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

I went to three doctors but they told me they couldn't do anything. My objective tinnitus springs to life occasionally when my allergies get bad, or at least that's what I figure is causing it. It'll go away in a few days or even a month on some occasions. Of course the subjective is constant.

 

The middle ear would point really to a mechanical fault or obstruction of some sort and your right for a problem like this Autifony will be useless unfortunately.The outer ear,middle ear and cochlea are all mechanical parts of the ear i.e they move when sound is detected.The ear drum vibrates and causes three little tiny bones in the middle ear to vibrate which then causes the hair cells to bend back and forward to the vibrations.But it is when the haircells bend that it changs from mechanical energy to electrical energy through the underlying connecting neuron the auditory nerve which is about 1 inch long and connected directly to the auditory brainstem.Autifony are targeting from here upwards the electrical energy of hearing which is all conducted through the brain through voltage gated channels.The second that haircell bends back these channels take over and carry the sound through the brain.Aut00063 aims to calm the activity of these neurons and as I mentioned before bring them back to a pre T state.And whatever doctors you visited are not well informed there is much that can be done for middle ear problems,there is a woman near where I live who worked in a noisy factory all of her adult life and went nearly completely deaf.See went to visit a specialist and it was determined that the little bones in her middle ear had nearly completely deteriorated,so they replaced them with prostetic ones and now once again she hears perfect.There is also a young chap who had a severe ear infection and nearly his whole ear drum was destroyed from it,so they replaced it with I believe some skin from his body im not sure I will have to ask him again and now he hears fine.About the only mechanical part of hearing that cant be replaced is the haircell but I do believe they are working on thatA small incision is made at the back of the ear and the middle ear space can be inspected without real risk,these doctors just dont want to help you but a lot can be done.

 

@attheedgeofscience , you must have some inside information. What do the scientists think about Autifony - how likely is it to succeed in curing/significantly reducing tinnitus?

 

Found another article that you guys might find an interesting read.....

http://cen.acs.org/articles/92/i14/Sound-Science.html

 

Adding to your link Rich- A short explanation of the role of K channels by Dr.Neil Bauman.

February 20, 2013: 10:29 am: Dr. NeilTinnitus
Loud Noise, Potassium Channels in the Dorsal Cochlear Nucleus and Tinnitus
by Neil Bauman, Ph.D.
In the past few years, scientists have discovered that tinnitus can arise in various areas of the brain when too much spontaneous neuronal activity takes place, and, for whatever reason, the normal inhibiting mechanisms fail to suppress it.
As time goes by, researchers are more and more zeroing in on the specific areas of the brain and the specific mechanisms that can lead to tinnitus. For example, Dr. Martine Hamann of the University of Leicester in the UK recently discovered that exposing your ears to loud sounds can trigger uncontrolled activity in the neurons of the dorsal cochlear nucleus. (The dorsal cochlear nucleus is the area of your brain that relays signals from your ears to other parts of your brain that decode and make sense of the sounds you are hearing.)
According to Dr. Hamann, normally neurons receive a sound signal, fire and then return to a state of rest. This happens because potassium channels help “drag down the cellular electrical activity to its resting state”. (1) This allows neurons to function in regular patterns in response to sound signals.
However, loud noises inhibit the potassium channels’ ability to properly regulate excess neuronal activity. This means these neurons do not return to their resting state. Instead, they “fire continuously in random bursts, creating the sensation of constant noise where none exists.” (1) We call this resulting noise tinnitus.
Now you know one reason why it is so important to protect your ears from loud sounds. You do not want to inhibit the function of the potassium channels or else some of the neurons in your dorsal cochlear nucleus may begin to fire erratically, and you could be left with loud tinnitus.
For researchers, the next step is to find ways to quickly get the potassium channels working properly again. The thinking is that when the potassium channels do their jobs properly, they will suppress all this extra neuronal activity, and this will greatly reduce or even eliminate tinnitus from this cause.

 

Great find Dan and this is from a few years back,just shows the route Autifony are going with their research and in my opinion this would explain perfectly how T develops,it shows that haircells might not play such an important role as once thought.

 

@bill 112, I'm wondering why the overexcited neurons just don't burn out and die.
Also, do you think non-UK citizens would be able to participate in Autifony trials???

 

This is a completely pointless post really but just want to say, out loud, COME ON AUTIFONY WE NEED THIS....lol

I am in UK and plan to do everything possible to get in on phase 2 trials

 

All the best to you ..have t since April 15th..not feeling too good . hope they find a cure soon, Hang there!

 

UCL in London collaborated with Autifony on the Phase I trial. I am guessing they will at least continue to use UCL as a test site. With that in mind, if you're interested about the Phase II trials it might be worth contacting someone within the Otolaryngology department of the clinical trials arm at UCL.

