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

[inadmin]

Was the sample size (58) ever published?

 

[Mark662]

Was the sample size (58) ever published?

It's all here in its depressing detail

http://www.autifonytherapeutics.com/autifony-news.asp

This is everything we know

 

[RaZaH]

Its an ongoing process, data is gathered , experience gained ..rinse repeat until there are concrete results.
There never was a reason to expect this to be some kind of cure , I agree with ATEOS in that we need to start being more factual about things. False hope is one of the sideeffects of T , lets not perpetuate that .

 

[Drecul]

It's all here in its depressing detail

http://www.autifonytherapeutics.com/autifony-news.asp

This is everything we know

So from the 29 people that received the medicine only 2 people had a positive effect? Did I read that correctly in another thread?
Where are the other 27 are they here on TT?

 

[inadmin]

It's all here in its depressing detail

http://www.autifonytherapeutics.com/autifony-news.asp

This is everything we know

I'm sure those people know a lot more than all of us together, but a sample size of 58 does look ridiculous in my very humble opinion.

 

[inadmin]

So from the 29 people that received the medicine only 2 people had a positive effect? Did I read that correctly in another thread?
Where are the other 27 are they here on TT?

No those are the two people that WE know about.

 

[linearb]

You're right, cars and planes have evolved greatly over the years, but they still roll on wheels and use wings to fly. Autifony's failure to deliver the goods, in my opinion, sets us back, to those days of dangerous vehicles and questionable air travel.

I get where you're coming from but disagree with your conclusion; I think that having a drug get canned pre-market with "whoops, we were wrong about the safety/efficiency ratio here, we'll get back to you" shows that the process is working, at least at a very basic level. No one is suggesting that Kv channels aren't useful targets, and it's even possible that AUT00063 itself will subsequently be determined to be useful in a different dose/protocol/etc.

 

[Silvio Sabo]

The attachment file discusses the limitations of the GAP detection tests for screening of tinnitus in animal models. It is these foundations that may lead to the wrong conclusions in the pre-clinical studies (of tinnitus), and, which may explain why a phase-II efficacy trial fails.

Just as I stated in an earlier post. We have to take a step back. Before we start conducting trials for new drugs we need to design a solid model for screening. Also because tinnitus is such an subjective experience and the annoyance it causes can vary greatly depending on the patients mental state and/or mood, it would also be a good idea to develop a method of diagnosing tinnitus objectively.

 

[Nucleo]

I get where you're coming from but disagree with your conclusion; I think that having a drug get canned pre-market with "whoops, we were wrong about the safety/efficiency ratio here, we'll get back to you" shows that the process is working, at least at a very basic level. No one is suggesting that Kv channels aren't useful targets, and it's even possible that AUT00063 itself will subsequently be determined to be useful in a different dose/protocol/etc.

I don't know how often failed drugs get a second chance.

 

[RaZaH]

Probably all the time,,,back to the lab , tweak the formula.

 

[linearb]

I don't know how often failed drugs get a second chance.

a given phase II/III trial can only assess on particular dosing regimen; AFAIK it's not especially uncommon to go through a few protocols before finding one that clicks. And, drugs which fail trials for whatever condition they were designed to treat, often pop up later on as candidates for treating some other tangentially related condition.

edit: it's also worth noting that the planned US trial of AUT00063 for age-related hearing loss, is proceeding as planned. If that ends up ending differently, then the drug will end up on the market, and being able to try it for tinnitus will just be a matter of finding a doctor willing to write a script for an off-label use of a brand new drug -- which in my experience is depressingly easy.

 

[Sailboardman]

Yeah but before we could build the first airplane we tested a lot of things, including putting wings on people. That didn't work out so well for the guy that jumped off a cliff and try to flap like a bird.

Then the Wright brothers managed to fly for about 100 yards using a glider.

Then we put a propeller on a glider and managed to fly a lot longer than 100 yards.

After that we had a sort of a side track trying balloons and airships. Airships are a story all by them selves by the way. At first we used hydrogen to fill them up. Then a bunch of people (about 100) burned to death in the Hindenburg disaster before we realized that was a bad idea.

Then we refined the propeller engines and airplane design to the extent that we could fly across the Atlantic.

