Autifony Therapeutics Phase I Study for AUT00063, for the Treatment of Hearing Loss and Tinnitus

@attheedgeofscience - what if you get a placebo in phase 2 ?

Also, would you wait for Autifony or will you go ahead with HIFU brain surgery?

 

Well... then you get the placebo... (or rather ). I am not sure what your question is? If AUT00063 is curative medicine, then continuous life-long treatment will not be necessary - in which case, I suppose, they could (and would) offer the treatment post clinical trial (as with the AM101 procedure). However, things are different here (vs. AM101). With AM101 you are essentially treated in "one go". But with AUT00063, treatment could go on for several weeks (as a minimum) - and I (very much) doubt that you would be allowed to take a "box of pills" with you back home. In other words: you would need to show up at the clinical trial centre day after day after day... But... I am unsure - these kind of questions are best left to the clincal trial study centres. If AUT00063 is not curative, then I doubt it will be offered post clinical trial. But again - I don't know, so I would rather not speculate. There should be plenty of information available shortly (ie. in the next few weeks).

I would need more time before I can answer that question. But I am not a drugs fan. And I generally prefer therapies which aim to fix whatever problem there might be in one go. We shall see.

 

@attheedgeofscience , what i meant was do the placebo group switch with the drug group after washout.

Also, would you be interested to PM me about Dr.Jeanmonod.

 

Hmmm... The best thing this forum could do is invite researchers to answer questions from time-to-time (or provide updates on a quarterly basis - something like that). These kinds of questions are always speculative. But playing the Devil's advocate here, I am not necessarily sure I would see long term pain as any different than long term tinnitus (from a "habitual stimulus" point-of-view). Would you? And yet, I know that there are examples of people who have had insufferable back pain and were cured "on the spot" by eg. back-surgery or a trip to the chiropractor (after having suffered several years). Also, anyone can swallow a pill and get pain relief "on the spot".

I see the term plasticity used a lot on this forum. I am not so sure I agree with the usage of this term in all instances. Plasticity or neuroplasticity in the textbook sense, is something that happens post physical trauma to the brain (eg. a severe blow to the head or a brain bleed) - and is the creation of new neural pathways. A key feature of a (physical) trauma - anywhere - is the formation of scar tissue. Scar tissue has no biological functionality except to "fill in the gap". Scar tissue is probably one of the biggest hurdles that the human body has created for itself. It is the very reason why a complete spinal cord injury will not recover on its own - and people with this type of injury will not walk again (even with stem cell injections this type of injury is a nightmare for both doctors and patients(!) to deal with; the results are not good at all). It is also the reason why burn victims have trouble regulating their body temperature because scar tissue does not possess the characteristics of normal skin (eg. sweat glands). Personally, I am not sure that tinnitus has too much to do with plasticity; if anything it has to do with a lack of plasticity (if you ask me...). In any event, the above is the reason why I always remind myself:

The field of medicine cannot be practiced on a blackboard

and

In medicine, 1 + 1 ≠ 2.

If people wish to spend hours and hours studying theories - I would suggest joining a physics or mathematics forum, instead. The field of medicine is best left to those who appreciate a hands-on approach and like to deal with (observed) facts.

Phase II vs. Phase III has to do with sample size.

 

Can you expand on this please?

 

Sorry if this has already been asked... What is phase IIb? Was there a phase IIa?

 

It would be really great if someone from here could get into the trial

Phase IIa is the one starting soon. Sometimes they make two phase II, therefore a and b. It's explained in the first few pages of this thread i think.

 

So I guess you could compare these potassium channel modulators (Retigabine and AUT00063) and the brain plasticity with weaning of an addiction, like nicotine for example? When someone stops smoking, the brain is still craving the nicotine for a couple of weeks, then the craving starts to fade, and the brain will adapt the "non-craving" to it's new normal state. Is this the brain plasticity at work?

 

How would you go about getting onto one of these trials?

 

I like the way you comapre the smoking to T.. Actually a good way to look at it.. Just hope it works that way!

 

They will release info about the trials, with inclusion criterias and such shortly on their website. My guess is that you have to be a UK citizen and fit the criterias. All the available info so far is in this thread if you want to know more.

 

Yup, that is my way of seeing it from all the explanations Benryu has made.

