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.
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.
mGLuR5
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:
What were they hoping for ?
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 ?
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.
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