatment for neonatal seizures back in 2015.  This then made it a bit awkward to suggest that children with severe autism might lower their risk of developing epilepsy by taking bumetanide. Since this is a blog, I can speculate.  I would imagine children with severe autism, who are bumetanide-responders, and who are treated from early childhood through to adulthood with this drug, will have a low incidence of developing seizures. Seizures develop in about 30% of those with severe autism (DSM3 autism) and are the leading cause of their early death.  

 A Poorly Constructed Trial?

If such an effective therapy shows no benefit in a trial with 400 participants, something has gone seriously wrong.

I did ask one researcher friend, who just replied bluntly that the trial must have been poorly constructed.  I thought that was a bit brutal, even by my standards.


Be honest and admit your limitations

Monty, aged 18, came top in maths among 15 neurotypical 16 year olds.  But the 45 pupils in the year had been split into sub-groups. Two groups of 15 taking extended maths and one group of 15 taking core maths.  For some reason, because Monty has autism they put him in the lower group.

Not to worry, after his coming top in the math test, the school agreed that he can move to one of the upper groups taking the wider math curriculum.

So Monty is no maths genius, he came top among the weakest group of typical kids.  That is the whole truth, which is different to the partial truth.

In a similar way, autism researchers need to accept that there may never be a unifying therapy for autism, one that benefits everyone.

Concentrate on the responders to your treatment and forget the rest.  If you over-sell your therapy, you will fail.

As I have said in this blog many times, most people with an autism diagnosis are not bumetanide-responders.  However, a significant minority of those with severe autism are responders to bumetanide and they will experience a transformative benefit.

Going from a basket case to a Maths Whizz even?


Apply common sense and don’t outsource everything

In previous clinical trials of bumetanide, critics said it was all a placebo effect because the parents knew when they were giving bumetanide rather than a placebo.  The bumetanide pill causes the diuresis and placebo does not.

Why can you not use a different diuretic as the placebo?  Answer that one!

Many people using bumetanide give up because of the diuresis.  With schoolkids, the parents will receive complaints from school about excessive toilet breaks.  There will be wetting of trousers, car seats etc.  There will be anxiety caused by urgently needing a toilet, when none is nearby.

So you need a strategy in advance of how to deal with the diuresis.

I was told that people in the one trial centre I know about, were told nothing about the diuresis and how to cope with it.  I was even told the clinician basically told the parents that it was a stupid trial.  Not a good way to ensure compliance with the trial protocol.

So what happens? Some parents will decide to stop giving the diuretic drug, at least on school days.  Maybe they think that a “double-dose” at the weekend will make up the difference.

Clinical trials are a business these days and are outsourced to companies that do this and nothing else.  Don't outsource the most critical part of your work, or at least supervise it.


Why, oh why, oh why?

I was contacted by a mother from the southern hemisphere who managed to get Bumetanide prescribed by a pediatrician, based on Ben-Ari's earlier publications.  The diuresis is proving a problem for her family, but the positive effects are clear, for example her son now uses the word “Mummy”, but only while taking Bumetanide.  If you are a Mum/Mom, that is a big deal.  He also now responds to his own name and is "more present", the hallmark sign of a bumetanide-responder.

She saw me on YouTube and sent me a long email, including the “why, oh why, oh why?” are more people not giving bumetanide to their child with severe autism.  There is no good answer.

This Mum, now realizing she is not alone, plans to continue Bumetanide therapy.

Good for her!


Who dares wins, or at least stands a chance

I was recently sent an email version of an old post I had written on myelination. The sender had read it and convinced her doctor to prescribe her son Clemastine.

Her son has a single gene autism that is known to feature impaired myelination.

I pointed out that in my blog there are many references to therapies shown to benefit different aspects of the myelination process, clemastine is just one.  Some of these therapies are OTC, like alpha lipoic acid (ALA) and the N-Acetyl glucosamine (NAG), that Tyler brought to everyone’s attention.

