AM-101

This is quite positive, thanks Markku for passing the message

 

Earlier in this thread was a discussion on how Xanax withdrawal could induce an imbalance between GABA and glutamate which could lead to excitotoxicity. Here's something from Wikipedia about withdrawal from benzos causing excitotoxicity. Seems to support the theory that Xanax can cause tinnitus since withdrawal from it can cause excitotoxicity which can cause tinnitus.

Excitotoxicity may be involved in spinal cord injury, stroke, traumatic brain injury, hearing loss (through noise overexposure or ototoxicity) and in neurodegenerative diseases of the central nervous system (CNS) such as multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, alcoholism or alcohol withdrawal and especially benzodiazepine withdrawal, and also Huntington's disease.[3][4] Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia[5] and status epilepticus.[6]

 

Thanks Mick. This underlines my theory if benzo withdrawal worsened my own T. Noise exposure probably damaged nerve cells and Xanax withdrawal damaged them more and worsened my T . Really horrible

 

Safety Results From Auris Medical AG's Clinical Development of AM-101 Presented at International Conference

May 17, 2013 –
Safety results from Auris Medical’s clinical development of AM-101 presented at international conference Key safety outcomes from Auris Medical’s clinical development of AM-101, a novel intratympanic (i.t.) treatment for acute inner ear tinnitus, were presented at the 7th International TRI Tinnitus Conference in Valencia, Spain. The accumulated data demonstrate that the treatment and the administration procedure are well tolerated and safe even when repeated several times. The outcomes were presented by Guido Muehlmeier, MD, Head of ENT Diagnostics at the Clinic and Policlinic for Otorhinolaryngology, Head and Neck Surgery of the Federal Armed Hospital of Ulm, Germany.

The clinical development programme with AM-101 so far comprises a total of three double-blind, randomized, placebo-controlled, clinical trials, of which two have been completed, and one is approaching completion. In the first of the three trials, a Phase I/II study involving 24 patients, the safety of a single dose administration of AM-101 was demonstrated in a dose escalation up to 0.81 mg/mL. It also revealed minimal systemic exposure from the treatment. These results have been published previously.

At the TRI Tinnitus Conference, key safety outcomes from the second study, a Phase IIb clinical trial, were presented for the first time. The study enrolled a total of 248 patients who were treated 3 times over 3 consecutive days either with AM-101 at 0.27 or 0.81 mg/mL or placebo. Study participants were monitored over 90 days. The primary safety endpoint was the occurrence of clinically relevant hearing deterioration from baseline to Day 30, defined as increase in the pure tone hearing threshold =15 dB in any two contiguous test frequencies.
The Phase IIb study confirmed the previous results from the Phase I/II trial and provided a wealth of additional safety and local tolerance data. As expected, the occurrence of clinically significant hearing loss was low, and there were no statistically significant differences between treatment groups, neither for the primary endpoint at D30, nor at any of the other study visits or overall. On average, hearing thresholds improved slightly over the 90 day observation period. There were no statistically significant and/or clinically significant differences in the frequency, intensity or relationship of adverse events between treatment groups in the Phase IIb study. Most adverse events were mild or moderate in intensity, and local rather than systemic. As expected, the majority of them were reported for a transient deterioration in hearing and tinnitus perception, which was mostly related to the tympanotomy performed prior to the injection. They usually resolved upon full closure of the eardrum. At D7, just 7% of eardrums were not fully closed, yet. Other procedure-related transient adverse events like vertigo, ear pain or inflammation were observed only rarely. Serious adverse events were also low in numbers and all considered unrelated or unlikely related.

Overall, more than 900 i.t. injections of AM-101 at concentrations of up to 0.81 mg/mL or placebo have been performed on patients suffering from acute inner ear tinnitus to date. “The accumulated data and experiences from the clinical trials reveal and confirm an attractive safety profile for AM-101,” stated Dr. Mühlmeier, who has been involved in the entire clinical development programme with AM-101 as a Principal Investigator. “They also demonstrate excellent tolerance of the AM-101 formulation in the middle ear and, importantly, also show high acceptance of intratympanic injections by patients.”

Detailed results on the Phase IIb clinical trial with AM-101 will be published in a scientific journal later this year. Preliminary outcomes from the ongoing third study (Phase II trial), will be released in summer.

