AM-101 TACTT1 Results Released

[Owch]

Yeah basically. We are having a healthy discussion about it here in the lab as I write this, so clearly its not set in stone.

For me to answer your question fully would add lots and lots of confusion to the rest of the forum members that I'm pretty sure I'd never have an adequate explanation for. But the short answer is NMDA receptors are responsible for neural plasticity, so you're on the right track.

NMDA receptor antagonists (blockers) decrease the strength of a pathological neuronal connection like tinnitus.

Will these NMDA receptor blockers help?
Probably.

Will they cure T completely?
Probably not, because the central (brain) component will remain.

Is that good enough?
Judging by the suffering I see all over this forum, I think we'd all be happy with a little relief.

Many thanks for the clarification

Am I being simplistic here, or would a combination therapy of something like AM-101 removing the 'root cause' and neural stimulation of some kind (vagal nerve or whatever the latest sound therapy is etc) to stimulate neural plasticity be an appropriate treatment for chronic tinnitus?

 

[jazz]

Yes, that's what I meant. A two-prong approach!

Please answer!

 

[Owch]

Yes, that's what I meant. A two-prong approach!

Please answer!

Three-prong... while we are at it, let's have some of those stem cells fixing-up our cochleas at the same time so we get our hearing back as well

 

[ResonanceCEO]

Yes, I know most chronic tinnitus research focuses on how the brain maintains its self-sustaining network that keeps the tinnitus precept active.

But there's not enough studies--yet--to determine if the brain will slowly unwind its maladaptive plasticity once the aberrant signals from the cochlea no longer feed the auditory cortex. When you examine research on topics like rTMS, there seems to be a consensus that although auditory and non-auditory sections of the brain are affected, the hub of the brain's maladaptive plasticity emanates from the auditory cortex. Correcting the cochlea will starve the auditory cortex of its input, which may create a domino affect on other brain structures.

Please correct me if I'm wrong or elaborate on any of these ideas!

This is pretty much right on the money!

 

[ResonanceCEO]

Chris

I know I asked you this earlier, but do you find it odd that these NMDA receptor blockers are still working to reduce the tinnitus signal 1.5-2 years after administration in individuals who appear to have been succesfully treated by AM-101? I don't know whether you would know this, but wouldn't the NMDA blockers work almost immediately in stopping the signal if they worked at all- do they work immediately in the treatment of other conditions-- the reason I ask is the people I have spoken to have noticed a gradual improvement after am-101 treatment, and that has always confused me and letft open the door, at least in my mind, that these people just habituated

And no I do not find it odd. I find it to be a pleasant surprise if true. Jazz's explanation above explains it best.

 

[Johno]

To all: Don't forget, memorization of cochlea damage induced T is still unproven theory.

 

[jazz]

This is pretty much right on the money!

Thank you! We appreciate your expertise in answering our questions.

 

[Champ]

To all: Don't forget, memorization of cochlea damage induced T is still unproven theory.

It's all conjecture actually, based on how researchers intrepret electric signals they see in the brain.

I'm like, 99.9% sure repairing the inner ear will fix it for almost every tinnitus case since the correlation between hearing loss and tinnitus is so great. Even in cases where it appears there is no hearing damage, I'm sure we'll find even just a few issues with the hair cells or cochlea itself is a potential trigger for tinnitus - keep in mind, a lot of people with hearing loss don't get it, so the parameters behind what constitutes "tinnitus potential damage" and "just hearing loss damage" isn't exactly known. We know a lot more about it now, but considering we haven't actually been able to "restore" a persons hearing, there's no solidly scientific reason to say it's going to stay. If you've gotten a bat to the head or something it might still help actually.

 

[RaZaH]

I really do not trust this " Tinnitus yet no hearing loss" . Fact is that almost all hearing tests are very coarse.
Its entirely possible to have hearing loss without it showing up on a standard hearing test.

 

[Erlend]

Well, I have my little theory that T is like this:

You need 3 things for it to arise, remove ONE, and it goes away. Fix the brain, but not the cochlea= cured. Fix the cochlea but not the rain = cured

 

[t-man]

Unless there is a problem somewhere in between. The cochlear nerve and brain stem could be damaged.

And no doctor wants to go near the brain stem.

 

[bill 112]

Can loud sounds damage the brainstem??How could they diagnose if your brainstem is damaged or even the cochlear nerve anyone know??

 

[ResonanceCEO]

I have seen no literature or evidence that damage to the brainstem is a factor in T or HL. Prob not a worthwhile path for discussion.

 

[Hattukoira]

I have seen no literature or evidence that damage to the brainstem is a factor in T or HL. Prob not a worthwhile path for discussion.