Before I go any further into the history of flight I think you get the picture.

We didn't go from nothing to supersonic jets. It took a lot of failures and deaths of pioneers before we managed to build a jet plane. Autifony is a failure bringing us one step closer to success. That's all.

Silvio,

I guess you missed my point? I agree, fantastic things will occur, many hundreds and thousands of years in the future. Unless you have found a fountain of youth somewhere, or plan on living a couple hundred years, you're still stuck here today, with no cure or treatment available.

 

[dan]

then the drug will end up on the market, and being able to try it for tinnitus will just be a matter of finding a doctor willing to write a script for an off-label use of a brand new drug -- which in my experience is depressingly easy.

Depressingly??? Speak for yourself, I think ur the only one's going to be depressed....

 

[amandine]

it's also worth noting that the planned US trial of AUT00063 for age-related hearing loss, is proceeding as planned. If that ends up ending differently, then the drug will end up on the market, and being able to try it for tinnitus will just be a matter of finding a doctor willing to write a script for an off-label use of a brand new drug -- which in my experience is depressingly easy.

Why would you want to take this for T? It does not work! If it did then the trial in UK would still be going on. Why do you think it was stopped? It did not work efficiently and yet you are still hopeful to take it for T? Why?

 

[Silvio Sabo]

Silvio,

I guess you missed my point? I agree, fantastic things will occur, many hundreds and thousands of years in the future. Unless you have found a fountain of youth somewhere, or plan on living a couple hundred years, you're still stuck here today, with no cure or treatment available.

The thing is. It doesn't have to be hundreds of years into the future. Have you ever heard of Moore's law? It's based on the observation that the advancement in the number of transistors in a dense integrated circuit doubles every two years. It has been this way since the 1960's. This is what makes computers more and more powerful. Although it has slowed down somewhat in the last couple of years the doubling in computing power is still shorter than 2,5 years in the present time.

What do I want to say with this? Technology in all fields advances rather rapidly and the more we know and the more advanced technology we have the easier it is to take the next step. Just look at the advancement in history. It took us about 200 000 years (the amount of time that the modern human race has populated the Earth) to build the first engine. And then in the following 150 years we built a space ship and went to outer space!

I believe that nanotechnology is going to revolutionize the medical field. Have a look here:
http://www.makeuseof.com/tag/nanotechnology-changing-future-medicine/

Here is a nice quote from the article linked above:

"Alternately, it's possible to use the same techniques used for nano-delivering chemotherapy to deliver other chemicals, like neurotransmitters and psychiatric drugs to specific brain regions with much more precision (including delivering drugs inside individual cells). Along with better neural pacemakers, this could also extend to a much broader range of therapies, including treatment for depression, anxiety, and even personality disorders."

What slows the medical field down are restrictions due to political and religious reasons. F.i. stem cell research has been held back at least 10 years because the president of the US thinks it's immoral to "play God". However those restrictions can't be there forever. At some point in the near future it will be set free and then I believe we are going to see things happen really quickly.

Why would you want to take this for T? It does not work! If it did then the trial in UK would still be going on. Why do you think it was stopped? It did not work efficiently and yet you are still hopeful to take it for T? Why?

I believe that most of us are thinking that Autifony messed up the trial by for one having too few people in the trial and believe that Autifony might have missed any potential subgroups that would benefit from the drug by not testing the drug on large enough amount of people.

Simply put: people are hoping they will be the lucky ones that the drug might work on much like Trobalt only worked for some and not for others. AUT0063 is by some still believed to be Trobalt 2.0.

 

[jeff W]

If anything I think the Autifony story shows the difficulties of drug development, but also points towards a bright future for pharmaceuticals. Being able to make and test molecular target drugs based on 3d computer models of ligands is very new. Being wrong about a specific Kv subchannel is no problem; other subchannels can be targeted through the same means.

Against what cost? The money poured into pharma trials is not sustainable. We all end up paying for the failure through other drugs that prove more effective. Cellular repair needs something much more advanced, the tech is there but the capitalist model doesnt see a viable profit avenue. "difficulties of drug development" thats humorously ambiguous, I will be more specific: pharma is the past, cellular repair is the future.