 

When is a realistic time we could expect an answer on how this 'drug' will work? half a year or later?

 

As stated earlier in this thread (or the retigabine thread), if someone from here can get into the trial, then that person can report back to us in real time. Otherwise we would probably have to wait quite some time to see the published results. The trial itself will probably be over 6 months long, then they will have to gather all the data and write a report which is also quite time consuming. Then they will publish it in some kind of scientific journal. This is unless Autifony themselves will keep us updated on how the trial is going, but that is very unlikely.

 

Modern medicine, like almost any scientific discipline nowadays, has its theoretical underpinning in biology, which in turn has its base in chemistry and that in turn in physics. (Reductionism is firmly established in the sciences). The directions that medical research (and from it, practice) takes are informed by theoretical constructs in all of the above fields (including hybrids like biochemistry, biophysics, etc.).

True, the ultimate arbiter of what is correct and what is not is empirical evidence (i.e. the 'observed facts'), but that is the case in all the sciences, including fundamental physics. However, just observing facts and having a hands-on approach is not sufficient by itself to achieve good results. That would be akin to just poking around here and there, trying this and that medicine/mixture/potion, and seeing what happens. And that begins to sound reminiscent of medieval medicine.

What is really needed is a coherent theoretical account of the observed facts, one which leads to understanding, abstraction/generalization, and the synthesis of new ideas, concepts, and testable theories. That is why spending hours upon hours (and more) studying theories is just as important in the field of medicine as it is in other sciences.

 

Here is a summary of the phases for clinical trials from Wikipedia. I don't believe you can skip Phase III.

Phases

Main article: Phases of clinical research
Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases 0, 1, 2, and 3, it will usually be approved by the national regulatory authority for use in the general population.

• Phase 0: Pharmacodynamics and Pharmacokinetics
• Phase 1: Screening for safety
• Phase 2: Establishing the efficacy of the drug, usually against a placebo
• Phase 3: Final confirmation of safety and efficacy
• Phase 4: Sentry studies during sales

Each phase has a different purpose and helps scientists answer a different question:

Phase 0 trials are the first-in-human trials. Single subtherapeutic doses of the study drug are given to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs).[28]

In Phase 1 trials, researchers test an experimental drug or treatment in a small group of people (20–80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 trials, the experimental treatment is given to a larger group of people (100–300) to see if it is effective and to further evaluate its safety.

In Phase 3 trials, the treatment is given to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.

In Phase 4 trials, postmarketing studies delineate additional information, including the treatment's risks, benefits, and optimal use.

Before pharmaceutical companies start clinical trials on a drug, they conduct extensive preclinical studies.
​

And here is an interesting graphic of the stages a drug goes through before approval in the US. It's from the FDA. The graphic below is a little blurry, but if you click on the FDA link, you'll go to a clear copy:

​

References:

http://en.wikipedia.org/wiki/Clinical_trial

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm289601.htm​

 

Not sure I understand your comment about plasticity and tinnitus. Surely tinnitus has to do with synaptic plasticity as opposed to forms of scar tissue? Still would like to know the timing/coding of this related to tinnitus. Still can't find studies out there. @jazz ??
Good to know that @benryu has indicated (as I have interpreted his posts anyway) that is is possible that specific potassium channel openers such as AUT00063 may be able to reverse this without continued use.
Any comments, anyone? Please let there be a neuroscientist on this site

 

Defn synaptic plasticity: "the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity."

To the extent that tinnitus may (or may not) be related to neuro-plasticity, tinnitus is therefore an indication of a lack of neuro-plasticity ie. neurons are in a dysfunctional state from which they cannot recover. If an external event (eg. acoustic trauma) brings about tinnitus - that's not a plastic change if you ask me. That's a dysfunction - or an introduced pathology - that occurs in a split second, and from which the body cannot recover. If the body was able to recover, then we would not have tinnitus anymore due to plastic changes that occur following the incident. The fact that we do have tinnitus means that plasticity did not occur. Hence a lack of plasticity, as I wrote earlier on in another post. Satisfied...?

The topic of scar tissue is something I mentioned just to reinforce that reality, and especially biology, is more complex than pretty models on a blackboard. Scar tissue and neuroplasticity tend to go hand-in-hand, post physical truama. Who knows what our inner ears look like at the cellular level after we have been treating them like doormats with noise and chemicals for 20 years? Just another variable to consider...