 

If you want to sign up to be eligible for clinical studies in their department, here is the form. I suppose you probably need to be a resident of the UK to qualify.

http://www.ucl.ac.uk/ear/forms/participateform

 

Hi Dan to be honest im not quite sure,im not a citizen of the U.K but that didnt stop the UCL professor I speak to from saying I couldnt participate,I know the golden rule is you have to be fluent in the native language which Im guessing you are,another forum member has asked me the same question and I will be speaking to the professer soon and will ask him about people outside of the U.K who are fluent in english to see if they are eligible for the trial.For your first question I wouldnt imagine so,its like people who are extremely hyperactive,a part of their brain and neurons within that part of the brain are faulty or overactive to some degree,that doesnt mean they are going to die as a result of their overactive or faulty nature.I believe its the same with T,the parts of the brain concerned with hearing and their neurons have become overactive but that doesnt mean they are going to die.They just need to be told to calm down and hopefully thats what Autifony will do.

 

Many thanks Hudson,

I have already emailed Autifony and got a response but I will be sure to also contact the UCL directly and I will fill out the form you linked.

Fingers crossed everyone....if there is a god then I damn hope he is reading this thread and sends some luck our way

x

 

@bill 112 , thank you so much for your explanation - these buggers can keep buzzing forever judging from other hyperexcitability disorders (epilepsy and so on) - until we force them to stop that is...
I much appreciate you talking to your professor our behalf, like you, I am more than willing to participate.

 

Oooo exciting, what kind of response did you get?

 

No problem Dan lets just hope that this is what people expect it to be,and also on a side note,if the neurons just up and died along the auditory brain this would be clearly seen on an MRI at one point or another.The funny thing about T and H patients is that they nearly always have perfectly clear MRI scans,a multitude of neurons dying or dead would be spotted.But when electro imaging is done thats where abnormalities appear,they can clearly see unusual hyperactivity in the auditory brain thus suggesting that these neurons are alive and well as they would not emit an electrical signal otherwise.The famous stroke victim cured of tinnitus is a proof of this,when a stroke occurs brain cell death begins to happen almost immediately,when his stroke occured it just so happened that the cells in his brain that were creating the T signal were killed thus ending his T.It proves the cells were alive before the stroke and then dead after the stroke ocured and it can be nearly quaranteed that if he was to have an MRI there would be abnormalities present as a result of brain cell death from his stroke.Best Wishes Bill.

 

@bill 112 and @dan You guys seem to know quite alot about the science behind all this. Your posts are always great to read. Do you guys have some kind of medical education?

 

Looks like a lot of ENTs dont have any

 

Well, what they learn about tinnitus is that there is very little that can be done about it.

 

Lapidus thank you for your comment and to answer your question on my education of the audiory system is this,I am not a professor or a scientist but I have done extensive research over the years and am regularly discussing research and my opinions with researchers and gain a lot of info from these well educated people.They have thought me nearly everything I know from the cochlea all the way up to the auditory cortex in fine detail and has given me a much better understanding of how the auditory system works.I have my own deep opinion on how this condition develops and researchers have tended to agree with me and for this reason I do believe this condition is curable.

 

That's it then, if for some unforeseen reason then this treatment doesn't work I will be asking for brain surgery to kill my hypo active neurons that is causing my T, solved!

I can definitely live with that! LOL

 

My tinnitus treatment plan has been focused on remedies that are currently available - or at least nearly so. When I started looking into possible treatments last summer, Autifony was an insignificant spot on the radar (as was AM101). Since then, things have changed. But like AM101, Autifony is still in clinical trial, and hence not a concept I am looking seriously into. It seems to me that Autifony is trying to do chemically what HIFU is trying to do surgically. Of course, Autifony will do more than just help with tinnitus - it will also prevent hearing loss and/or treat hearing loss. As far as I know...

Current Pipeline Overview

Audion/Eli Lilly & Co.
◾ Preclinical small molecules for hair cell regeneration

Auris Medical
◾ AM-101, an N-methyl-d-aspartate (NMDA) receptor antagonist in Phase III studies to treat tinnitus
◾ AM-111, a peptide that inhibits a stress kinase called JNK for the treatment of noise-induced hearing loss

Autifony Therapeutics
◾ AUT00063, a small-molecule modulator of the Kv3 voltage-gated potassium channel, expected to start Phase II studies to treat age-related hearing loss in second-half 2014

GenVec/Novartis
◾ CGF166, a gene therapy to restore hair cells; an Investigational New Drug Application (INDA) was filed in early 2014

Inception/Roche
◾ Preclinical small molecules to treat hearing loss (undisclosed target)

Oricula Pharmaceuticals
◾ Preclinical small molecules to prevent aminoglycoside-driven hearing loss

Otonomy
◾ OTO-201, a sustained-release antibiotic in Phase III studies for children receiving ear tubes; an NDA filing is expected in first-quarter 2015
◾ OTO-104, a sustained-release steroid in Phase IIb studies for treatment of Ménière’s disease
◾ OTO-311, a sustained-exposure formulation of an NMDA receptor antagonist; an INDA is expected in first-quarter 2015

Sound Pharmaceuticals
◾ SP-1005, an oral formulation of ebselen, a small-molecule mimic and inducer of the antioxidant enzyme glutathione peroxidase, approved to start Phase III studies to prevent noise-induced hearing loss
◾ SP-3005, an oral formulation of ebselen, slated to start Phase II studies to prevent noise- and chemotherapy-induced hearing loss

 

Source of this list can be found in this article: http://cen.acs.org/articles/92/i14/Sound-Science.html

 

Great reminder of this recap @attheedgeofscience, it gives a clear view of the actual pipeline.