Is the young man in question going to improve in function taking one or all of these 3 therapies? At least the mother in question is going to give them all a good shot.

Good for her.



I have received quite a few comments and messages about the Bumetanide trial failure.  Many are along the lines of “what do we do now?” and “how long will we have to wait?”

It looks like it pays to be an early adopter, rather than having faith that clinical trials will be structured and implemented properly. 

It has been suggested in the research that a large, 10g, daily dose of the OTC supplement TMG (trimethylglycine) may have an equivalent chloride lowering effect to bumetanide.  There is only anecdotal evidence to support this, but it seems to work for our reader Nancy's adult son - good job Nancy!  The other potentially chloride lowering drugs are more difficult to obtain than bumetanide itself.

There likely will never be a single unifying therapy for autism, just like there can never be for cancer.  In both conditions it is all about specific sub-types.

You would think that the previous trial failures in autism would have caused people to learn this important lesson.  

Hopefully, in the future Suramin clinical trials, where two competing companies are using the same therapy, it will not be assumed that everyone must be a responder for the therapy to be valid.  From the data, it does look like Suramin improves symptoms in a significant percentage of those with severe autism; but the same can also be said of Bumetanide, based on the earlier trials

In December Monty will commence his 10th year of Bumetanide therapy. We have made short breaks periodically to check it is still needed. For our case of autism, Professor Ben-Ari clearly got the science right and transformed a little boy's future life, something Ben-Ari can always be proud of. 

Saturday 29 February 2020

Clinical Trials – Bumetanide and Memantine & Making Sense of it all in a Single Book

This week I received a message: -

“Your Bumetanide treatment is on trial among 25 teenagers here and parents are loving it”

My reply, brief as usual (unlike my blog posts)


I did not mention that in the first phase of the trial 50% of the teenagers are going to be on the placebo.  It is Dr Ben-Ari’s treatment.

A clinician told me that all the parents of children, to whom she has prescribed bumetanide, think their children are responders and is wondering how to deal with the parental placebo effect.

I had another clinician telling me, “I guess from your experience with the blog, most people are not responders to Bumetanide”.  Then came an analysis of the recent tiny study in China that showed on average there was a measurable improvement on the CARS scale (Childhood Autism Rating Scale), but the question arose was “is this response large enough for parents to notice?”

Memantine (Namenda)

A few years ago, Memantine was also trialled at the University Hospital where we live, the same one that is part of the current Bumetanide study.

Memantine was subject to a rigorous multi-center study of nearly one thousand children a few years ago.  The FDA did not like all the off-label prescribing of Memantine for autism and asked the producer to carry out a serious clinical trial.

The first phase of the trial was to identify the responders, those responders then were to be enrolled to two follow-on trials to collect additional useful data.  The trial was terminated after the first phase was completed because in the subsequent trials the placebo produced as good results as Memantine.

So, we should assume memantine is no good for autism?


In spite of spending millions of dollars and liaising with the FDA on the detailed structure of the trial, the producer did not know how to organize an autism trial properly?

I was just writing a part of my autism book that reviews all the drugs trialed to date in autism and I noted that Antonio Hardan (for me, Dr NAC from Stanford) has published a review of data from those expensive Memantine trials.

… the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

I think that is Hardan-speak for “I think Memantine can be a useful therapy, for some people”.  I am not totally sure and I can see why Barney Rubble might be left scratching his head. 

Hardan is about to become Stanford's Dr Nexium, as he runs a clinical trial of the acid lowering drug esomeprazole (Nexium).  I am not sure why he thinks this will improve autism.  I think it will make some people's autism worse, because over time it will cause intestinal dysbiosis.

Intestinal Dysbiosis Secondary to Proton-Pump Inhibitor Use

Autism for Dummies?

Writing a comprehensive book about autism is quite a task.  If it is too complicated nobody will read it, but if you do not go into the how and why of autism, you have not contributed very much.