What do you think about this theory that people with Hyperacusis have damaged auditory nerve fibers?
I'm actually almost completely habituated to my loud T but I have hard time with H and ear pains.

Quote from wikipedia:

There is speculation that the efferent portion of the auditory nerve(olivocochlear bundle) has been affected (efferent meaning fibers that originate in the brain which serve to regulate sounds). This theory suggests that the efferent fibers of the auditory nerve are selectively damaged, while the hair cells that allow the hearing of pure tones in an audiometric evaluation remain intact.

http://en.wikipedia.org/wiki/Hyperacusis

 

[Johno]

My Father has tinnitus – white noise type hissing and hearing loss, because he works in the past as a metal turner and was exposed to noise above 80Db for 45 years. He is fully habituated, because his T is'nt tonal, just white noise type hissing and it comes slowly and gradually, no in one short time.

But – he has of course (like 90 percent of people) transient spontaneous tinnitus attacks (tonal, with temporary hearing loss). And he said, and this is important – If he had TST attack, this attack turns off his chronic hissing, he is hearing only pure tone. And when the tone goes away, hissing returns.

He has chronic T more than 10 years. And now, is cochlear damage T memorizable or not? This is one of the reason, why I doubt about this theory. (but of course i can't say, it is'n true, I am not scientist)

 

[Johno]

One more interesting fact: I have bilateral noise induced T (acustic trauma). I have mild hearing loss too from it. But, in my left - better hearing ear, tinitus is more louder than in my worse hearing right ear.

 

[Stina]

@ResonanceCEO Advice from professionals is valued highly on this board so thank you very much for the insight How is your company's research going?

 

[dizzy lizzy]

Oh guess thats a good thing cause i been on lexapro 10 mg low dose for like 2 years now and plan on stayin on it for a long long timeeee

does the lexapro stop the ringing or just tones it down

 

[Hudson]

does the lexapro stop the ringing or just tones it down

I take lexapro and it does neither for me. What it does do is help to keep you from experiencing the kind of sustained high levels of anxiety and crippling panic attacks. Sometimes that's the worst part of having tinnitus.

 

[Grace]

does the lexapro stop the ringing or just tones it down

Yeah like hudson said it dont calm or help with T it just helps with anixety its pretty good i think

 

[RaZaH]

One more interesting fact: I have bilateral noise induced T (acustic trauma). I have mild hearing loss too from it. But, in my left - better hearing ear, tinitus is more louder than in my worse hearing right ear.

Exactly the same as me , I wonder if the less damaged one is hanging on to almost dead "hairs"leaving me with T ?

 

[jazz]

Exactly the same as me , I wonder if the less damaged one is hanging on to almost dead "hairs"leaving me with T ?

Although hearing loss and tinnitus are correlated, they are not predictive. As you know, some people have perfectly normal audiograms and very aggressive tinnitus. For these people, researchers speculate that tinnitus ears are damaged in ways that are not detected by standard hearing tests. You two probably fall into that category. I do too. I have minor hearing loss in the upper frequencies--not even enough for a hearing aid--but I wear two of them in the hopes of stimulating my auditory cortex with sounds it may be lacking.

Hearing tests are also somewhat crude. They don't measure everything. But I'm not an expert. Other people on the board are qualified to answer your questions.

But regardless of your hearing loss and your tinnitus levels, AM-101 may be beneficial in quieting your noise. The main question is how long of a window will the drug be effective. Three months? A year? Or several years with perhaps decreasing efficacy as time progresses?

Here is something you might be interested in reading:

http://www.ncbi.nlm.nih.gov/pubmed/21940438

J Neurosci. 2011 Sep 21;31(38):13452-7. doi: 10.1523/JNEUROSCI.2156-11.2011.

Tinnitus with a normal audiogram: physiological evidence for hidden hearing loss and computational model.

Schaette R1, McAlpine D.
Author information

Abstract
Ever since Pliny the Elder coined the term tinnitus, the perception of sound in the absence of an external sound source has remained enigmatic. Traditional theories assume that tinnitus is triggered by cochlear damage, but many tinnitus patients present with a normal audiogram, i.e., with no direct signs of cochlear damage. Here, we report that in human subjects with tinnitus and a normal audiogram, auditory brainstem responses show a significantly reduced amplitude of the wave I potential (generated by primary auditory nerve fibers) but normal amplitudes of the more centrally generated wave V. This provides direct physiological evidence of "hidden hearing loss" that manifests as reduced neural output from the cochlea, and consequent renormalization of neuronal response magnitude within the brainstem. Employing an established computational model, we demonstrate how tinnitus could arise from a homeostatic response of neurons in the central auditory system to reduced auditory nerve input in the absence of elevated hearing thresholds.

