Otonomy Starting Phase 1 Trial in 2015 for Tinnitus

[Danny Boy]

Why's the target always the ear? We know it's a brain problem, so why the ear?

 

[attheedgeofscience]

Why's the target always the ear? We know it's a brain problem, so why the ear?

Seems like you have some reading to do...

Q: I'll ask a question I'm sure a lot of people will be asking - is there any known reason why AM-101 couldn't help those with long term tinnitus?

A: So far, AM-101 has been tested only in the acute stage, which according to some guidelines extends up to 3 months from onset. There is a certain consensus among experts that inner ear (peripheral) tinnitus may become centralized in some patients after the acute stage, which means that the target for a treatment may shift from the inner ear to the brain. However, the exact mechanism and timing of such centralization is unclear, and it must be noted that a considerable number of tinnitus sufferers will probably never experience any centralization at all. In the absence of reliable diagnostics to distinguish between peripheral and central tinnitus, we consider it prudent to explore AM-101's time window with a step-by-step approach. First, we need to demonstrate that AM-101 works in the acute stage and get it approved – in a second step, we will expand on this and seek to find out how far we can go. This is reflected by the design of our European trial, where we are testing AM-101 primarily in the acute setting, but in a separate stratum also in the post-acute setting (up to 12 months from onset).

Source: www.tinnitustalk.com/threads/auris-medical-q-a.8201/

...and you were one of the members who raised a question with Auris Medical in the Q&A where the above material was taken from.

 

[Silvio Sabo]

Why's the target always the ear? We know it's a brain problem, so why the ear?

Well it all starts in the ear. If your hearing is damaged by noise then there is damage somewhere in one of the many places that are responsible for hearing. You can have dead hair cells, you can have a damaged connection between hair cells and nerve cells, you can have nerve damage in the auditory nerve or one of it's connecting nerves and so on.

The brain part are the DCN and the auditory cortex. We can see that the DCN and the auditory cortex are hyperactve. But why is that? My guess is that it's a secondary effect of damage to one of the above mentioned.

If you are refering to the HIFU treatment then you are basically treating the cells that are responding to this faulty signal. You are not treating the signal it self. So your damaged nerve or hair cells will still behave like before but your brain will loose the ability to hear the distress call. If you understand what I mean. So you will no longer experience the T. sound. At least that's how I have come to understand it.

It would be very strange if loud noise would cause brain damage. It makes no sense!

 

[Zimichael]

In T. sufferers there seems to be something wrong with these channels. So that nerves fire even thouogh there is no stimuly.

From my now somewhat rusty memory of all this...

The K gates (potassium gates) are "stuck" and thus not allowing those K ions back into the neuron to "normalize" to the slight polarization that occurs under the normal resting neuronal state...which is required before a new "action potential" (firing) can occur. Thus, getting back to "normal" polarization and behaving "correctly" thereafter = only firing when there is enough new polarization (from new, legitimate stimulus) to cause an "action potential" to occur (FIRE!)...Getting stuck in a hyperpolarized state (un-normal) is like getting stuck in a "sorry we are out to lunch here and not going to open the doors/gates, so bugger off"...condition.
This is what the Potassium Channel Modulators are attempting to address. To overwhelm the gates and re-open.
As so expressed in my somewhat crude analogy of many moons ago = "Let's kick those bloody doors open and get this show back on the road, back to normal functioning". Which would mean "untsticking" the tinnitus condition.

Something like that. Best, Zimichael

 

[Silvio Sabo]

From my now somewhat rusty memory of all this...

The K gates (potassium gates) are "stuck" and thus not allowing those K ions back into the neuron to "normalize" to the slight polarization that occurs under the normal resting neuronal state...which is required before a new "action potential" (firing) can occur. Thus, getting back to "normal" polarization and behaving "correctly" thereafter = only firing when there is enough new polarization (from new, legitimate stimulus) to cause an "action potential" to occur (FIRE!)...Getting stuck in a hyperpolarized state (un-normal) is like getting stuck in a "sorry we are out to lunch here and not going to open the doors/gates, so bugger off"...condition.
This is what the Potassium Channel Modulators are attempting to address. To overwhelm the gates and re-open.
As so expressed in my somewhat crude analogy of many moons ago = "Let's kick those bloody doors open and get this show back on the road, back to normal functioning". Which would mean "untsticking" the tinnitus condition.