My elder son has suggested calling it “Autism for Dummies”; but that was not helpful suggestion.  We probably all count as Dummies, when it comes to autism, even Dr Naviaux, who I think knows the most.

I like the book written by a US Academic who treated his "untreatable" brain cancer (Gioblastoma, life expectancy 14 months), by reading the research and applying off-label therapies, using cheap generic drugs.  He has lived long enough to publish a second edition.  The first edition has a cover that looks like a medical textbook; he learned his lesson and the second edition looks more like a cookery book.

Before using pharmaceuticals to treat autism, we used a Peter-created, ABA-inspired, home therapy program.  Amongst many resources, we had two old, but excellent books - they were published nearly 40 years ago.  One was blue and one was yellow (code named by me and therapists as the yellow and blue books), one was about increasing good behaviors and the other was about reducing bad behaviors.  I could not leave them lying around at home, because in the tittle of these use cute looking books was in large print “SEVERE RETARDATION”.  The books are great and of course they should have been combined into a single book. 

I am not a fan of giving a nice name to somethings that is bad.

To me, intellectual disability sounds like not being very good at playing chess.

Accept bad news and move on.

Peter’s Book

I decided to have three sections in my book and have a nice cookery book style cheerful cover, so nobody can be embarrassed.  I will not be citing endless complicated research papers. 

I start with all the general issues that are relevant to understanding autism, that do not relate to complicated science.  I finish with a section on how autism can be treated based on applying the research findings to date, what ideas I came up with myself and other people’s ideas shared on this blog. 

Sandwiched in between easy reading section 1 and practical section 3, is a more heavy-going section 2; it is a simplified review of the biology and chemistry that is relevant to autism.  These are things you need to know to make any sense of those tens of thousands of published autism papers, that most people do not know exist.

Section 2 is not going to be a favourite for Roger, but I think he will like sections 1 and 3.  To really judge what to do in the therapy part (section 3), understanding at least part of section 2 is advisable and that is why it has to be there.

It is just like fixing your car, it does help to know a little bit about how it works, before you start tinkering with it.  Even the mechanic at the dealership does not know everything about how it works, but hopefully he knows enough.

If the mechanic cannot fix your car, you just sell it. You may feel a pain in your wallet, but no long-term guilt.

The autism is equivalent is putting your child into an institution, or group home.  You either feel guilty at this point, or later on when something goes terribly wrong. 

I am forever having to fix things - from cars to computers, to solar panels, air conditioners, blocked drains, a leaking swimming pool etc.  Once you realize the "experts" are often not so expert, you engage yourself to solve the problems; or at least tell the expert what you want him to do, like “I found the leak, here it is, now fix it like this”.

Don’t skip section 2, invest time to learn some biology.

Wednesday 10 February 2016

More Failed Autism Trials and (28 million) thoughts as to why

Two autism therapies mentioned in this blog have recently failed in their clinical trials.

The selective mGluR5 antagonist mavoglurant failed in two trials funded by Roche and Coronado Biosciences threw in the towel with its Trichuris suis ova (“TSO”) program.  TSO are parasites that are introduced to the gut to modify the immune response, they are thought to help conditions like ulcerative colitis and some autism.

"Coronado Biosciences (NASDAQ: CNDO) has decided to no longer pursue the development of its Trichuris suis ova (“TSO”) program. The Company is terminating all on-going TSO trials, including the Company’s Phase 2A clinical trial of TSO in pediatric patients with autism spectrum disorder. A preliminary analysis of data from this trial failed to demonstrate any signal of activity."

The original user of TSO in autism documented his case here:-

It has been a long time since the father updated his site. Does he still give TSO to his son?

This adds to a growing list of very expensive failures.

The good news is that people are beginning to wonder why these, and all the previous trials, "failed".  Perhaps some were not failures, rather narrowly selective successes.  A new initiative is underway called Autism Biomarkers Consortium for Clinical Trials to try to develop more objective measures both for diagnosing autism in young children and for tracking changes.