About acute inner ear tinnitus
Tinnitus, the perception of sound without external acoustic stimulation, is a symptom common to various ear or other diseases. Inner ear tinnitus may be provoked by various injuries to the cochlea, the organ of hearing, such as overexposure to noise or disruptions in its blood supply. It may be short and just transitory; however, it may also become permanent. Tinnitus of less than three months of duration is considered acute, while tinnitus that is older than one year is considered chronic.

Inner ear tinnitus may be only a slight nuisance, but often it has a serious impact on the ability to sleep, relax, or concentrate, or it may lead to tiredness, irritation, nervousness, despair, frustration, or even depression. As of today, there exists neither a universal standard of care for acute inner ear tinnitus, nor a truly proven, effective treatment method.

About AM-101
AM-101 contains a small molecule that selectively blocks N-methyl-D-aspartate (NMDA) receptors. Emerging evidence suggests that NMDA receptors in the cochlea play a major role in the occurrence of tinnitus following inner ear excitotoxicity, which is characterized by excessive synaptic release of glutamate, the principal neurotransmitter in the auditory system. Cochlear excitotoxicity may be triggered by, for example, trauma (e.g. exposure to excessive noise), neuroinflammation, disturbances in inner ear blood supply (anoxia/ischemia), or the administration of certain ototoxic drugs. It has been hypothesized that the upregulation of NMDA receptors induced by cochlear excitotoxicity is responsible for aberrant excitation of auditory nerve fibres, which is perceived as tinnitus.

The development of AM-101 is based on research conducted at the INSERM Institute for Neurosciences of Montpellier, France. The clinical development of AM-101 was initiated by Auris Medical in 2007. Following proof of concept, confirmatory Phase III clinical trials are currently under preparation. Patents have been granted in more than 30 countries worldwide to date.

About Auris Medical
Auris Medical is a biotechnology company developing specific pharmaceutical compounds for the prevention or treatment of inner ear disorders, an area of great unmet medical need. The Company is currently focusing on the development of treatments for acute inner ear tinnitus (AM-101) and for acute inner ear hearing loss (AM-111) by way of intratympanic injection with biocompatible gel formulations. In addition, Auris Medical is pursuing early-stage research and development projects. The Company was founded in 2003 and is headquartered in Basel, Switzerland.

 

I still don't understand why "acute tinnitus" should differ from "chronic tinnitus". I don't buy an explanation that "it gets lodged in your brain".

 

I think they are only treating people before the 3 months onset because they have better chances of having this drug released to the public. Results with previous drugs like neramexane didn't meet standards at phase3 because of this. Just my guess.

But i think it would be great to have a phase 3 drug on the market especially for tinnitus, even if it's for the first 3 months. I guess it could give a better understanding of this disorder on a greater scale.

But the way, phase 3 for AM-101 starts in August 2013 and ends in December 2014.

 

But still, I don't understand why the tinnitus itself should differ.

At least they're trying something. Anything else would be odd, considering how many of us there are.

 

Thanks James for locating and sharing this article!

 

Yes, but I'm still not convinced. At any rate... if only they fix it, I'm happy.

 

I think the most simple evidence of this phenomenon would be some people with severed auditory nerve still experienced tinnitus.

http://www.tinnitusresearch.org/en/facts/brain_en.php

 

And how do we know that wouldn't happen with someone with acute Tinnitus?

 

You've got a point there. If AM101 ever hits the market, we'll have some more insight i hope.

If phase 3 ends in Dec 2014, how long more can it take before the drug is available to public ?

 

Hi All

Very new to the forum (my story here: https://www.tinnitustalk.com/threads/new-to-the-forum-hello.1677/) despite having tinnitus for 4 years - has become a real issue for me in the last 1 year or so (high pitched hiss that seems to have taken over my right ear/head).

I agree with James regarding the comment on targetting this on tinnitus sufferers less than 3 months. It makes perfect sense for the company to do this to move the product to market more quickly. The hypothesised solution looks very sensible in deed and I do hope the phase 3 trials produce significant results, as it will at least give T sufferers SOMETHING to try when everything else has not worked.

This is a great forum and we can get through this together - keep the support coming and stay strong guys, it's very reassuring to know there are companies out there actively working on this, as the end market is just too big for it to be ignored.