Something like that. Best, Zimichael

Yes, what you are discribing is sortof like a cramp in the muscle. If you are low on potassium you can have cramps or spasms in your muscles becouse there is not enough potassium to reverse polarization. So T. is basically a hearing cramp.

 

[skoupidis]

From my now somewhat rusty memory of all this...

The K gates (potassium gates) are "stuck" and thus not allowing those K ions back into the neuron to "normalize" to the slight polarization that occurs under the normal resting neuronal state...which is required before a new "action potential" (firing) can occur. Thus, getting back to "normal" polarization and behaving "correctly" thereafter = only firing when there is enough new polarization (from new, legitimate stimulus) to cause an "action potential" to occur (FIRE!)...Getting stuck in a hyperpolarized state (un-normal) is like getting stuck in a "sorry we are out to lunch here and not going to open the doors/gates, so bugger off"...condition.
This is what the Potassium Channel Modulators are attempting to address. To overwhelm the gates and re-open.
As so expressed in my somewhat crude analogy of many moons ago = "Let's kick those bloody doors open and get this show back on the road, back to normal functioning". Which would mean "untsticking" the tinnitus condition.

Something like that. Best, Zimichael

Interesting theory. If correct, it should explain many things. Like why T is accompanied by hearing loss at those frequencies. Or the hyperacusis and distorted hearing. Basically it explains why you hear sounds when you shouldn't and why you don't hear sounds properly when you should. It explains why T and hearing loss are interconnected. So, restoring proper function of this anomaly of the inner ear should not only get rid of Tinnitus but get hearing in its proper track. This is what Autifony tries to do I guess, hence "For T and hearing loss".

However, this theory doesn't connect to the hair cell therory (could be different situations) and also has a flaw: Why the ear cannot repair itself in that case? We know of inability to regrow hair cells, but what stops the ear mechanism from repairing itself in this case?

 

[Sharpfire]

Why's the target always the ear? We know it's a brain problem, so why the ear?

Nobody for sure knows the true cause for tinnitus unfortunately, but I suspect it may be both the ears and brain, i.e damage in not necessarily ear structures, but ear neurons (remember, neurons connect to the CNS), which leads to hyperactivity in the brain. If this was the case, a cure would tackle either or both of those systems.

I've spoken in person to a researcher that has been working on NMDA receptors for over 20 years, and he told me that it's very plasuable for NMDAR antagonists to reduce or eliminate the effects of tinnitus (remember, NMDA receptors lie on the surface of neuronal cells).

 

[Danny Boy]

Nobody for sure knows the true cause for tinnitus unfortunately, but I suspect it may be both the ears and brain, i.e damage in not necessarily ear structures, but ear neurons (remember, neurons connect to the CNS), which leads to hyperactivity in the brain. If this was the case, a cure would tackle either or both of those systems.

I've spoken in person to a researcher that has been working on NMDA receptors for over 20 years, and he told me that it's very plasuable for NMDAR antagonists to reduce or eliminate the effects of tinnitus (remember, NMDA receptors lie on the surface of neuronal cells).

That's why, I'm interested in taking campral with trobalt.

 

[NiNyu]

Why the ear cannot repair itself in that case? We know of inability to regrow hair cells, but what stops the ear mechanism from repairing itself in this case?

From what I have read there are kind of walls around those bundles of hair cells that are solid in mammals. Whereas in birds they are very soft and if hair cell damage occurs the adjacent cells can regrow new hair cells.

I've spoken in person to a researcher that has been working on NMDA receptors for over 20 years, and he told me that it's very plasuable for NMDAR antagonists to reduce or eliminate the effects of tinnitus (remember, NMDA receptors lie on the surface of neuronal cells).

When?

 

[skoupidis]

From what I have read there are kind of walls around those bundles of hair cells that are solid in mammals. Whereas in birds they are very soft and if hair cell damage occurs the adjacent cells can regrow new hair cells.

No, I was referring to abnormal firing, not the hair cells. As I wrote, we don't know if they are connected. And if they are, and abnormal firing is caused by damaged hair cells, how on earth could they stop it without fixing the damage (hair cells)?

 

[NiNyu]

No, I was referring to abnormal firing, not the hair cells. As I wrote, we don't know if they are connected. And if they are, and abnormal firing is caused by damaged hair cells, how on earth could they stop it without fixing the damage (hair cells)?

