Arbaclofen trial is back on for autism.

[Otter]

Pharma giant and social degenerate, Hoffman-LaRoche Ltd., pulled the plug on arbaclofen trials for autism last May leaving a lot of children who were on the medication and living much improved lives, without any medication.

Being typical amoral, sociopathic corporate types with no social conscience, Roche issued a three paragraph statement saying the drug failed its trial objectives. So, tough sh-t.

Anyway, the hew and cry from the parents appears to have been so great that Seaside Therapeutics, who developd the drug, had a rethink and the trials may be back on Epiphany: Autism Clinical Trials, Arbaclofen (STX209), Curemark CM-AT and the Clever Chiropractor

The problem is, of course, with the whole nature of double blind trials, that the result depends on what is chosen as the "endpoint" and in the case of arbaclofen, the endpoint selected was "social withdrawal". So, although the drug worked miracles for many children, their improvement was not described as "social withdrawal" so....FAIL.

Seems now Seaside is going to set different endpoints. Watch this space.

[Otter]

Arbaclofen trial is back on for autism.

Meeting Coverage
Failed Autism Drug Study Has Silver Lining

Published: Nov 1, 2013
By John Gever , Deputy Managing Editor, MedPage Today
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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

AUSTIN, Texas -- The primary endpoint was missed in a phase II trial of arbaclofen in autistic children and adolescents, but positive signs in secondary analyses still give hope for the drug, a researcher said here.

Among 150 patients ages 5 to 21 with autism spectrum disorder (ASD), no difference in change from baseline in lethargy and social withdrawal scores from the Autism Behavior Checklist (ABC) -- the study's primary outcome measure -- was seen in those assigned to arbaclofen versus placebo (-5.4 points, SD 0.78 with arbaclofen; -6.0 SD 0.75 with placebo; P=0.518), reported Walter Kaufmann, MD, of Boston Children's Hospital.

Kaufmann attributed the missed endpoint to an unexpectedly strong placebo response while presenting at the Child Neurology Society's annual meeting

But arbaclofen, the R- enantiomer of the spasticity drug baclofen, did show some significant advantages over placebo on some secondary measures. These included severity scores on the Clinical Global Impressions (CGI) scale and, among certain subgroups, Vineland II socialization scores, Kaufmann said.

Arbaclofen's developer, Seaside Therapeutics of Cambridge, Mass., said it planned to conduct another trial to confirm the results of these secondary analyses.

Diane Treadwell-Deering, MD, of Texas Children's Hospital in Houston, told MedPage Today in an email that the missed primary endpoint was a major problem for the drug.

Nevertheless, the secondary outcomes "are enticing, and should lead to some study redesign, using different primary outcome measures that are more likely to capture the improvements suggested by the findings of this study," said Treadwell-Deering, who is leading a trial of arbaclofen for social deficits in fragile X syndrome patients.

"Finding a robust outcome measure that adequately captures the improvements found in this study will be the challenge for the next trials," she said.

Arbaclofen is believed to be responsible for most of racemic baclofen's clinical effects, with a relative potency of 10- to 100-fold, Kaufmann said. The main effect is to stimulate GABA (gamma-aminobutyric acid) neurotransmission.

This mechanism has only recently emerged as a potentially beneficial approach to autism spectrum disorders, owing to findings from electroencephalographic studies in ASD patients suggesting that GABA modulation could help normalize electrical activity in the brain.

Also, findings in animal and clinical studies of arbaclofen in fragile X syndrome, which resembles ASD in some ways, supported a benefit for the drug.

Currently, social deficits in ASD are treated mainly with behavioral therapies, Treadwell-Deering said.

"While recommended, these therapies are seldom as successful as we would like; also, they are costly and time-consuming," she said. "The importance of the discovery of a medication that successfully targeted social deficits in ASD could not be overemphasized."

In the current trial, Kaufmann and colleagues enrolled 130 patients meeting DSM-IV criteria for autistic disorder, 17 with Asperger's syndrome, and three diagnosed with pervasive developmental disorder "not elsewhere classified" in the DSM-IV system.

Half the patients were 5 to 11 years old and nearly 80% were male.

They were randomized 1:1 to arbaclofen or placebo for 12 weeks. Drug doses ranged from 5 to 15 mg two or three times daily, with doses titrated to maximize CGI improvement. Most patients in the 5 to 11 age range ended up at 10 mg three times daily or, in the placebo group, the equivalent number of pills; most older patients received 15 mg three times daily or the placebo equivalent.

Kaufmann said that, in a post-hoc analysis, the research group decided to examine whether outcomes were different in participants with relatively higher versus lower IQ, with 70 as the cutoff.

There was still no advantage or disadvantage for arbaclofen in the primary outcome of ABC lethargy and social withdrawal score. But Vineland II socialization and communication scores emerged as suggesting greater mean improvement from baseline with arbaclofen in the higher-IQ group, as follows:

Communication: +4.0 (SD 11.23) with arbaclofen; +0.8 (SD 6.82) with placebo
Socialization: +5.9 (SD 14.19) with arbaclofen; +2.6 (SD 9.19) with placebo.

Also, across both IQ strata, socialization scores improved markedly with arbaclofen relative to placebo when the analysis was limited to 93 patients who had the same raters at baseline and at the final evaluation. Those receiving arbaclofen had a mean increase of 7.1 points (SD 1.38) compared with an increase of 1.8 points (SD 1.26) with placebo (P=0.006).