"The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multicenter research study based at Yale that spans Duke University, Boston Children’s Hospital, the University of Washington/Seattle Children’s Research Institute and the University of California, Los Angeles. The aim of the consortium is to develop reliable and objective measurements of social function and communication in people with autism."

NIH provides $28M to study autism biomarkers via its Biomarkers Consortium

That is a lot of money.

I wish them well.

I do not think they fully realize the task facing them.  There are hundreds of “autisms” and many are dynamic, so changing over time.  Even if you find a responder to a therapy, if you tested the same person six months later he might not respond positively. 

It is highly unlikely that any single therapy can target all the symptoms in any case of autism.  So multiple therapies will be needed.

For many people, autism is a moving target, any kind of allergy, tooth issue or other inflammation could cause a false negative.

Single Gene vs Idiopathic Autism

It should be much easier to develop treatment for single gene autisms, like Fragile X, than for the idiopathic (“we have no clue what causes it”) autisms.  The above trials by Roche were in Fragile-X, where at least you know that all the subjects in the trial started with the same single gene dysfunction. 

But do they have other genetic/epigenetic dysfunctions?  Do they all have the same downstream dysfunctions? 

Fragile X is caused by a lack of the FRMP protein, perhaps the only time to correct this is very early in life.  Thereafter you have the downstream consequences, some of which overlap with ideopathic autism, some of these may well be treatable. 

 Autism Case Reports and Anecdotal Evidence

A good source of information remains published case reports.  These are documented pieces of anecdotal evidence showing what appeared to help a particular person. Here is one highlighted recently by Agnieszka, a reader of this blog.

Beta-Lactam Antibiotics as A Possible Novel Therapy for Managing Epilepsy and Autism, A Case Report and Review of Literature

The index patient is a 9 year old boy with autism spectrum disorder diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). He suffered from generalized tonic-clonic epilepsy from age 4. He had taken multiple different medications such as phenobarbital, sodium valporate, and carbamazepine with sufficient dosages and durations without favorable control of his epilepsy. According to his parents’ reports, the patient took cefixime 200mg/day to control diarrhea about 2 years ago. The seizure episodes were dramatically decreased 3 days after starting the medication while the there was no change in his anti-epileptic medication regime. The seizure episodes were controlled for about 5 months, after which the number of seizure episodes again increased. His highly educated parents administered cefixime 200mg/day to control seizure again. They reported that seizure attacks were controlled markedly after taking cefixime for three days. The patient was not febrile while the medication trials were administered. Both parents reported that they repeated this trial for several times to control the seizure episodes in the recent years. The epilepsy was controlled in all of the trials after taking cefixime for 3 to 5 days. Then, they discontinued cefixime after 7 days. They reported that there was a marked decreased in the number of seizure attacks as well as aggressive behaviors.

You cannot read too much into any one case report, other than to note how many totally unrelated interventions seem to benefit unique cases of autism.  This only goes to show that totally unrelated dysfunctions can manifest themselves as “autism”.

If you grouped all the anecdotal evidence together you would have some interesting reading.  If someone actually followed up on these anecdotes and did some additional investigation on each case we might learn very much more.

Previous Autism Clinical Trials

When I read the original clinical trials of NAC and Bumetanide in Autism, the results seemed good enough to me to warrant my own trial.

I do not see why there has not yet been a follow up of Stanford’s trial of NAC.  There was a patent (below) and then nothing.  It clearly works in many people, but most clinicians will not prescribe it until it is “evidence based”.  Those granted the patent should then go and collect some more evidence.

Bumetanide has also been patented for autism and the next stage of trials will follow, we are informed.

I will be interested to see whether the phase 3 trials are solid enough to convince mainstream clinicians to actually prescribe it.  "A diuretic for autism, come on, be serious!"