It wouldn't hurt, but does it make a (real) difference? Will it get you cured faster? Will it speed up clinical trials? Who cares about discussing theories left, right, and centre. The only thing that matters is results. The tangible kind, that is.

 

this is not true- why would an IV of lidocaine temporarily do away with tinnitus for people who have had it over a decade if the tinnitus was somehow magically memorized or encoded in the brain--- just more deductive crap ( much like jastebroff's "the model") from tinnitus experts which will ultimately be discredited

 

...couldn't have said it half as well myself

 

I agree. I hear of tinnitus disappearing in chronic cases. Not habituation. Tinnitus is gone. Many stories of suppression through drugs etc. Therefore something somewhere along the line (call it plasticity/brain chemistry change etc) must be reversible @Mpt @attheedgeofscience
Hopefully AUT00063 will lead this theory.

 

And just to be real clear here (since we are discussing biology and matters of importance): the "pretty models" I was referring to, are not the ones that come with two legs and wearing a bikini. Those particular models, I have absolutely nothing against. You can leave them "hanging around" on blackboards anytime...

 

It's also referred to as "negative plasticity" in tinnitus literature.

 

Thought I would add my 1.5 cents to this "plasticity" discussion...and no, I am not a neuro-scientist at all. Far from it. However, I have found that having a model, or theory, or 'explanation' of what could be going on with AUT00063, Retigabine, and the "K-channels" group (Maxipost is the latest 're-invader' in the game), actually helps me feel more...Mmmmmmm??? Accepting of my T and H perhaps? Or patient with it? Or...whatever. It's been good for me.

"Plasticity" as we have been throwing around in quasi @benryu fashion (apologies if I slander thee), or general discussion on this and the Retigabine thread...sort of means the ability of the brain, or aspects of neural function, to change over time - even if that is not that long of a time. I do not see it in the same light as I think I understand my general concept of what happens with stroke patients (like my mother). With stroke I get a sense that the damage ("scar tissue"???) is so permanent that the areas of the brain affected are more or less written off. Their 'road bridges' (neuronal pathways) fell in the river and are not going to miraculously come back and make a whole new, or even second-hand, bridge.

The brain, being such a smart-arse, then gets going and sniffs around for areas and roads that are just lying around being underused - or in the same despicable condition as many of our roads (all the $$$ went to wars and...Ooops) are here. Basically, they get dusted off and opened up, so that more adventurous traffic starts to travel down them. With more traffic the road starts getting more attention and even gets on the local 'map'. The repair crews finally wake up to the reality and go: "Oh shit! Look we have a bunch of traffic here so let's make sure we put it on the maintenance schedule"...Or whatever. In short it becomes > mainstream.
I don't consider this to be "plasticity". Maybe the speed with which some of those changes take place has "plastic" elements, but that's way beyond my pay grade.

The "plasticity" thing to me relates more to the "habits" learned or potentially learned, that then "stick"...even if they are totally dumb for something as smart as the brain. I think Tinnitus is just a dandy example of that. Like: "Duh, you guys in CONTROL, what's so cool about this loop???!!! Stop watching retinal football and fix this!" CONTROL of course blows it off because they consider it to be an auditory app. problem and the audio fix-it crew should go and deal with the fried hair cells, or "boutons", or whatever...and until then, bug the hell off! (Management scum!)

Now (again, to me) this "plasticity" can be a potential good thing or bad thing. For simplicity I will just consider "new habits/changed habits" like what happens presumably with T. - which was not there at first, then something happens (Mick Jagger, Bomba, Gentamycin, etc.), and it becomes a "permanent malfunction".

OK, so say we have this "T. event" and there is a lack of plasticity? Well maybe this sudden T. would just freak out the audio crew, who jump up and have all kinds of political debate about what to do, act just like our Congress and get nowhere for ages....and then someone notices that the T. went away! They all cheer and get back to the important stuff like dining with lobbyists.
Maybe here the "plasticity" was 'under the influence' of say....a Benzo!!!...if we go with the theory (which apparently is in the Jasterbrof book - which I have no intention of reading) that they "impair" plasticity:

'Alprazolam (Xanax)and other benzodiapzepines impair plasticity in the brain and reduce learning ability, thus counteracting TRT (and habituation).We strongly oppose the use of alprazolam for tinnitus.'

