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

Bumping this thread because there is a new paper on PubMed about KV3 and tinnitus (Charles Large is again one of the authors). The generation of tinnitus in the brain is once again linked to the fusiform cells of the DCN (Dorsal Cochlear Nucleus). This is also the underlying theory in the treatment that is in trail @ The University of Michigan (the brain zapping method known as Signal Timing .

The chemical that tames the 'screaming' cells is AUT1. The paper can be found here:

https://www.ncbi.nlm.nih.gov/pubmed/29421326

In line with the research above, Autifony (the one that failed us with Aut63) also seems in the game for development of a treatment (although describing the development very subtle with 'Hearing disorders'). The moment the new experimental compound (target: Kv3.1) gets a name it will be time to make a new thread...

 

This is very interesting. Thanks for posting.

 

So they are updating some old medicines or coming out with a new medicine(s)?

 

From what I have read in that paper abstract it is for noise induced tinnitus only?

 

Yes, that's exactly what they have written.... and it is a fine example of scope narrowing due to risk avoidance. Modern research is influenced by profit driven stakeholders who don't care about progress but are purely intrested in money. Because of this researchers tend to narrow their expectations towards the most probable outcomes (with other words: a fix of noise-induced T brings more money).

But (as a person who has acquired T from inflammation) I think this paper is positive for all types of T. In the abstract they clearly stated that they have tested the effects of AUT1 for noise induced but also for the chemically induced T by the chemical TEA. The latter is probably a simulation of toxicity by drugs or inflamations that cause T.

And... for both causes of T induction (noise induced and TEA) the effect of AUT1 was the same.... so no worries for now...

 

So from what i read, this is a new medicine that they are developing? Also, is this only for acute tinnitus or also for chronic tinnitus?

 

Nobody knows besides Autifony. Time will learn us.

 

Quite vague that for people who care about money they need to narrow down the research goals. Tinnitus is a potential big money machine itself. Either noise induces, infection, sudden deafness or else.

 

Let's make that specific then. Where does funding for tinnitus research come from?

The department of defence...national health services?? The first funds research because the payout for debiliated soldiers with noise-induced T costs on the long term much more money then finding a cure (they are not funding research because they want to help humanity). The second funds research because the toll of tinnitus on the workforce and the loss of money on wellfare payouts. Especially targeting young people getting T because of the popularity of 100 dB earbud listening.

So we could conclude that a solution for noise-induced T equalls big money. Other causes like infection or drug induced ototoxicity are nothing more then niche 'markets'.

 

Actually, I'm quite surprised that the DoD isn't doing more to combat tinnitus as it is the #1 complaint of returning veterans. There might be a study here and there but if congress cares about veterans as much as they say that they do, there would be pouring development funding in like crazy.

Considering all the billions of dollars that go towards top secret black budget projects, they can't allocate something like 1 billion dollars towards the treatment and prevention of hearing loss/tinnitus?! A soldier is expected to be around gunfire, explosions and loud noises but it's only been an afterthought at this point.

 

The US Government could care less and views soldiers like disposable pawns.

TRT competes with actual research that aims to cure hearing loss and T&H

 

If there was large enough movements and publicity the government wouldn’t have any other choice than to help veterans since it’s #1 problem they come back with. But as I see it there’s not really any process of that happening currently

 

There are two trials going on for hair cell regeneration
GenVec and Frequency therapeutics

Affichem, Decibel and Otonomy are interested in nerve fiber repair which may alleviate tinnitus and hyperacusis

 

You forget Audion, they are also in HC regeneration trial

 

I think he was more talking about the Government's involvement. They need to be more involved.

 

Well... this is confusing. Apparently in treating T Aut63 turns out to be a very effective drug at lowering the symptoms as much as 60%... for hamsters...:

https://www.ncbi.nlm.nih.gov/pubmed/29453003

If they only could make this work for humans I could finally stop wasting my time on PubMed in my conquest for finding new treatment insights

 

Well.. that's interesting. I really believe it's a brain thing simply because the ears can't generate noise. Did they Only fail due to the way of taking the drugs? Did they inject the mice directly in the brain?

 

The hamsters had intraperitoneal administration of AUT00063.
https://en.wikipedia.org/wiki/Intraperitoneal_injection

 

Since it is some +3 years ago I created this thread in the slipstream of the Summer of 2014 after I had had multiple dialogues with Autifony Therapeutics as well as some of the personnel at the study centres, I wanted to briefly return for a "comment or two".