 

[jazz]

I don't know if this appears elsewhere in this post, but I couldn't find it. Here's a link to the full text of AM 101's Phase II trial:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966923/

 

[Mpt]

Jazz.... That's exactly what I think we've all been looking for... Thanks

 

[Mpt]

I would be interested in hearing people's thoughts... It's not great but minor totally discouraged either

 

[Hudson]

Let's break these results down:

"The study overall failed to demonstrate a treatment benefit based on the change in MML. However, AM-101 0.81 mg/ml showed statistically significantly better improvement for tinnitus loudness, annoyance, sleep difficulties, and tinnitus impact in patients with tinnitus after noise trauma or otitis media. The subgroup of ISSNHL-related tinnitus patients did not show conclusive results. The study drug and I.T. injections were well tolerated."

1. The primary end point, MML or minimum masking level, failed. This is not that surprising. Researchers will often use the same frequency as the masking sound for ALL the patients involved, as a controlling mechanism. It is the minimum level at which you can't hear your tinnitus anymore. Now, if you're someone like me, who has very high frequency tinnitus, when someone plays a 8 khz masking sound to me, they're going to have to crank it up pretty loud for me not to hear my tinnitus. Why? It's not because my tinnitus is super loud, but because it's so high pitched. If I listen to it, I can hear it in almost every situation just because of that very reason. I'm not surprised that the study did not meet this end point. I don't think that it shows failure at all, just a poorly defined end point measurement for the study.

2. Tinnitus at the end of the day is a subjective condition. That has always been one of the difficulties researchers face. How do you form a study around something you can't really objectively measure? As a result, they have often had to rely on subjective measurements, such as the "improvement for tinnitus loudness, annoyance, sleep difficulties and impact" for patients with tinnitus after noise trauma or otitis media. This is the more important end point here, IMO. Patients that received the active substance showed statistically better improvement. That means they controlled for the placebo effect. People couldn't just have been "adjusting better" because they thought they were getting some form of treatment. If Joe A. says his tinnitus quieted by half, but that can't really be measured because they play the same MML frequency for all patients, I would very much believe Joe A's tinnitus quieted by half.

3. People often claim that tinnitus clears up on its own in a short amount of time, and therefore we can't be sure if AM-101 is working. While that is true that tinnitus can clear up on its own in a relatively short period of time, this is being taken into account by including people in placebo groups. The people in the placebo group are getting really no treatment at all. They think they might be, but they can't be sure. In reality, they're getting their ear drums punctured and they aren't even getting the esketamine. So if tinnitus were magically clearing up for a huge number of people, I think the investigators would have a very difficult time showing any statistical differences between the treatment groups in their study.

 

[MikeA]

For unilateral cases looks like the largest difference between placebo and high dose groups was over the collective "very much improved" and "much improved" groups. When including the "somewhat improved" groups the totals were 65% placebo group vs. 75% in the high dose set. Not much difference there.

 

[jazz]

@Hudson Excellent points!

And you're right about MML. I can't mask mine at all; I can't even determine its tone accurately. (Plus, I have a few noises with varying intensities.)

Anyway, my favorite sentence in the report is:

[T]he potential for efficacy [should be] explored beyond the 3-month time window since the cutoff point for discriminating between acute and chronic tinnitus must be considered arbitrary anyway.
​

Great news for us chronic folks!

Although chronicity will undoubtedly be a factor, I am hopeful that by combining several treatments (ear and brain) chronic tinnitus sufferers will be cured, or their head noise will be rendered imperceptible.

 

[Grace]

@Hudson Excellent points!

And you're right about MML. I can't mask mine at all; I can't even determine its tone accurately. (Plus, I have a few noises with varying intensities.)

Anyway, my favorite sentence in the report is:

[T]he potential for efficacy [should be] explored beyond the 3-month time window since the cutoff point for discriminating between acute and chronic tinnitus must be considered arbitrary anyway.
​

Great news for us chronic folks!

Although chronicity will undoubtedly be a factor, I am hopeful that by combining several treatments (ear and brain) chronic tinnitus sufferers will be cured, or their head noise will be rendered imperceptible.

Yeah i think so too! Once am101
Is out or autfony then people will be on that and then can also do a combined treatment and i believe since this wasnt done yet that, the results will be really good for chronic T

 

[t-man]

but I wear two of them in the hopes of stimulating my auditory cortex with sounds it may be lacking.

How do you expect this to work? Once a frequency is gone from your hearing, it's gone for good. Your hearing aids are programed to take frequencies you can no longer hear and convert them to frequencies that you can.