..damage in not necessarily ear structures, but ear neurons (remember, neurons connect to the CNS), which leads to hyperactivity in the brain. If this was the case, a cure would tackle either or both of those systems.

We also know that cutting the auditory cochlea nerve won't resolve T in most cases. Thus it's the neurons in the brain. We can't fix the hair cells. The cochlea has the size of a pea. So.. our best shot is the brain. Unless there's a miracle drug that could regrow hair cells once injected into the perilymph liquid of the cochlea, which is next to impossible?

They know exactly how the whole hair cells in birds work and yet they can't fix those in mammals. It's nature.. we can't copy nature with the blink of an eye. It's all a lost cause. Can someone please slash my brain? Please?

 

[jeannie]

what about the new finding of tinnitus affects parts all over the brain??

 

[Sharpfire]

From what I have read there are kind of walls around those bundles of hair cells that are solid in mammals. Whereas in birds they are very soft and if hair cell damage occurs the adjacent cells can regrow new hair cells.



When?

Like 2 months ago

 

[NiNyu]

he told me that it's very plasuable for NMDAR antagonists to reduce or eliminate the effects of tinnitus (remember, NMDA receptors lie on the surface of neuronal cells).

No. I meant, when is he releasing this NMDAR antagonists that reduces the effects of T ?

 

[Danny Boy]

No. I meant, when is he releasing this NMDAR antagonists that reduces the effects of T ?

In some cases it makes people's tinnitus worse. Personally I didn't do the trial out of fear, so I'll never know if it does help...I don't know if I made the right or wrong choice. I'm talking about AM-101 by the way.

 

[Sharpfire]

No. I meant, when is he releasing this NMDAR antagonists that reduces the effects of T ?

Sorry if what I wrote was misleading, but this individual has been working on NMDA receptors, their agonists and antagonists etc for reasons other than tinnitus. My comment was just an informed opinion of his that doesn't really 'mean' anything scientifically.

 

[NiNyu]

I'm talking about AM-101 by the way.

AM-101 makes only sense when you really get it and not a placebo. It's just too invasive and a placebo control group is completely useless due to spontaneous recovery! We talking acute T here.

 

[attheedgeofscience]

It's just too invasive and a placebo control group is completely useless due to spontaneous recovery!

The spontaneous recovery would hold true for both sub-sets (i.e. placebo and AM-101). This can therefore be taken into account via statistical analysis - a fact I actually know very little about (in practice) due to my business finance background. But if my memory from some 15 years ago does serve me correct, there tests such as the t-test which - with the right assumptions (most important of which is likely to be the n-value of the sub-set) - can determine statistical significance between two groups of data.

In plain simple language: if AM-101 is effective and if enough participants are enrolled with proper and consistent inclusion criteria between both groups, you would expect to see a more significant amount of improvement versus the placebo group. But both number of participants and adherence to inclusion criteria are - and would be - important factors to consider (and observe). And if I recall anything from my business statistic lectures, the most important criteria in statistics is always the n-value. If "n" is large enough you can pretty much disregard most assumptions behind the various tests and do anything with the data (within limits, of course).

attheedgeofscience
28/APR/2015.

 

[sakrt]

This kinda stuff never comes to Australia

Thank your country for this mate. Truly -as they care for your health at least, because the corruption from USA has not intruded there, yet- for a reason. Your gov't/country has established higher regulations of disallowing outside questionable products/drugs that may not have been approved. The misconduct between FDA and big Pharma corporations in USA is quite bad. The good news is the public and independent agencies are catching up and bringing awareness of it.
In regards to educating yourself in your region to protect yourself and even request further info on certain drugs - contact/follow-up on International health to get unbiased info.
USA corruption re: FDA:
http://www.anh-usa.org/once-again-the-fda-deliberately-keeps-us-in-the-dark-about-bad-science/
http://www.slate.com/articles/healt...ntific_misconduct_are_hidden_from.single.html

International - http://www.anhinternational.org

 

[NiNyu]

The spontaneous recovery would hold true for both sub-sets (i.e. placebo and AM-101).

Precisely, and that's why it makes no sense for acute T. Chances are that all those that did improve had simply a spontaneous recovery, which renders the placebo group useless. Moreover, less patients were treated in the process.

However, if every patient got AM-101, this way they would have gotten more patients to begin with, and most of them did improve significantly they could conclude that their drug indeed works. Otherwise we are back at
spontaneous recovery.