 

@Littlebailey thanks for your interesting description.

Has anybody dabbled in potassium modulating chemicals, is there any data on them affecting tinnitus in any way?
I know autifony is different, cleaner targetting, but existing potassium drugs must have some effects you'd think.
Also, what other areas will potassium drugs affect, not that any of us care too much about side effects.

littlebailey, do you know anything about tcd (disrhythmia)....I thought that was the "source"
hence some surgical lesioning approaches. Since llinas identified type2 calcium channels
as the culprit, why has nobody reported anywhere about taking, say, type2 calcium channel blockers
like valproate,etc.


Here's the 2010 pdf that cites llinas (look at References for good links to llinas)
http://www.rsds.org/pdfsall/JonesEG_Pain_2010.pdf

For those who like to read, this imo is worth a read, it dovetails with autifony.

"By contrast, when TCRs drift towards hyperpolarization, be-
cause of a potassium leak current[10], a low threshold calcium
conductance dependent on T type (Cav 3.1) calcium channels,
which is inactivated at normal resting membrane potentials, is
activated (‘‘de-inactivated”). This results in a low threshold cal-
cium spike and a short, high-frequency burst of action potentials.
This burst is succeeded by a return to hyperpolarization and a rep-
etition of the burst. The TCR cell is then said to be in ‘‘burst mode

....application of drugs
that interfere with T type calcium channel function and prevent
low frequency bursting may provide a new strategy for reversing
TCD and alleviating not only CRPSI but also the numerous other
conditions that are coming to be recognized as having their basis
in TCD."


llinas is the guy to read. he links a whole range of conditions,
it's possible he nailed the "source" years ago.


this is probably worth a thread of its own but its so linked to autifony
insofar as its a potassium calcium relationship.

Just my few cents anyway.

 

@john2012

Currently the only potassium channel modulator on the market today is Retigabine marketed for epilepsy.
It is however a Kv7 modulator - it only prevented tinnitus from developing in clinical studies.

Type 2 Calcium channels are predominant in the thalamus which is the final stop before tinnitus reaches auditory cortex - not an ideal target pharmacologically speaking(?). Valporate has nasty side effects so I've heard.

 

attheedgeofscience said: ↑
It seems to me that Autifony is trying to do chemically what HIFU is trying to do surgically.

Great clear point. We're looking for a pharmacological alternative to HIFU.


And low voltage–activated (T-type) calcium channels CONTROL thalamocortical bursting behaviours.
They have a pacemaker gating function, which is why they are now drug targets for epilepsy and neuropathic pain.

from a Frontiers articlet:
"The fine-tuning of neuronal excitability relies on a tight control of Ca2+ homeostasis. The low voltage-activated (LVA) T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms) play a critical role in regulating these processes." But while there are drugs which non-selectively hit T-channels, there's a shortage of drugs targetting the sub-types eg 3.1,etc.

Dan said:
Type 2 Calcium channels are predominant in the thalamus which is the final stop before tinnitus reaches auditory cortex - not an ideal target pharmacologically speaking(?). Valporate has nasty side effects so I've heard.

Well said Dan. But there must be some anecdotal evidence somewhere on the net giving us a clue if this is the right direction. Tinnitus is so commonly triggered by so many drugs (presumably because of CNS Stress as a common denominator), there must be cross-references.

A number of epilepsy drugs block calcium channels. Like ethosuximide, valproic acid, etc.

Interestingly, ethosuximide was found (by Huguenard) to reduce low-threshold Ca currents in T-channels in freshly removed thalamic neurons but they were unable to replicate this success with valproic acid.

I was hoping that there'd be enough data on the net based on the zillions of prescriptions issued each year.


On a connected note,
does ANYBODY know of ANYBODY who has ever been to Zurich to be HIFU treated by Dr.Jeanmonod?
It actually works I believe for tremors, etc. but has wider scale application as you all already know.
He treats a LOT of people. Has anybody read ANY successful patient feedbacks?

 

This is just a thought that popped up in my head recently; Since phase 1 is done, that means that the pill itself exist. Do you guys think that the people on Autifony already have tried this on a person with T? If for instance someone on the research team have T, or maybe has a friend with T? But this is something they've done off the record so to speak.

 

If I was a scientist who had T I sure would try on myself although I would remember that I could only be considered as a case-study as one person doesn't show anything, also that phase 3 is the only phase that shows efficacy

 

Phase 2 also shows efficacy (?) Different dosages are tested on humans with tinnitus.