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

#632
john2012 said:
yeah, thanks Hudson

Hi Christian, lidocaine isnt an angel but illustrates something central worth targetting.

another thing, Too much lidocaine causes tinnitus. so will dosage be important to Autifony?

I really do hope we are close to a cure.
there's so many freakin sub-units i pray autifony can hit the right ones.
Dan assures me we can consider the rats chronic so take heart from that. thanks Dan.


sand and langguth's 2011 study adds weight to this area of research. a lot of it sounds klingon but you get the idea.
anyone who can translate gets a free latte. but don't sweat it, just curious.

"A complex interplay of multimeric potassium channel-forming proteins in auditory perception calls for follow-up examinations of interacting molecules that control the excitability of sensory neurons, including structures that are targeted by anti-tinnitus drugs. For lidocaine, these candidates comprise KCNA1 and KCNC1, plus KCNH2 [37,38], which has also been implicated in phenytoin effects [39]"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180252/
Click to expand...

This is just a much more elegant way to say what I wrote above, Lidocaine or Phenytoin are strongly linked to sodium / potassium channels. Lidocaine is a sodium blocker and Phenytoin reduces the amplitude of sodium-dependent action potentials through enhancing steady state inactivation of sodium channels.
In simple words they close the sodium valve in the brain, and here in our case in the auditory system. By doing so, sodium channels are at the level of the defective potassium channel common to chronic T. sufferers. (THis is why it turns off the T. for a moment, but it's not the good philophy, and it's not targeting the specific P channel).

In fact, as soon as the drug is gone sodium become dominant again and prevent the auditory system to go back in a resting state. (Turn on big speakers and turn the sound up without any music or noise, you will hear a continuous buzz in the speaker. THis is pretty much what happens for us).

The big difference with the AUT00063 is that it doesn't try to reduce sodium channels to a defective state, but it helps potassium channels to go back to a normal state of activity. Over the time it's going to train it again to work normally because the circuit itself is not damaged as demonstrated in this article:

http://informahealthcare.com/doi/abs/10.3109/14992027.2013.846482

It's like a manual car that stalled, it's nothing more than to protect the engine that it does so, it doesn't mean your car is broken, you just have to turn the key to start the engine again. It's pretty much what AUT00063 is trying to do.
 
#633
Whilst reading a previous press release from them, and further to the above explanation on how this compound is expected to work, i noticed the below sentance within their document ( this may have been discussed before, if so ignore me... )

"The Phase I trial also explored a variety of novel pharmacodynamic endpoints and interactions, which confirmed the engagement of the drug with the Kv3 ion channel target, and provided further supporting evidence for dose selection in the Phase II studies."

So, they must have been able to test that this compond got to act on the Kv3 target somehow. Any one know how this would have been tested ?

Given they are looking to modulate the Kv3 activity to normal state using this compound, does this not mean that some people, who did this phase one test, must have had overactive Ions and the tests showed that this slowed them down... otherwise if there were no overactive Ions on any of the phase one people then what test could they do to prove the connection ?

Maybe i am totally left of centre here, and there maybe a simple test done to prove this connection between this compound and Ion's, but anyone else have any idea how to explain the above sentance ?
 
#634
111 said:
Whilst reading a previous press release from them, and further to the above explanation on how this compound is expected to work, i noticed the below sentance within their document ( this may have been discussed before, if so ignore me... )

"The Phase I trial also explored a variety of novel pharmacodynamic endpoints and interactions, which confirmed the engagement of the drug with the Kv3 ion channel target, and provided further supporting evidence for dose selection in the Phase II studies."

So, they must have been able to test that this compond got to act on the Kv3 target somehow. Any one know how this would have been tested ?

Given they are looking to modulate the Kv3 activity to normal state using this compound, does this not mean that some people, who did this phase one test, must have had overactive Ions and the tests showed that this slowed them down... otherwise if there were no overactive Ions on any of the phase one people then what test could they do to prove the connection ?

Maybe i am totally left of centre here, and there maybe a simple test done to prove this connection between this compound and Ion's, but anyone else have any idea how to explain the above sentance ?
Click to expand...