Apologies if this quote is wrong, but it is just an example model anyhow.

In this case the "lack" of plasticity may be a good thing as it meant the adaption and potential to form a "habit" through this "plastic functionality", was out to lunch due to GABA intoxication. Well cool...Who the hell wants T. anyhow???!!! Phew...sure glad plasticity was compromised there.

And so on...Obviously the inverse could be true. Obviously there are tons of variables. However, getting back to when "plasticity" does set in, it seems to me that (counter to my example of the trashed bridge earlier) the bridge across the river gets buckled, or kicked down-stream a few yards, and traffic gets totally weirded out. It does not go and find a completely new way to Kansas.
While this was happening the repair crews were in CONTROL for some chill TV time, and contrary to their fix-it mandate, they let it slide, (or if we are sympathetic to them)...when they finally see it all it's way too much of a mess to fix.

Ta, taaaaaa!!! Then the GREAT CAPED K+ HERO arrives out of the blue (are the pills blue???) and just starts kicking butt left, right and center. Being a Marine by distant training, doors get blown open, doors get blown back, doors do God knows what. But when the repair crew come out of hiding they are amazed to find the the bridge has been repaired and more or less back to where it was. Not quite perfect, as interaction with a Super-hero of such stature is bound to leave scratches on the paint.
In conclusion, "plasticity" has been affected. This time in a good way...for us lot anyhow.

OK, to end up here, I am going to steal a quote from me on the Retigabine thread just to show how little we really know about this stuff...even though as I said, I find these ideas and 'explanations' comforting. This was on a sister drug to Retigabine that came up - Maxipost:

On Maxipost, rather interesting to note - yet another WTF???...with Tinnitus:

Unexpectedly, the R-enantiomer *[ sort of mirror image opposite ~ Zimichael] of Maxipost, R-Maxipost, which has no anxiolytic effects and negatively modulates Kv7.2-Kv7.5, also suppressed behavioral evidence of tinnitus. Our original hypothesis was that Kv7.2-Kv7.5 channels might play a key role in tinnitus generation and that Maxipost but not R-Maxipost would suppress tinnitus; however, it appears that a shared mechanism between Maxipost and R-xMaxipost, such as inhibition of Kv7.1 channels or activation of BK channels or some novel mechanism common to both compounds, underlies salicylate induced tinnitus as both compounds completely abolished behavioral evidence of tinnitus in a dose-dependent manner.

Basically as I understand this in simple English..."If you kick the door (K channels) down, you get a positive effect. If you close the door (K channels) and bolt it, you get a positive effect." I mean WTF?????? That's like saying if your turn the power off the light goes on. If you turn the power on, the light goes on. Just goofy...But what's new with T huh?!

Trippy huh?! "Plasticity" in all it's wonders?????!!!!!

Best, Zimichael

 

I don't see how that necessarily follows from the definition you gave. From the definition, plasticity is not about recovery (to some 'normal' homeostatic level), but rather simply the stregthening of synaptic response in response to increased activity, and weakening in response to decreased activity.

 

Plasticity doesn't mean that a condition can't me treated. it basically means that it needs additional help because its not able to do it on its own. That explains why tinnitus rarely leaves on its, as for example, clinical depression - the brain is not able to adjust itself to new changes. Of course Im not an expert on it but if the brain is not able to get rid of problems itsself there must be some reason to it...

 

Meaning the tinnitus needs help to be pushed away?-- and actually treated

 

yes I think thats what it means Of course it needs the right treatment and I doubt the same treatment will work for everyone. However, if there already is one it will help develop other drugs. There seems to be quite a lot of research going on so I dont see why this shouldnt happen.

 

@lapidus - was there any info that went out about how long Phase 2 would normally take? I'm just trying to determine a timeline here. Does anyone recall how long it was from when phase 1 completed to when phase 2 will start in October? According to an auto reply i received from Dr. Charles Large, he stated that if the phase 2 trial is successful they plan to extend it to US for further studies. I'm wondering if successful, we might see trials in the US by end of 2015, or am i being way too hopeful?