 

[linearb]

Against what cost? The money poured into pharma trials is not sustainable. We all end up paying for the failure through other drugs that prove more effective.

Er, this is a pretty bold and controversial statement; do you have some evidence/research/whatever to back it up? Pharma profits are at an all time high, and it's pretty easy to come up with a list of 10 drugs from the last 10 years that have been wildly profitable. Safety and efficiency is a different story, and there are perils here, but the idea that the pharma model is failing because of an inability to profit seems... dubious.

Cellular repair needs something much more advanced, the tech is there but the capitalist model doesnt see a viable profit avenue.

Again, this is a sweeping and pretty controversial statement; why do you feel this way? Any treatment that is
* patentable
* effective
* somewhat safe

is going to thrive in the current model.

"difficulties of drug development" thats humorously ambiguous, I will be more specific: pharma is the past, cellular repair is the future.

There are lots of things in the future that might make existing technologies obsolete; however, as I have said repeatadly, drug development is really in its infancy, it's only been within the past few decades that we have understood to some extent how transmitter and transporter systems work, and had the ability to start to design novel agents that target specific physical structures. So, I think saying that the party is already over, would have been like calling the automotive industry a failure right as the Ford Model T was approaching scale production...

View attachment 8138

Yes, I am well aware of the tinfoil-hat paranoia around the hearing aid industry (whose total profits are less than the largest single drug companies). Why is this relevant here? Do you have some brand new evidence that there's a vast cabal of shadowy hearing aid salesmen who are working in collusion with Autifony to suppress their results?

Lol.

 

[linearb]

I believe that most of us are thinking that Autifony messed up the trial by for one having too few people in the trial and believe that Autifony might have missed any potential subgroups that would benefit from the drug by not testing the drug on large enough amount of people.

I think laymen acting like they understand clinical trials and drug potential better than trained professionals who stand to directly profit or lose money from a failed drug is a little bizarre.

Simply put: people are hoping they will be the lucky ones that the drug might work on much like Trobalt only worked for some and not for others. AUT0063 is by some still believed to be Trobalt 2.0.

Believing things without any factual reason isn't a sign of being a maverick, it's a sign of being unrealistic (or being a religious zealot).

 

[RaZaH]

Progress is not linear.

 

[erik]

Why Too Many Clinical Trials Fail -- And A Simple Solution That Could Increase Returns On Pharma R&D

http://www.forbes.com/sites/davidgr...ion-that-could-increase-returns-on-pharma-rd/

 

[Aaron123]

from
John Arrowsmith & Philip Miller, "Trial Watch: Phase II and Phase III attrition rates 2011–2012"
Nature Reviews Drug Discovery, 12, pg 569 (2013) doi:10.1038/nrd4090

emphasis added with the assumption that we can think of AUT00063 as a CNS drug. Interesting that the reason for failure was not disclosed for 13 out of 29 CNS drugs so there is significant uncertainty about the true failure rate by category.

.....

During this period [2011-2012], there were a total of 148 failures between Phase II and submission (also including Phase I/II studies in patients and major new indications of already marketed drugs). Of these, 105 had reported reasons for failure. The majority were due to a lack of efficacy (56%) or to safety issues (28%); here, safety includes those failures that were due to an insufficient therapeutic index.

When looked at by phase, for the most recent year range, the proportion of failures due to lack of efficacy was higher in Phase II (59%), but still disturbingly high in Phase III and beyond (52%). The proportion of failures due to safety issues is higher in Phase III and beyond compared with Phase II — at 35% and 22%, respectively — which may be due to safety issues that only become apparent in larger numbers of patients and/or longer trials.

......

When the failure rates are broken down by therapeutic area, oncology and central nervous system (CNS) disorders account for 44% (30% and 14%, respectively) of all the 105 failures between Phase II and submission for which reasons have been reported. However, almost 50% of CNS and endocrinology (diabetes) failures (13 out of 29, and 4 out of 8, respectively) are excluded from these numbers because the reason for the failure has not been disclosed. Oncology and CNS are areas in which it can be difficult to establish clear efficacy signals in small or short-duration Phase II trials, which reinforces the need to design trials that can deliver data that are sufficient to support good decision-making, and to have suitably discriminatory proof-of-concept criteria agreed prospectively.