Nothing would surprise me.

Funding for Future Trials

It would be a bold person who invested any profit-seeking capital in autism trials, but they keep coming forward.  Here is another new one, OV101 from start-up Ovid.

The only reliable source is public money and philanthropy.

It looks like the US NIH (National Institutes of Health) still has deep pockets and Jim Simons keeps backing his Foundation.


Roche may not have succeeded with their mGLuR5 drug, mavoglurant, but mGluR5 remains a target for treating schizophrenia and autism

Receptors in brain linked to schizophrenia, autism

Disruption of mGluR5 in parvalbumin-positive interneurons induces corefeatures of neurodevelopmental disorders

What would a successful Autism Trial look like?

Given the heterogeneous nature of autism, even a really effective drug might not look so good in the data.  Very specific drugs that counter the disorders where there can be both hypo and hyper, will come out with some good responders, some with no effect and a sizable number with a bad effect; so on average not so good.

Drugs that affect the most common down stream effect, oxidative stress, would come out best.  So I the results Hardan obtained in his Stanford trial of NAC will be as good as it gets.  Those results were enough for me, but not so impressive to many.

Now reconsider a long forgotten trial of an anti-depressant drug, developed from a first generation antihistamine.

This trial has a rather eclectic mix of 26 subjects, but 36% were responders, either much improved or very much improved in a wide variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. However the authors judge the trial drug as: 

  "Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder" 

What were they hoping for ?



The aim of this study was to conduct a naturalistic, open-label examination of the efficacy and tolerability of mirtazapine (a medication with both serotonergic and noradrenergic properties) in the treatment of associated symptoms of autism and other pervasive developmental disorders (PDDs).

Twenty-six subjects (5 females, 21 males; ages 3.8 to 23.5 years; mean age 10.1 +/- 4.8 years) with PDDs (20 with autistic disorder, 1 with Asperger's disorder, 1 with Rett's disorder, and 4 with PDDs not otherwise specified were treated with open-label mirtazapine (dose range, 7.5-45 mg daily; mean 30.3 +/- 12.6 mg daily). Twenty had comorbid mental retardation, and 17 were taking concomitant psychotropic medications. At endpoint, subjects' primary caregivers were interviewed using the Clinical Global Impressions (CGI) scale, the Aberrant Behavior Checklist, and a side-effect checklist.


Twenty-five of 26 subjects completed at least 4 weeks of treatment (mean 150 +/- 103 days). Nine of 26 subjects (34.6%) were judged responders ("much improved" or "very much improved" on the CGI) based on improvement in a variety of symptoms including aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia. Mirtazapine did not improve core symptoms of social or communication impairment. Adverse effects were minimal and included increased appetite, irritability, and transient sedation.


Mirtazapine was well tolerated but showed only modest effectiveness for treating the associated symptoms of autistic disorder and other PDDs.

I think that was a successful trial that should have been followed up, rather then being forgotten.

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.

Wednesday 27 November 2013

Autism Clinical Trials, Arbaclofen (STX209), Curemark CM-AT and the Clever Chiropractor

In the world of clinical trials for drugs, judging success and failure can be highly subjective.  They try to make it as logical as possible and the method works pretty well for assessing things that you can measure objectively.

Primary and Secondary Endpoints
To quote Pfizer:

A trial endpoint of a clinical trial should fulfill three criteria: (1) be measurable and interpretable, (2) sensitive to the objective of the trial, and (3) clinically relevant. The endpoint can be either clinical or surrogate in nature.
If you are developing a drug to lower cholesterol or to increase survivability after a traumatic brain injury, it is pretty easy to define your endpoints.

When it comes to autism, one of the major hurdles is to define objective measurable endpoints.  As it stands today, none of the assessment tools are really fit for purpose, when Big Pharma is supposed to come along and invest hundreds of millions of dollars in some bright spark’s idea.