From my perspective, it is not clear what Autifony Therapeutics has in store with the overhaul their pipeline has received in relation to hearing disorders. At this point, just the target (Kv3.1 channels) is mentioned, not the compound they intend to use. This is relevant because in the latest paper (paywalled), AUT00063 was the compound of interest and the earlier failed clinical trial (QUIET-1) which employed AUT00063 was specifically referred to in the conclusion – which is not included in detail in the abstract (but the excerpt can be seen below for those without access):

"The suppressive effects of AUT00063 on spontaneous activity are important from a clinical standpoint because increases in spontaneous activity have long been known to be a neural correlate of tinnitus. The observed suppression of hyperactivity in the present study, therefore, suggests that AUT00063 may have a suppressive effect on the tinnitus percept in humans. A double-blind, placebo-controlled trial of the efficacy of AUT00063 in patients with subjective tinnitus, sponsored by Autifony, was recently completed in the U.K. (NCT02315508, ClinicalTrials.gov). Unfortunately, the trial did not meet its primary endpoint, which was a reduction in tinnitus score measured using the Tinnitus Functional Index (TFI). Plasma levels of AUT00063 in subjects were similar to those achieved in rodents following a 30 mg/kg i.p. dose. The apparent absence of effect of AUT00063 in this trial likely reflects the heterogeneity of the tinnitus population studied and the possible insensitivity of subjective rating scales such as the TFI to changes in tinnitus percept. In addition, whereas the present preclinical study examined activity immediately following drug administration, the clinical trial outcomes measures were obtained 28 days following treatment. It will therefore be important to assess the persistence of the effect of AUT00063 in the rodent model with chronic dosing. More direct measures of auditory brainstem neural activity in patients would also be useful to allow a better translation of rodent study results in humans."

So, what the above means is that:

• Autifony Therapeutics could be revisiting AUT00063 once more (due to the observations mentioned above re: clinical trial design in relation to the 28-day observation timepoint).
• Autifony Therapeutics could be moving forward with AUT1 or AUT2 (which were already described in a comparison publication in 2016. I recall finding it odd at the time, that new publications were surfacing and decided not to do much with the information (in part because "tinnitus" was not mentioned even once in the entire paper – if I recall correctly).

Of course, a possibility is also that tinnitus is not "on the menu" at all, but instead problems related to hearing clearly with background noise present, or... something else altogether.

 

As a molecular biologist, do you believe in the progenitor cell activation? What are your thoughts on that?

 

Thanks to @Luman for linking The Summer 2018 issue of Tinnitus Today:
http://www.ata.org/sites/default/files/TinnitusToday-Summer2018-08-web.pdf

The Steps Involved in Taking a Pharmaceutical Concept from Research, to Preclinical Trials, to Advanced Trials, to Market
JO: What do clinical findings tell us about the future course of AUT00063 research?
Dr. Nadia Pilati (NP): We strongly believe in the Kv3 mechanisms and think these channels are heavily involved in hearing disorders, where their activation is crucial. We’ve conducted two clinical trials of AUT00063 in age-related hearing loss and tinnitus. Although AUT00063 was safe and well tolerated by subjects during the trial, the results did not show a beneficial effect of the compound. While this was disappointing, it was also a source of learning, because we were able to understand more about the compound’s mode of action. We now have evidence that suggests that a more potent compound could succeed where AUT00063 failed. Though we consider these clinical trials groundbreaking, we are now more aware of the importance of different tests selected in trials and think that the right hearing test could also have an impact on the course of a study.

JO: Should those suffering from tinnitus, hyperacusis, or hearing loss be optimistic about pharmaceuticals being available in their lifetimes to treat their respective conditions?
NP: Definitely. Every day we learn more, even from failures. We learned a tremendous amount from our previous clinical and preclinical studies and hope to be able to run another clinical trial with a more potent compound that could revolutionize the treatment of tinnitus and hearing loss.

 

Nothing really new, but a full article released today about the clinical trial. See link above or attached file:
https://www.sciencedirect.com/science/article/pii/S0378595518302909

 

Thanks

The duration of tinnitus symptoms required for inclusion in the QUIET-1 study was set to >6 months and <18 months. Although somewhat arbitrary, these durations were chosen to exclude participants with relatively acute tinnitus that might spontaneously remit, and those with a long-standing tinnitus that may involve different mechanisms to those responsible for the generation of tinnitus and may be more resistant to change (Landgrebe et al., 2012).

Treatment-related change in the global TFI score showed no statistically significant difference between AUT00063 800 mg once-daily and placebo groups in the Full Analysis Set (Table 4).

Sad news