......

 

[Aaron123]

Why Too Many Clinical Trials Fail -- And A Simple Solution That Could Increase Returns On Pharma R&D

http://www.forbes.com/sites/davidgr...ion-that-could-increase-returns-on-pharma-rd/

Just a quick comment for anyone who reads this article and wonders about the the term "underpowered" that shows up several times.

Statistical power is the a probability that a test will reject the null hypothesis (usually no effect) in favor of the alternative when in fact the alternative is true.

What is relevant for the article and for the discussions about AUT00063 is the sample size and how that relates to power - and being "underpowered". A "power analysis" can be done to determine the sample size that is necessary to detect an effect of a particular size with a given level of confidence. As an example, if you wanted to be 99.99% certain to detect a tiny effect of a drug on some outcome - when there is an effect, you would need a huge sample. If you can tolerate being less certain (the article talks about 80 or 90 percent) of finding a larger effect, then the sample can be smaller.

What we know in the present case is that the intended sample was 150. We know the primary outcome was the change in the tinnitus function index (TFI). The TFI ranges from 0 to 100 with larger numbers indicating more severe problems. So the null hypothesis is that there is no effect (i.e., the true change in TFI is the same for treatments and controls), and the alternative is that there is a larger reduction in TFI for treatments than controls. The power of the test is the probability that we find that the reduction in TFI is larger for the treatments than controls when it truly is.

Presumably, the 150 came from a power analysis where they decided that they wanted to be able to detect a difference of say 5 points in the reductions in TFI 90% of the time if in fact there is an effect. We of course don't know what the true values are where I have said "5" and "90%". A concern, based on the article, is that the test might have been underpowered. It was probably underpowered compared to what we would have liked, but sample size costs money...

 

[Mark662]

Just a quick comment for anyone who reads this article and wonders about the the term "underpowered" that shows up several times.

Statistical power is the a probability that a test will reject the null hypothesis (usually no effect) in favor of the alternative when in fact the alternative is true.

What is relevant for the article and for the discussions about AUT00063 is the sample size and how that relates to power - and being "underpowered". A "power analysis" can be done to determine the sample size that is necessary to detect an effect of a particular size with a given level of confidence. As an example, if you wanted to be 99.99% certain to detect a tiny effect of a drug on some outcome - when there is an effect, you would need a huge sample. If you can tolerate being less certain (the article talks about 80 or 90 percent) of finding a larger effect, then the sample can be smaller.

What we know in the present case is that the intended sample was 150. We know the primary outcome was the change in the tinnitus function index (TFI). The TFI ranges from 0 to 100 with larger numbers indicating more severe problems. So the null hypothesis is that there is no effect (i.e., the true change in TFI is the same for treatments and controls), and the alternative is that there is a larger reduction in TFI for treatments than controls. The power of the test is the probability that we find that the reduction in TFI is larger for the treatments than controls when it truly is.

Presumably, the 150 came from a power analysis where they decided that they wanted to be able to detect a difference of say 5 points in the reductions in TFI 90% of the time if in fact there is an effect. We of course don't know what the true values are where I have said "5" and "90%". A concern, based on the article, is that the test might have been underpowered. It was probably underpowered compared to what we would have liked, but sample size costs money...

Sample size does cost money, but they did have £2.2M to play around with

 

[Aaron123]

One final thing to follow up on power, sample size, and the decision to stop the trial. If the sample was supposed to be 150 and it might have been underpowered, how can they possibly stop at 58?

With preliminary data, they can again calculate the probability that they will find a positive effect of AUT00063, and they ultimately decided that that probability was too low to continue.

I think there is an analogy that we can all relate to that might make this clear if it isn't: Suppose a student who has a 50% in a course going into the final exam wants to know if they can get an A in a course which requires a 90% overall grade. If the final exam only counts a little, it is probably mathematically impossible to get from a 50% to a 90%. However, if the final exam counts a lot, it may be mathematically possible to get a 90%, but it is very unlikely based on the performance up to that point. If we take the extreme case where it would require a 100% on the final to get to 90% for the course, we can see that, given that the student only has a 50%, that is very, very unlikely.