Arbaclofen, Seaside Pharma & Roche
The Swiss giant, Roche, recently had just such a problem.  They had partnered with a spinout company from MIT called Seaside Therapeutics.  One of the projects was to complete the trials of a fragile X targeted drug, called Arbaclofen (STX209).  During the 4+ years of trials Seaside had changed the primary endpoint.  Arbaclofen started out as drug to treat one aspect of behaviour, but by the time they got to phase 3  clinical trials this had been changed to lethargy and social withdrawal scores from the Autism Behavior Checklist (ABC).
Quite logically, Roche assessed the result of the stage 3 trial against its primary endpoint.  Based on the total cohort in the trial, Roche determined the drug to be a failure and pulled the plug on financing the drug further.
The owner and developer of the drug, Seaside, even though they have recently raised $90 million, said they could no longer continue to fund the trial and all those kids in the trial would have to be weaned of Arbaclofen ASAP.
It turns out that among the families involved in the trial there were many reports of wonderful improvements on Arbaclofen.  They even formed a group to lobby for a continuation of the trial.  There website is interesting.
It now appears that Seaside has had a rethink and will try again with a new trial with a new primary endpoint (mark 3).

Background on Arbaclofen
Some of the first studies of Arbaclofen were conducted in patients with Fragile X syndrome, a genetic condition caused by a change in a gene called FMR1, which normally is needed to make the brain grow properly. Fragile X is the most common form of inherited intellectual disability in boys and can be a cause of autism or related disorders. In those Phase 2 trials, Arbaclofen was shown to decrease social withdrawal and improve adaptive social function.

A  Phase 2a study conducted at 8 sites and involving 32 children showed significant positive behavioral outcomes, including improved scores on the Aberrant Behavior Checklist-Irritability Score (ABC-I) and on the ABC-Social Withdrawal Scale. The most common adverse events were agitation, irritability, fatigue, psychomotor hyperactivity, insomnia and diarrhea. Most resolved without dose changes, but one serious adverse effect did occur during down-titration of the medication.
In July 2011, Seaside Therapeutics, announced that 25 sites across the nation will be involved in a new clinical trial to involve approximately 150 ASD patients between the ages of 5 and 21.
STX209 is an orally-administered GABA-B agonist; the drug acts by stimulating the release of GABA, a neurotransmitter in the central nervous system. GABA inhibits the release of glutamate, an excitatory neurotransmitter, for which an overabundance negatively affects the ability of neurons to communicate with each other.

The GABA "A" receptor, is a chloride channel, while STX209 targets the GABA "B" receptor, which is a G-protein coupled receptor and regulates a different set of molecules from GABA "A".

The original basis for starting this blog was my success with bumetanide, which is affecting the GABA “A” receptor.  In the brain, bumetanide blocks the NKCC1 cation-chloride co-transporter and thus decreases internal chloride concentration in neurons.

Medicine as an art and a science
Mark Bear is a neuroscientist at MIT and he was the co-founder of Seaside Therapeutics.  He is clearly a very brainy guy.
There is a derivative of his Arbaclofen called Arbaclofen Placarbil.  I found it interesting that this substance was also being trialed as a therapy for Multiple Sclerosis and GERD.  GERD is the medical term for heartburn/indigestion.
Incidentally, Arbaclofen Placarbil failed both trials.

Now to the Clever Chiropractor and her Pancreatic Enzymes
People outside the US will find it very strange that in the US chiropractors and osteopaths have the same right to prescribe drugs as conventional medical doctors. 

Outside of the US, if you want to be a doctor you have to apply to medical school and in most countries the competition is very tough. There is no plan B if your exam grades slip.  In the US it is different, if your grades and resources are not taking you to the Harvard, you can opt to become an osteopathic physician or a chiropractic physician.
Rather than Harvard or MIT, Joan Fallon trained as a chiropractor at Palmer University.

Not surprisingly the scientific community is skeptical of her autism treatment, which is linked to pancreatic enzymes.  After all, how can a chiropractor know more than Ivy League neuroscientists?