All the best,
Mission

 

I believe a drug has to show efficacy in two separate Phase 3 trials to gain regulatory approval with the FDA at least in the US. I am assuming it's fairly similar in Europe due to past experience supporting legal personnel who work with regulatory commissions in the EU. With the FDA in the US, typically a company submits the application and it can take the FDA anywhere from 3-9 months to approve or reject a drug. There's quite a bit of paperwork and hoops they have to jump through to even submit to the FDA; it's by no means a quick process. The FDA may speed approval of some drugs if they have a relatively safe profile and they meet a need that is not addressed by the current "gold standard" treatment. Which, in the case of tinnitus, there is none.

AM-101 is setting up a separate Phase 3 trial for acute tinnitus onset up to 12 months by the end of this year, but it's only in the EU that it will be happening.

From what I've read about AM-101 on Auris' website, they expect to have Phase 3 data in hand by 2015. I would guess that means they are shooting for a 2016 mid year approval assuming all goes well. Of course, this is all just specualation.

 

I was surfing AURIS website and had another look at their page explaining how AM101 works. It is very interesting and actually changed my understanding of Tinnitus and how it works ... how I always understood it is that the neurons are firing at random (or in synch as read somewhere else) and this causes a phantom sound. But here they say, in my understanding, that the neurons are actually killed. Anyway, Have a read and share your idea.. My main question is: What are cochlear NMDA receptors, where are they, how do they work?

Thanks

AM-101
Treatment of inner ear tinnitus

A large number of tinnitus cases may be due to single or repeated incidents of excitotoxicity in the cochlea, which can be provoked e.g. by exposure to excessive noise, fluctuations in the blood supply to the cochlea or certain ototoxic medications. Excitotoxicity leads through the excessive release of the neurotransmitter glutamate to neural degeneration, which may in turn lead to tinnitus. While the exact mechanisms responsible for the appearance of tinnitus following excitotoxicity remain to be elucidated, it seems highly likely that some dysregulation of cochlear NMDA receptors lies at the heart of the problem. Accumulating evidence suggests that the “phantom sound” is generated by dysregulated NMDA receptors which produce aberrant firing of the auditory nerve.

Frequently asked questions

How does AM-101 work?

AM-101 is a non-competitive antagonist of NMDA receptors which blocks the unwanted activity of NMDA receptors in the cochlea. According to our hypothesis, this can suppress the aberrant excitation of the auditory nerve that is perceived as tinnitus.

 

They should test with chronic sufferers too!

 

Not sure if this has been posted anywhere else, had a quick look and didn't see it anywhere, feel free to delete this if it's a repost.

Auris Medical : development of novel pharmaceutical therapies to prevent or treat severe inner ear disorders

Hope they have some success with the post-acute group!

 

I hope they do one in Sweden, that the only chance I have

 

Sounds so efficient! Is this treatment established? Is it performed anywere?

 

Yep, on the other hand. If it is SO bad that you take the drastic step of cutting the audiotory nerve. You probably have T much worse than us (at least me), so the chances of them having a stronger brain T than you and me are big I think. So in such a mild case as I think mine is, I think a AM101 after 2 years could help. But ofcourse, I think that because I want that to be true.... But it's not impossible

 

http://www.tinnitus-study.info/uk-home


re the am101

 

Thanks, did anyone else find it kept saying you entered the wrong code even if you didn't ?

 

Hey guys i recently got in contact with someone regarding the trials, and I was wondering what would you do? Would you enter the trial or not? Looking for advice because i tend to be a bit of a risk taker in terms of decisions i make in my life, so my family and friends knowing this is not giving me objective advice. They think i am setting myself up for something dangerous. Any advice, input , or perspective would be greatly appreciated .Thanks!!

 

I do wish we could see the actual data. It says that there is no statistical difference in the placebo and the drug in adverse effects. But I don't think that means it doesn't have adverse effects. The placebo and drug can cause effects in the same way. Maybe something to the eardrum or all the liquid in the ear. Some one correct me if I'm wrong but that is possible isn't it?

 

Look at it this way cullen AM101 at this stage is an experimental drug and what happens with experiments well sometimes they go right and sometimes they go wrong either way its a gamble this is new territory for the medical world so how can they say what will and will not happen

 

Of course anything can happen. I'm aware of that but I think there is some good information as to whether it is safe or not . It is a risk but a calculated one. The articles markuu brought up are very helpful and I haven't heard of anyone getting worse from the drug itself. If they would have published the previous trials that would take a lot of the stress off lol. In any case from what I know it seems encouraging.