They do extensive blood and urine testing. They look for the metabolites of the compound of action. They also look for molecules that would be released in the event of the mechanism of proposed action occurring. A lot of these tests are pretty high tech these days, I think they can test for single cell events even. That's just my guess though.
 
#637
Tom Soria said:
Is there date i can mark on my calender for when the next big update on autifony will be or when phase 2 trials start?
Click to expand...
I second that. Although, I think as soon as any news does come, they will be posted in this thread before you can say "potassium channel modulator".
 
#639
Here is some background on Autifony. I don't believe it appears anywhere in the thread. The excerpts are from a June, 2013, article on Pharmatching.com. Of particular interest is the amount of funding they've received and the parties sponsoring their research:

What do age-related hearing loss and schizophrenia have in common? Not much, on the face of it. However there is growing evidence that the two disorders may have a link through the dysfunction of certain ion channels in the central nervous system. Ion channels are membrane proteins that help convert chemical or mechanical messages into electrical signals in the cell.

Autifony Therapeutics Ltd, a spin-out of GlaxoSmithKline Plc, is actively exploiting this research space. Specifically, it is looking to develop new small molecule compounds that modulate the Kv3 potassium channel in the brain and thereby treat patients who either have an age-related hearing loss and tinnitus, or schizophrenia.

On 1 July, Autifony and researchers at the University of Manchester and Newcastle University received a £1.9 million grant from the UK Technology Strategy Board to develop a Kv3 potassium channel modulator for schizophrenia. The collaboration has total funding of £2.75 million. It will enable researches to select a compound from a group of potential candidates and take the molecule through preclinical development to a first clinical trial.

This comes just a month after Autifony started a Phase 1 study in healthy volunteers of another compound that targets the same ion channel – but for the age-related hearing loss and tinnitus indications.

...

Since its founding in 2011, Autifony has raised £15.75 million, which includes a £5 million investment from Pfizer Venture Investments, announced on 4 June at the time of the Phase 1 trial start. Initially, GSK took a minority stake in connection with the start-up. This stake has since been diluted and the company's three largest shareholders are now SV Life Sciences, Imperial Innovations Plc and Pfizer Venture Investments. [emphasis added]

UCL Business Plc also has a small stake in connection with Autifony's work with University College London's Ear Institute on the hearing disorder project.​

I wonder when they plan on going public? I'm presuming they will wait for positive results from their Phase IIa trial for tinnitus. Within the last two weeks, Auris Medical (EARS) and Otonomy (OTIC) announced their IPO filings. This is a great time for biotechnology IPOs, even for those with a small pipelines. See references below.

References:
 
#640
jazz said:
Here is some background on Autifony. I don't believe it appears anywhere in the thread. The excerpts are from a June, 2013, article on Pharmatching.com. Of particular interest is the amount of funding they've received and the parties sponsoring their research:

What do age-related hearing loss and schizophrenia have in common? Not much, on the face of it. However there is growing evidence that the two disorders may have a link through the dysfunction of certain ion channels in the central nervous system. Ion channels are membrane proteins that help convert chemical or mechanical messages into electrical signals in the cell.

Autifony Therapeutics Ltd, a spin-out of GlaxoSmithKline Plc, is actively exploiting this research space. Specifically, it is looking to develop new small molecule compounds that modulate the Kv3 potassium channel in the brain and thereby treat patients who either have an age-related hearing loss and tinnitus, or schizophrenia.

On 1 July, Autifony and researchers at the University of Manchester and Newcastle University received a £1.9 million grant from the UK Technology Strategy Board to develop a Kv3 potassium channel modulator for schizophrenia. The collaboration has total funding of £2.75 million. It will enable researches to select a compound from a group of potential candidates and take the molecule through preclinical development to a first clinical trial.

This comes just a month after Autifony started a Phase 1 study in healthy volunteers of another compound that targets the same ion channel – but for the age-related hearing loss and tinnitus indications.

...