Peter, on the other hand, thinks that Fallon is actually far more savvy than the very brainy people over at Seaside.  Her therapy may, or may not be effective, but her method of developing it is highly effective.
First she raised $6 million to start her company Curemark, then as trials progressed she very recently she raised another $18 million.
The reason I like what Fallon is doing is that she has figured out which sub-type of autism is helped by her therapy and she has identified a bio-marker for that subgroup.

Hallelujah, a street-smart autism researcher !
If you want to enroll in a clinical trial for Curemark’s CM-AT, first they will screen out the 50% that do not have the biomarker.  Fallon is making sure that her clinical trial results look as good as possible, by only including those subjects most likely to benefit.  This may sound like common sense, but in autism research this is a revolution.

CM-AT therapy and the biomarker
The reason the autism world are skeptical of Fallon, is that she is going on about Secretin and pancreatic enzymes.
Many years ago parents thought that Secretin was going to be the wonder cure for autism; it turned out not to be.  By reading her patents, it is clear that Fallon has some faith in the role of secretin, in addition to enzymes produced in the pancreas.

What impressed me was how she has screened the kids allowed into her clinical trials.

·         Inclusion criteria:
o    Child is 3-8 years old
o    Child has a diagnosis of autistic disorder
o    Child must have a low fecal chymotrypsin level (we will measure)

·         Exclusion criteria:
o    Child must have no dietary restrictions (other than for a nut allergy)
o    Child may not have an allergy to pork products
o    Child may not have a history of severe head trauma or stroke
o    Child may not have had a seizure within the past year
o    Child may not be diagnosed with: HIV, cerebral palsy, endocrine disorder or pancreatic disease
o    Child may not be taking any enzyme product, amino acids, secretin product or stimulant medication currently 

Low fecal chymotrypsin level” is a standard lab test available all around the world.  Over the years Fallon has found that it is a biomarker of the kids who benefit from her patented mix of enzymes sprinkled on their meals.
You actually can buy a very similar product called Creon, or Kreon, depending on which country you live in.  The reason why you cannot be in the trial if you have a pork allergy, is that they use the pancreas of dead pigs to make the enzymes.  This is bad news if you are Jewish, Muslim, a Seventh Day Adventist, or indeed the pig.

The active ingredient in Creon is Pancreatin. Pancreatin contains the pancreatic enzymes lipase, amylase and protease. These assist the digestion of fat, carbohydrates and proteins.

Update on trials of CM-AT
Here is a link to the always-helpful Simons Foundation, with the expected skeptical comments from experts:-

Now Curemark have finished there phase 3 trial, and guess what? It met both primary and secondary endpoints and has been “fast-tracked” by the FDA.

Congratulations Joan !!!
One of the secrets of her success was to have the good sense to enroll herself in a course on clinical investigation run by Harvard/Massachusetts general hospital.
Curemark Begins NDA Submission for CM-AT Autism Treatment
CM-AT had previously been granted Fast Track status by the FDA, a designation given to drug candidates that treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs. The rolling submission process allows companies with a Fast Track designation to submit the NDA in sections to the FDA as they are completed.
“Initiating our ‘rolling NDA’ submission is a major step in the registration process for CM-AT,” said Dr. Joan Fallon, Curemark founder and CEO. “We have an extraordinary opportunity to help many children with autism improve the quality of their lives and we will continue to work closely with the FDA to make that happen.”
Curemark previously announced the successful completion of its Phase III multicenter clinical trial of CM-AT for autism. CM-AT met both primary and secondary endpoints in its double-blind, randomized, placebo-controlled study of children with autism at 3 to 8 years of age.


I would suggest those researchers who believe that diet can be an effective therapy in sub-types of ASD take good note of Joan Fallon's methods. You might indeed be right, but unless you can prove it, the skeptics will always hold sway.