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**kronkcarr** · October 20, 2013, 04:42 PM

Setback for Arbaclofen in Autism

I hear you about baclofen. Plus it's cheaper than a new drug!

**spiritwolf333** · October 21, 2013, 08:01 PM

Setback for Arbaclofen in Autism

Very disappointing. I have to believe some company will pick up where Roche left off -or maybe this is just a political game to get more money. Too bad for those who have hope with Arbaclofen.

**Otter** · October 31, 2013, 01:04 AM

Setback for Arbaclofen in Autism

My understanding of arbaclofen is that it is a chemical which, when ingested, turns into baclofen. It has fewer side effects because it has been modified. I also understood that LB has the same benefit, that it has fewer side effects so I was wondering whether LB might be a way forward for these people who have had their arbaclofen stopped.

It highlights what is wrong with big pharma. Apparently, Roche spent $90 million on developing this drug, which cost pennies. So where did the money go? No doubt, into the bank accounts of directors, doctors, researchers etc to give sick kids a pill that costs next to nothing to make. The money could have been used to actually supply the drug to those for whom it worked but because the trials were structured in the way they were, the drug won't be approved, at least not soon, and not until a new trial is set up which looks for different results.

Anyone heard from Lo0p??

**Lo0p** · November 1, 2013, 05:27 PM

Setback for Arbaclofen in Autism

Here

**Lo0p** · November 1, 2013, 05:35 PM

Setback for Arbaclofen in Autism

Otter;1577192 wrote: My understanding of arbaclofen is that it is a chemical which, when ingested, turns into baclofen. It has fewer side effects because it has been modified. I also understood that LB has the same benefit, that it has fewer side effects so I was wondering whether LB might be a way forward for these people who have had their arbaclofen stopped.

I won't comment on this and can't engage in this discussion. But I'll invite terryk to come in and give a big fat no/negative to this line of thought.

Although, if I recall, terryk mentioned that all baclofen was a 50/50 mixture of baclofen and...what?

baclofen's isomer?
racemic (r-baclofen)?
arbaclofen?

**terryk** · November 1, 2013, 10:48 PM

Setback for Arbaclofen in Autism

Lo0p;1578342 wrote: I won't comment on this and can't engage in this discussion. But I'll invite terryk to come in and give a big fat no/negative to this line of thought.

Although, if I recall, terryk mentioned that all baclofen was a 50/50 mixture of baclofen and...what?

baclofen's isomer?
racemic (r-baclofen)?
arbaclofen?

The baclofen we all take is racemic baclofen, a 50/50 mixture of R-baclofen (also known as L-baclofen) and S-baclofen (also known as D-baclofen). R-baclofen is the therapeutically useful one, while S-baclofen may be the cause of some side effects.

D-Baclofen is an antagonist at baclofen recepto... [Pharmacology. 1985] - PubMed - NCBI

https://www.mywayout.org/community/f2...tml#post915988

Arbcalofen Placarbil turns into pure R-baclofen when it is metabolized.
-tk

**Lo0p** · November 2, 2013, 01:03 AM

Setback for Arbaclofen in Autism

Okay...

I'll make some phone calls.

edit: I must be the "Bueller..." you mentioned back in 2010. I was there. I read that when you wrote it, I remember. I don't know if that's funny or not. :H

**Lo0p** · November 2, 2013, 01:31 AM

Setback for Arbaclofen in Autism

I never read the one about D (or S) baclofen being an antagonist. That would have set sirens off in my brain.

I remember seeing pictures of the two somewhere.

I can't call till Monday and it's the kind of call where they're going to have to call me back. I think I'll shoot them an email and follow it up with a phone call.

**Lo0p** · November 2, 2013, 03:50 AM

Setback for Arbaclofen in Autism

I am aware that LB (anecdotally) has a lower side effect profile than most baclofen originating from pharmacies in most people.

Again anecdotally, however I know and speak to more people that take LB than are in most studies, I am also aware that there is a tendency for it to be more potent in terms that we consider relevant to us (switch dosages etc.). I know quite a few people who take less than 50 mg/day (30mg is a common number). One who takes 5 mg/day and has tried to take none without success (5 mg is their switch dose and has been so for...a year).

This ^^ is true, when filtered through my brain. If anybody wants to ask me about any of this, do it privately please. Below is just conjecture.

It is definitely, across the board not 5 times as potent, but:

These were studies done in rats not humans. And we're talking about something a lot more complicated (switch dosages) than a tail flick test in an attempt to accurately measure nociception, which, without looking it up I remember to be something like: the brain's registration or reception of pain signals. I'm just going to go ahead and assume they were talking about nociception at the spinal column and what I'm going to call reflexes, winging it:

Reflexes that do not involve the brain are responses to external stimuli on a peripheral limb (leg, arm, tail). A tail "flick" response I think are what these researchers were attempting to consider a relevant replacement in humans for the response elicited when a doctor taps on that tendon below your kneecap with that rubber hammer and expects your quadricep to tense up and kick your lower leg forward. This type of a reflex is received by your spinal column and a reflexive impulse is immediately sent back by your spinal column eliciting the kick response which is quick. Much quicker than the secondary response, which travels up your spine to your brain (all the way to your cerebral cortex I believe) at which point you can engage the rest of your senses to determine the cause and make an actual "informed" decision about how to react to the stimulus.

Baclofen's main site of action for it's historically intended (second :H) purpose was the GABA B receptors on the spinal column. MS patients get relief from their muscle spasticity due to baclofen's action on the GABA B receptors on the spinal column. Which was probably the reason for this study.

Anyway, back to the topic at hand, Stratus (my technical administrator) posted a study about Arbaclofen placarbil on our forums: The First Drug that Could Ease Social Withdrawal in Autism - Baclofen for Alcoholism and Other Addictions

It is unlikely that he circulated here, although Otter may have.

What do we know about Arbaclofen placarbil? It's a prodrug? Why? For patent purposes? You mentioned it was metabolized. By the liver? So after first pass metabolism is it mostly converted to R Baclofen?

When R baclofen is ingested (I'm assuming) it passes through the hepatic artery and the liver mostly untouched, makes it rounds and is excreted by the kidneys more or less with the stated half life, unless you ingest high doses (something else I think I read)...?

**terryk** · November 2, 2013, 08:41 AM

Setback for Arbaclofen in Autism

Lo0p;1578507 wrote: I never read the one about D (or S) baclofen being an antagonist. That would have set sirens off in my brain.

I remember seeing pictures of the two somewhere.

I can't call till Monday and it's the kind of call where they're going to have to call me back. I think I'll shoot them an email and follow it up with a phone call.

I just realized what "LB" stands for. I thought it was L-baclofen (the isolated therapeutically active enantiomer, also known as STX209) , which theoretically is more potent, should (theoretically) cause fewer side-effects, and is the relevant component of Arbaclofen Placarbil.

As far as I'm aware, Liquid Baclofen is still racemic baclofen, the 50/50 mixure.

An explanation of the benefits of arbaclofen placarbil

-tk

EDIT: I just came across this commentary (about Xenoport dropping AP for MS) that raises an interesting point about clinical trial design and actual measurement of drug efficacy:

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?"

"You may be interested to know that Acorda's trials of fampridine, also used an enrichment design. This means that only responders are entered into the double-blind placebo-controlled study. This design may seem counterintuitive, but it is what the Regulators now expect for symptomatic therapies

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