 

[Silvio Sabo]

Precisely, and that's why it makes no sense for acute T. Chances are that all those that did improve had simply a spontaneous recovery, which renders the placebo group useless. Moreover, less patients were treated in the process.

However, if every patient got AM-101, this way they would have gotten more patients to begin with, and most of them did improve significantly they could conclude that their drug indeed works. Otherwise we are back at
spontaneous recovery.

I think you misunderstood what ATEOS was saying. In both groups there will be people who will have spontaneous recovery however in the AM-101 group there should be more people making a recovery and/or more people a making full recovery then in the placebo group. This is why they are doing the tests. If the results in the two groups are the same then AM-101 isn't working since it isn't better then placebo.

This is why that "n" number has to be high enough. Because if you did the test with let's say 5 people in each group you might end up with all 5 people in the placebo group recovering spontaneously and none in the AM-101 group just by pure chance! But if you have 100 people in each subgroup then you will be able to get data that is statistically useful.

If you gave everybody the drug then you can't draw any conclusions regarding if the drug is better then placebo since all of your positive results might be just placebo and not the drug.

This is standard protocol for double blind testing. The double blind stands for that both the patients and the doctors treating them are unaware if the patient is receiving placebo or the real drug. This is so that the patients response will be genuine as if received real drug but also because the doctors might do a poorer job with the placebo group if they knew who they were (this is one of the explanations to why some people benefit from Homeopathy. The Homeopaths usually have better people skills then regular M.D.'s and tend to listen and care for their patients more and some people feel better just because they feel that they are being listened to even though they basically just get water).

The only people who should know who gets what are the ones that run the trial. And they should never meet the patients.

The whole point is to see if the drug is better then placebo and to do so one has to eliminate all other aspects then the drug it self. So no human feelings from doctors treating patients or the patients them selves must have any part in the results, only the drug!

 

[NiNyu]

I think you misunderstood what ATEOS was saying. In both groups there will be people who will have spontaneous recovery however in the AM-101 group there should be more people making a recovery and/or more people a making full recovery then in the placebo group.

Unlikely, if you consider all the different causes of acute T. It's possible that the placebo group will have more spontaneous recoveries than the AM-101 one. Even though the drug was effective.

If you gave everybody the drug then you can't draw any conclusions regarding if the drug is better then placebo..

Of course you can, if a significant number of patients recover you can conclude that the drug indeed is effective. The placebo is irrelevant. We talking acute T here! In this case placebo = natural recovery (well, almost but with holes in your eardrum).

(this is one of the explanations to why some people benefit from Homeopathy. The Homeopaths usually have better people skills then regular M.D.'s and tend to listen and care for their patients more and some people feel better just because they feel that they are being listened to even though they basically just get water).

The thing is, that works only with pills. And psychological disorders. Not T !

The only people who should know who gets what are the ones that run the trial.

What if they mix it up?

The whole point is to see if the drug is better then placebo and to do so one has to eliminate all other aspects then the drug it self.

Isn't is obvious? Just take questionaries with those patients not willing to partake in the AM-101 study. Then compare the data with those that got the real AM-101. You cannot eliminate the aspect of cause. And that's crucial in acute T. Hence double blind testing is pointless.

 

[earsnothappy]

This shit just pisses me off. Please stay on topic. Off topic posts should be deleted. Including this one.

 

[Silvio Sabo]

Unlikely, if you consider all the different causes of acute T. It's possible that the placebo group will have more spontaneous recoveries than the AM-101 one. Even though the drug was effective.



Of course you can, if a significant number of patients recover you can conclude that the drug indeed is effective. The placebo is irrelevant. We talking acute T here! In this case placebo = natural recovery (well, almost but with holes in your eardrum).



The thing is, that works only with pills. And psychological disorders. Not T !



What if they mix it up?



Isn't is obvious? Just take questionaries with those patients not willing to partake in the AM-101 study. Then compare the data with those that got the real AM-101. You cannot eliminate the aspect of cause. And that's crucial in acute T. Hence double blind testing is pointless.

I'm sorry but you just don't seem to get it!

I and many others have tried to explain this to you and some of us have degrees in sciences of medical research. The way you think it works was done once, then they discovered the placebo effect.

But heck if you think you still know better then all of the medical researchers in the whole world and would like the medical science to go back 100 years then be my guest, advocate for the removal of double blind testing. I will no longer take part in this discussion.