A responder analysis showed that considerably more patients receiving arbaclofen with single-rater evaluations achieved improvements of at least 5, 7.5, and 10 points in Vineland II socialization scores. For example, 51% of this arbaclofen subgroup had increases of at least 5 points, compared with 28% of the corresponding placebo subgroup.

Kaufmann described arbaclofen as "generally well tolerated," but withdrawals due to adverse events were somewhat more common with the drug (eight patients versus two in the placebo group). Moreover, one of the patients assigned to arbaclofen had serious suicidal ideation.

Other events prompting withdrawal included aggression, emotional upset, sleep problems, skin rash, dyskinesia, oculogyric crisis. One patient in the placebo group also withdrew because of suicidal ideation, and another because of insomnia.

Treadwell-Deering said the apparent outcome differences in the IQ strata "should be controlled for in future trials."

The study was funded by Seaside Therapeutics.

Both Kaufmann and Treadwell-Deering had relationships with Seaside Therapeutics. Some co-authors of the study were employees of the company.

[terryk]

Arbaclofen trial is back on for autism.

As far as how the arbaclofen trials have been going, I found some interesting thoughts from someone on this blog:

Multiple Sclerosis Research: XenoPort to drop Arbaclofen for MS spasticity

"This study shows that even in late stage development (phase 3), with a drug that has more than a fighting chance, things can go wrong and you get a negative result. The Home - ClinicalTrials.gov trial entry (NCT01359566) suggest they did not use an enrichment design. Why? GW Pharma have shown so elegantly in their Sativex trials that this is the only way to do spasticity trials. In addition, the study used a co-primary outcome; i.e. (1) change from Baseline in maximum Ashworth scale score (6 hour post-dose time point) and (2) a Patient Global Impression of Change (PGIC) score. We now know that the Ashworth is not a good outcome measure; it is not responsive to change and unreliable. At first glance 228 MSers seems to be massively underpowered for these outcomes; there appears to have been 4 arms (placebo vs. 15mg vs. 30mg vs. 45mg) or 57 MSers per arm. For the Ashworth scale you need several hundred per group. I would be very keen to do a post-mortem of this study to see if we can learn something useful from this failure. I sincerely hope that this drug did not fail because of poor trial design."

"Is this another story of a baby being thrown out with the bathwater?"

(link to my original posting of this on MWO here)

-tk

[spiritwolf333]

Arbaclofen trial is back on for autism.

I am excited to the read that the trials are back on for Autism using Arbaclofen. My wife teaches autistic children and she is glad to see this news as well. She often speaks of the social withdrawal part autism.

So much to research and learn about new medications and the new uses of baclofen for differing illnesses. IMO, it's great to know that people are continuing to search for better methods to treat current illnesses -even trying ing to improv current medications.

[Samandkatharine]

Arbaclofen trial is back on for autism.

I have a high functioning Aspergers son, and it would not give this to him. Are we talking non verbal low spectrum autism?

Sam

[Otter]

Arbaclofen trial is back on for autism.

Samandkatharine;1645140 wrote: I have a high functioning Aspergers son, and it would not give this to him. Are we talking non verbal low spectrum autism?

Sam

I have no idea.

It seems that the idea of these illnesses being linked to problems of some sort in the hippocampus? is gaining ground rather than the approach of giving someone a label and then saying, "it's a mystery!"

Is that a typo? You would not give your son baclofen?? I have started taking it again at low dose of 20 mg a day. My wife insists I take it. She is on 60 mg a day, split into two doses of 30 mg morning and night and says I need it... I don't quite understand why you would not try it with your son. Dr. Chick specializes in Aspergers. He also uses Baclofen but I don't know if he uses it for Aspergers. I would consider giving it to my son. Having taken it myself I don't have a problem with it at all. It is either beneficial or useless/harmless so it is a no-brainer to try a drug like that.

[Otter]

Arbaclofen trial is back on for autism.

It seems to me that there is a qualitative difference in the work being done in relation to studies of baclofen for alcoholism and those of arbaclofen for autism. I think it is probably a result of involvement of La Roche in the arbaclofen trials and the money and potential profit. There just seems to be more interest from serious scientists who are prepared to write about it.

Maybe it is also because we are talking about children and a "clean" middle class illness which isn't attributable to lack of will power. Maybe it is all the same and people who become alcoholics had something akin to autism, or developed something akin to it by taking alcohol.

The arbaclofen studies are going down a route which is much more understandable and sane. There is some promise, and it is worthwhile since it is a childhood illness. Since Arbaclofen is new, it can be licensed and patented for this purpose, and can make a profit. Hooray for free enterprise. So, people are not afraid to invest in. When it goes wrong there is no problem with doctors expressing a view that there is a problem with double blind trials. Proper doctors analyse the issues, understand where the problems arose, and take a different approach, and will likely work on it until they get the right result. Then Seaside will have something marketable and then doctors will hear about it because it is advertised in medical journals and magazines and pushed by big pharma.

The French have been able to do much the same with baclofen. The great thing about their Prescribing Guidelines is it shows they didn't give up when there were problems. They looked at other factors in the recovery process and addressed them. Unlike the Garbutt approach a few years back where doses at 30 mg failed to give any decent result. He just stopped there. We haven't seen him coming out and being critical and analytical about his approach or the need to take a different tack, maybe going to higher doses, using complementary treatments. Nothing. It is most peculiar.