Since its founding in 2011, Autifony has raised £15.75 million, which includes a £5 million investment from Pfizer Venture Investments, announced on 4 June at the time of the Phase 1 trial start. Initially, GSK took a minority stake in connection with the start-up. This stake has since been diluted and the company's three largest shareholders are now SV Life Sciences, Imperial Innovations Plc and Pfizer Venture Investments. [emphasis added]

UCL Business Plc also has a small stake in connection with Autifony's work with University College London's Ear Institute on the hearing disorder project.​

I wonder when they plan on going public? I'm presuming they will wait for positive results from their Phase IIa trial for tinnitus. Within the last two weeks, Auris Medical (EARS) and Otonomy (OTIC) announced their IPO filings. This is a great time for biotechnology IPOs, even for those with a small pipelines. See references below.

References:
Click to expand...

Super post, very informative and encouraging in a way $$$$ ! :D
 
#641
I know autifony is starting up with acute T in the UK, and hearing loss
For the united states.. But come phase 3 does anyone think that they will do chronic 1+ in the uk and possibly a tinnitus trial in the united states? I now understand why they need to start with accute.. To get better results.. And once that kicks ass then they hopefully will turn to the chronics and test it out.
 
#642
Grace said:
I know autifony is starting up with acute T in the UK, and hearing loss
For the united states.. But come phase 3 does anyone think that they will do chronic 1+ in the uk and possibly a tinnitus trial in the united states? I now understand why they need to start with accute.. To get better results.. And once that kicks ass then they hopefully will turn to the chronics and test it out.
Click to expand...

Grace, Autifony is for chronic T. A person who has had tinnitus for 11.999999 months, has chronic tinnitus.
 
#643
dan said:
Grace, Autifony is for chronic T. A person who has had tinnitus for 11.999999 months, has chronic tinnitus.
Click to expand...

Yes this is for chronic T. but @Grace is right and it is likely they start with recent chronic T. (<12 months) for the study for pracical & marketing reasons. Indeed it may help to have clearer as well as faster results that will lead in a more impressive proof of concepts.

But again, if this drug is working, it will work for LONG LONG chronic T., it will just take a bit more time to heal :)

(if you wonder why I explain dat earlier in the thread)
 
#645
This is why everyone on here should be watching what happens with our T sufferers trialing retigabine, basicly if retigabine works even if only while on the drug then I think we can be confident that Autifony (actually targeting T) will most likely be the cure that we all are looking for!

Very exciting times!

Rich
 
#646
RichL said:
This is why everyone on here should be watching what happens with our T sufferers trialing retigabine, basicly if retigabine works even if only while on the drug then I think we can be confident that Autifony (actually targeting T) will most likely be the cure that we all are looking for!

Very exciting times!

Rich
Click to expand...

I agree, we are marching toward a cure, but if retigabine doesn't work, it doesn't mean the AUT00063 won't work, there are a lot of kv7 potassium channel sub divisions, we know it's in the area, but finding the exact right one with the right dosage is key, and a lack of precision, unexpected interaction, or simply the wrong dosage could lead to a failure. Let's not forget we are talking about inner cell mechanisms and connectivity, the more acurate the more efficient.
 
#647
dan said:
@benryu , yeah i saw your wicked explanation :)

"recent chronic T" - interesting...
Click to expand...

According to Auris medical, the Tinnitus is accute under 3 months. Between 3 & 12 months it's referenced as a subacute Tinnitus, and it's chronic after 12 months.

The subacute is inclusive of both accute and chronic and can be then referenced either as an extented acute T. phase or a recent chronic T. phase.

:D
 
#648
Sorry people if I sound negative but:

1. Whay is everyone so excited when this hasn't even been tested on humans and
2. If any success when would this be available

I'm having my fingers crossed but at the same time I'm very scared it may not work
 
#649
Received:25 June 2013
Accepted:11 February 2014
Published:20 February 2014
© 2014 Wu et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

Abstract
Background
KCNQx genes encode slowly activating-inactivating K+ channels, are linked to physiological signal transduction pathways, and mutations in them underlie diseases such as long QT syndrome (KCNQ1), epilepsy in adults (KCNQ2/3), benign familial neonatal convulsions in children (KCNQ3), and hearing loss or tinnitus in humans (KCNQ4, but not KCNQ5). Identification of kcnqx potassium channel transcripts in zebrafish (Danio rerio) remains to be fully characterized although some genes have been mapped to the genome. Using zebrafish genome resources as the source of putative kcnq sequences, we investigated the expression of kcnq1-5 in heart, brain and ear tissues.