 

[NiNyu]

I'm sorry but you just don't seem to get it!

I got it, but you don't get my point, I'd say.

The way you think it works was done once, then they discovered the placebo effect.

They did discover the placebo effect with acute T (injections through the tympanic membrane) ?

..advocate for the removal of double blind testing.

In case of acute T and injections through the tympanic membrane, yes! As said, it makes no sense since there are just too many causes for acute T. Moreover, you won't get a placebo effect with acute T. It's either spontaneous recovery or the drug or nothing.

 

[Silvio Sabo]

I got it, but you don't get my point, I'd say.



They did discover the placebo effect with acute T (injections through the tympanic membrane) ?



In case of acute T and injections through the tympanic membrane, yes! As said, it makes no sense since there are just too many causes for acute T. Moreover, you won't get a placebo effect with acute T. It's either spontaneous recovery or the drug or nothing.

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

Please read it before embarrassing your self any further.

 

[attheedgeofscience]

Please read it before embarrassing your self any further.

Agreed.

And @NiNyu perhaps you should try to Google the following keywords: "six sigma pharmaceutical industry" in relation to the following comment of yours:

What if they mix it up?

I realize you are in a certain amount of difficulty with your hearing loss (and tinnitus), but your comments belong to places (and intellect) such as that of a kindergarden.

Please stop your comments. It's thoroughly embarrassing to read your posts in a thread where I have managed to get hold of the CEO of an otology pharma which is now funded with capital of 344 million dollars. Do you think the company would have managed to gather that sum of money if there wasn't some substance to what they are researching? Otonomy Inc has generously agreed to provide this forum with information as the OTO-311 clinic trial preparations continue. I have already supplied this board with one such piece of information earlier on, and there will be more to come. But if they should suddenly refuse after seeing what takes place on a public forum, I cannot blame them!

If you wish to read (and understand) more about the mechanism of action of the various otology related drugs aimed at treating tinnitus, you can read the excellent commentaries that the pharmaceuticals Otonomy and Auris Medical have supplied the business world with:

Otonomy Inc:
www.sec.gov/Archives/edgar/data/1493566/000119312514266440/d724113ds1.htm

Auris Medical AG:
www.sec.gov/Archives/edgar/data/1601936/000119312514253454/d684505df1.htm

Needless to say, there is a lot of financial information in financial statements, but the statements also contain a wealth of information in relation to their drug candidates and pipelines. It is well worth a read.

attheedgeofscience
02/MAY/2015.

 

[jeffie7]

Maybe something worth following for updates.

http://finance.yahoo.com/news/otonomy-present-two-upcoming-investor-113000527.html

SAN DIEGO, May 6, 2015 (GLOBE NEWSWIRE) -- Otonomy, Inc. (OTIC), a clinical-stage biopharmaceutical company focused on the development and commercialization of innovative therapeutics for diseases and disorders of the inner and middle ear, today announced that David A. Weber, Ph.D., president and chief executive officer, will present at two upcoming investor conferences:

• Bank of America Merrill Lynch 2015 Health Care Conference, Encore at The Wynn, Las Vegas, May 13, 2015 at 5:00 p.m. PT (8:00 p.m. ET).
• UBS 2015 Global Healthcare Conference, Sheraton New York Times Square Hotel, New York, May 18, 2015 at 4:30 p.m. ET.

A live audio webcast of each presentation will be available through the Events and Presentationspage of the company's corporate website (www.otonomy.com).

 

[Zechariah]

Maybe something worth following for updates.

http://finance.yahoo.com/news/otonomy-present-two-upcoming-investor-113000527.html

Lets hope they get shitloads of money

 

[attheedgeofscience]

Maybe something worth following for updates.

Yes, perhaps it wasn't clear when I wrote the following earlier on in this thread:

...where I have managed to get hold of the CEO of an otology pharma which is now funded with capital of 344 million dollars.

In any event for those who are interested, I have updated the information on the complete otology- and neuro-otology pharma field in the following post (see pdf-file attachment):

www.tinnitustalk.com/threads/overview-promising-treatments-for-tinnitus-and-hearing-loss.3982/page-3#post-52953

It contains financial information, company information, clinical trial information and timelines, drug candidates and to some degree non-publicly available info that I have managed tracked down. There are now 14 different pharmaceuticals listed in the file.