With data on 58 people, probability of "getting an A" must be so low that they elected to stop the study and save some money and time. What is a bit interesting is that, in the analogy, the "final exam" counted for quite a bit since they still had 92 people to go assuming they got to 150 subjects. Thus, the performance on the 58 must have been pretty bad.

 

[Silvio Sabo]

Sample size does cost money, but they did have £2.2M to play around with

They had more than that. That was just what they got from the UK. However if the drug indeed isn't working then it's better to spend it on something else. I'm sure AUT0063 isn't the only compound in their portfolio.

 

[Mark662]

They had more than that. That was just what they got from the UK. However if the drug indeed isn't working then it's better to spend it on something else. I'm sure AUT0063 isn't the only compound in their portfolio.

Without knowing all the facts, and with what we know at present about this failed trial, they may find it extremely difficult in the future to gain funding or investment into similar compound studies.

 

[attheedgeofscience]

Thus, the performance on the 58 must have been pretty bad.

...Agreed, and which is what I wrote a couple of days ago:

The consensus seems to be that for the QUIET-1 trial to have been terminated based on interim data, it must mean that there has been very little efficacy shown.

Listen... the results were poor, and, furthermore the science from the pre-clinical studies was perhaps based on flawed assumptions:

• Wrongly simulated tinnitus in the animal models (i.e. method of induction of tinnitus is important)
• Startle reflex GAP detection model for screening of tinnitus
• Chronicity

I don't have insights of the trial itself, and so, the above is just speculation on my part, but I have been corresponding with background sources in the past 4 to 5 days...

In addition, the following journal (see attachment) states that (see underlined sections):

1.2 Animal models of tinnitus

Several tinnitus animal models have been established. In most animal models, salicylate and noise trauma are used for tinnitus induction. Conditioned response methods and gapstartle reflex methods are used to assess behavioral correlates of tinnitus. Even if the development of animal models has already provided important insight into the neuronal mechanisms involved in the pathophysiology of tinnitus [9], their validity for the different aspects of tinnitus is still a matter of debate [26].

Since the behavioral validation is currently still restricted to the perceptual aspects of acute tinnitus, the available models probably reflect tinnitus-related alterations in central auditory pathways leading to the phantom percept. It remains to be determined whether the transition from acute into chronic tinnitus and its emotional and cognitive aspects are also reflected.

attheedgeofscience
15/OCT/2015.

 

[Zimichael]

This is what I can say. Perhaps additional findings will materialize from the CLARITY-1 trial, where participants - besides age related non-cochlear hearing loss - may also see an improvement in their tinnitus (as a bi-product of the trial). I am not sure about the inclusion criteria, and so, it could be that patients with tinnitus are excluded (in which case the argument doesn't hold)

Patients with tinnitus are not excluded. However, you do have to take the TFI (Tinnitus Functional Index - do a search it is on TT) questionnaire, and I was blown out of the window just on the few "quality of life" questions, let alone the rest. Their threshold level on the TFI was 24. Above that you got the boot.
*[See this if you want more details - read down to it: https://www.tinnitustalk.com/thread...ng-loss-and-tinnitus.6516/page-65#post-122808 ]
And oh...this was c/o the Sacramento CA folks doing the trial, and as we know from the UK zoo with AUT00063, it may be that different places bend the rules, or don't follow the rules, or misinterpret the rules, or whatever-the-hell with the rules for entry criteria].

Zimichael

 

[Mark662]

They had more than that. That was just what they got from the UK. However if the drug indeed isn't working then it's better to spend it on something else. I'm sure AUT0063 isn't the only compound in their portfolio.

Unfortunately, the UK money was specifically for a clinical trial of AUT00063

 

[ruben ruiz]

What dos the hearing aid industry have to do with securing a possible cure or relief of Tinnitus?
Hearing aids and their effect for tinnitus are rare. A huge percentage of those struck with T have hearing that is acceptable and or fine. I have a small dip at 8,000. If the Hearing aid industry is that ruthless may those who run the industry rot in hell. I firmly believe that there is greed involved regarding politics and industry.