Results
Overall expression of the kcnqx channel transcripts is similar to that found in mammals. We found that kcnq1 expression was highest in the heart, and also present in the ear and brain. kcnq2 was lowest in the heart, while kcnq3 was highly expressed in the brain, heart and ear. kcnq5 expression was highest in the ear. We analyzed zebrafish genomic clones containing putative kcnq4 sequences to identify transcripts and protein for this highly conserved member of the Kcnq channel family. The zebrafish appears to have two kcnq4 genes that produce distinct mRNA species in brain, ear, and heart tissues.

Conclusions
We conclude that the zebrafish is an attractive model for the study of the KCNQ (Kv7) superfamily of genes, and are important to processes involved in neuronal excitability, cardiac anomalies, epileptic seizures, and hearing loss or tinnitus.

Keywords:
Zebrafish (Danio rerio); kcnq1-5; RNA transcripts; Kcnq protein; Zebrafish genome; qRTPCR; Tinnitus

Full Text:
http://www.biomedcentral.com/1472-6793/14/1
 
#650
1472-6793-14-1-2.jpg
 
#653
dan said:
6-7 years? way earlier than that, if it works.
Click to expand...

how would it be earlier? if it takes around 1 year for a test phase + some time to prepare for the next one would it really be earlier? I think AM101 started in around 2009 with the trials and they will finish in 2015. Im spseaking about the average person, not someone who has connections.
 
#654
Ok, so from 2009 to 2015 is 6 years total. Autifony started 2011 I believe, so in 3 years they will be done.
Also if phase 2 studies are a big hit, they will fast track it like a mother @#$%er.
 
#655
dan said:
Ok, so from 2009 to 2015 is 6 years total. Autifony started 2011 I believe, so in 3 years they will be done.
Also if phase 2 studies are a big hit, they will fast track it like a mother @#$%er.
Click to expand...

well if they will just start with phase 2a followed by phase 2b + phase 3 and 4 according to my calculations it will take 1,5,+1,5+2= 5 + time to get on the market. But I could be wrong.. I do not see AM101 speeding up though so I dont see why Autifony should.
 
#658
Stina said:
well if they will just start with phase 2a followed by phase 2b + phase 3 and 4 according to my calculations it will take 1,5,+1,5+2= 5 + time to get on the market. But I could be wrong.. I do not see AM101 speeding up though so I dont see why Autifony should.
Click to expand...

What you're describing is the worse case scenario.
It's likely that the drug gets an expanded access, that could let the more lucky of us get it in the next 1,5 years, and most of us in the next 3 years.

I was told by my audiologist that the AM101 had an expanded access in certain regions, including Montreal, I have the business card ot the person in charge of giving access and I am gonna call her soon to discuss.

Drug_Evaluation_Process.jpg
 
#659
benryu said:
What you're describing is the worse case scenario.
It's likely that the drug gets an expanded access, that could let the more lucky of us get it in the next 1,5 years, and most of us in the next 3 years.

I was told by my audiologist that the AM101 had an expanded access in certain regions, including Montreal, I have the business card ot the person in charge of giving access and I am gonna call her soon to discuss.

View attachment 2362
Click to expand...

yes but AM101 is not availale for a person like me (living in Estonia). I was not speaking about people who have connections or live in the countries where the trials are being held but about the average person. So obviously for people like me there will be the worst case scenario for Autifony and for people who come from countries with more advanced medical care and/or connections it will be 1,5-3 years.
 
#660
The second that we hear the results and efficiancy of the drug ( for the chronics) and accute.. And if it turns out to be a winnnerr then i feel this will blow up and you would think theyd like to get it out asap to make some mulaaaa$$$$$$!!! Ofcorse what do i know but i feel it would go pretty easy breezy if it turns out to be amazing results!
 

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