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:-

http://autismtso.com/

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.

Compositions and methods for treating autism and autism spectrum disorder 

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.

mGLuR5

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

Salk team spotlights a new mGluR5 target for schizophrenia, 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 ?

A naturalistic open-label study of mirtazapine in autistic and other pervasive developmental disorders.

Abstract

OBJECTIVE:

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).

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

Central histamine (dys)function, antidepressants, appetite, autism and behavior

One day last week Monty, aged 12 with ASD, was watching an old Tom and Jerry DVD.  These DVDs, along with the other action-packed ones, once got hidden away because they drove Monty wild; now they do not.

This is what I was doing while Tom was chasing                                                                         Jerry.

I received another interesting comment from a reader who found a small dose of an antidepressant had a very positive effect on his 9 year old daughter:-

“My daughter (9, ASD) recently started on a very small dose of Remeron, in an effort to increase weight and as a bonus, hopefully improve sleep. It has done both. It also had an immediate unexpected but delightful side effect of improved social skills, more fluent speech and increased amount of conversation. The first day she tried it she made friends with random children in the park, and they had a discussion about how they would design their dream playground. (DD said she would invent and upside down slide, where you start at the bottom and slide up.) It has been amazing for her (so far.)  ”

In most families it is the parents who take the antidepressants.

I recalled that one class of antidepressant was actually developed from an old antihistamine drug, tricyclic antidepressants.

Remeron, otherwise known as Mirtazapine, is indeed a tricyclic antidepressant.

Not only is Remeron, in effect, a first generation antihistamine, i.e. one that was not designed to stay outside the blood brain barrier, but it is a rather potent one.

Within the brain Remeron/Mirtazapine:-

H₁R occupancy (H₁RO) of mirtazapine reached 80-90 % in the cerebral neocortex

Histamine H₁ receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers.

This means that 80-90% of the type 1 histamine receptors in that part of the brain are blocked from action.

Histamine Receptors and the Blood Brain Barrier

There were several earlier posts in this blog regarding histamine.

There are four known types of histamine receptors H1, H2, H3 and H4.

In one way or the other, all four are likely relevant to autism.  Drugs are not yet available for H4.  H3 therapies are likely to improve cognitive function in some. H4 appears to play a role in the overexpression of mast cells in allergic tissues.  So those with severe mast cell issues should watch the H4 drug pipeline.

Histamine H4 Receptor Mediates Chemotaxis and Calcium Mobilization of Mast Cells

An important point to remember is that while histamine does not cross the Blood Brain Barrier (BBB), H1 antihistamines do cross, including the ones designed not to cross.

All antihistamines cross blood-brain barrier

Within the brain, histamine functions as a neurotransmitter, but it is not the same histamine as that released by mast cells in your nose, when you have hay fever.  Histamine is also produced inside the brain.

H3 receptors in the brain modulate the release of histamine.  Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H₁ receptors in the cerebral cortex. Consequently, unlike the H₁ antagonist antihistamines which are sedating, H₃ antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease and also for ADHD.

H1 agonists should increase appetite and H3 agonists should reduce appetite.  So one day do not be surprised to read about wonder H3 slimming pills.

Outside the brain (CNS) all four types of receptor are found and have specific functions.

H1 receptors modulate circadian rhythm (sleep) as well as all those allergy and asthma symptoms.

H2 receptors modulate sinus rhythm (in your heart), stimulate  gastric acid secretion, inhibit antibody synthesis, T-cell proliferation and cytokine production.

So histamine dysfunction would contribute to many conditions that are known to be comorbid with autism:-

·        Obesity and also low appetite (both extremes)

·        Poor sleep

·        GERD/GORD/reflux

·        Cognitive impairment

·        Allergy

·        Mood disorders

As usual things are complicated, because the histamine receptors are slightly different in each part of the brain so your histamine antagonist/blocker “sticks” better on some than on others.  So one H1 antihistamine will be more sedating, or more appetite-increasing than another one.

H1 antihistamines in Autism

Most attention in this blog has been directed to the effect of H1 antihistamines outside the brain/CNS.  To a greater or lesser extent, all H1 antihistamines are also mast cell stabilizers.  They reduce the release of histamine itself, as well as blocking H1 receptors (and so relieving allergy symptoms).

Blocking the release of histamine outside the BBB stops the release of inflammatory cytokines like IL-6, which can, directly or indirectly, cross the blood brain barrier.

However many people report that common H1 antihistamines seem to improve autistic behavior, irrespective of any allergy being present. My assumption is that this may be the case with nine year old girl, certainly worth investigating.

Either there is a mild allergy that has gone unnoticed, or this must be the effect of blocking H1 receptors within the brain/CNS.

H3 antihistamines in Autism

I think it quite likely that some people with autism and schizophrenia would experience cognitive improvement from H3 antagonists.

It is perhaps odd that nobody has investigated the cognitive effects of Betahistine.

Betahistine has a very strong affinity as an antagonist for histamine  H₃ receptors and a weak affinity as an agonist for histamine H₁ receptors.

The disadvantage is that betahistine increases histamine levels outside the BBB, so not good for someone with asthma.

There is data on the effect of Betahistine on weight gain in schizophrenia:-

Reducing antipsychotic-induced weight gain in schizophrenia: a double-blind placebo-controlled study of reboxetine-betahistine combination.

It was safe, well tolerated and did reduce weight gain.  I would have liked to know the effect on cognitive function.

Conclusion

There may be too much histamine being released, or its degradation might be impaired (DAO, SAMe, & HMT are all implicated in autism/schizophrenia), or there may be over/under expression of histamine receptors in certain places.

For example in schizophrenia,  metabolites of histamine are increased in the cerebrospinal fluid of people, while the efficiency of H₁ receptor binding sites is decreased.

The role of the central histaminergic system on schizophrenia.

It would not be surprising if people with autism and histamine/mast cell related issues outside the brain, also have central (in the brain) histamine dysfunctions.

There are only 24,000 genes found in humans (there are 700+ autism genes).  As a result these genes have to be reused many times all over the body.  Any dysfunction may be reappear in surprising parts of the body.  Add to this the way the body is controlled by feedback loops and you can see a how very many things are inter-related.

This also explains why very clever ideas can work in vitro (in the lab) but completely fail when applied to humans. "Stumbled upon", which must really annoy some clever scientists, is a very valid discovery method and can still earn you top marks.

This also means that many potential therapies can have unintended side effects. Like the H3 antagonist Betahistine, which can cause gastric acid problems and itching.  Betahistine acting in the brain might be good for cognition, but might not be without drawbacks elsewhere in the body.

Coming back to Tom and Jerry and where this post started

As usual Jerry got the better of Tom.

Since continued used of Remeron might lead to obesity, it would be interesting to see if the autism benefits were maintained by using a more conventional H1 antihistamine.  The older ones should better cross the BBB, but will be more sedative.

The people currently using conventional H1 antihistamines to treat their n=1 case of autism, might want to compare the effect of the very small dose of Remeron.

The people using second generation conventional H1 antihistamines (Zyrtec, Claritin etc) to treat their n=1 case of autism might want to compare the effect of the old fashioned versions that, like Remeron, have high much higher H₁R occupancy in the brain.

For those still hungry (too much histamine) for more:-

 The histaminergic system in brain: neurophysiology

Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse

The role of hypothalamic H1receptor antagonism in antipsychotic-induced weight gain.

  

Therapeutic potential of histamine H3 receptor agonist for thetreatment of obesity and diabetes mellitus