AM-101 Clinical Trial — Participants Updates and Discussion

Yeah very disappointing

 

This is disappointing news. But something will be learned from this trial, that will eventually lead to treatment, so it's progress no matter how negative the results are.

As mentioned before, well done Auris Medical for attempting this trial, innovative and bold trials are what we need to keep learning more about this condition. And back to the drawing board...

 

The stock plunged to 2 dollars from a height of 7 in February this year

 

yes the day before, the "rocket" was +30%, which was clearly not justified, so it is normal that it went down to -60% yesterday.

I was enjoyed to participate at the very beginning according to the feedback I had from my ENT doctor that this may be a promise drug, some people have been cured, that there was no risk, only temporary adverse effect...but this was before AM101...

But since this day my feeling has changed, because there is a day or a life after T onset but for me there is another life (survival life is much more appropriated) after AM101 injection.

What positive think can I have from this trial knowing that I :
- Have suffered a lot during the injections.
- Was forbidden to take anything else during the trial.
- Have now a worsened T/H condition
- And knowing that the results are very bad (meaning that perhaps there are ~5% of all the participants which are struggling with worsened T/H)

In addition, what is the explanation/reason for this significant gap between results from the phase 1 and phase 2 with 248 participants showing a significant improvement in tinnitus severity and loudness compared to yesterday phase 3 results !

I really hope that I (and for all of you too) will not have any new adverse effect in the future (like a fast degradation of the T and /or hearing compared to other non participants people) because there is no after sale service here.

I stop being angry now because my T is also (another bad side effect) much more reactive to emotion than before.

I will whish you all good luck for the next and really be careful with clinical trials. We have only one life and it is so precious !

Cheers.

 

I wonder if discussion on online forums can influence this. The placebo / nocebo effect especially with something as subjective as tinnitus.

I still do think that any cases of prolonged worsening after the injections was most likely procedure related and not drug related. Especially if suctioning was used. I was lucky enough to have very capable surgeons do my injections (neurotologists) and for the most part they went smoothly.

 

Not surprised at all,I saïd befor that the T is a brain disorder .

 

You have been hoping for some time that they would fail.

 

Hi folks, I've been reading the forum for a bit but this is my first post. The disappointing news regarding Auris compelled me to create an account.

Obviously, this is extremely disappointing for all of us. Still, I remain hopeful for Scifluor to yield more promising results---not a cure perhaps, but at least a treatment that will offer significant suppression. While I'm a layman, the science behind Scifluor's efforts seems a more sensible approach. Guess we'll all have to wait and see.

If nothing else, I find it wonderful that companies are devoting time and money to research. When I first battled tinnitus (in 1994---the road towards habituation was the worst year of my life), I was told to just live it, nothing could or would ever be done, etc. At least the problem is being tackled in ways that don't involve pseudoscience, holistic medicine, or other such nonsense. I am not by nature an optimistic person; still, I can only think that good things will come, eventually.

 

I dont think there is acute tinnitus or cronic tinnitus there is only one wich is tinnitus.and this last is devided in two: subjective and objective. They would target a brain and forget ears It's my opinion I am not an expert

 

I'm no expert either, by any means, but I agree with you. Solve the problem in the brain, and cure T whether you've had it for 10 years or 10 minutes. Just my guess of course.

 

I think there are many types of tinnitus, more than doctors recognize. But I do agree, it is likely you more of a neurological problem.

 

wow, what a disappointment.
i was hoping for better results.
even if it didnt worked for me,
Auris still got me intrigued...

About AM 111

Efficacy
In a Phase 2 trial, patients with ASNHL following acute acoustic trauma or sudden deafness were enrolled within 48 hours from onset. Patients with severe to profound hearing loss (i.e. hearing thresholds ≥ 60 dB at the three worst affected test frequencies) who were treated with AM-111 0.4 mg/mL showed a clinically revelant improvement in hearing threshold, speech discrimination and a higher rate of complete tinnitus remission compared with placebo.

 

I think we all sort of knew it....we only have oddv out of 10s of members whose T got better.

In the study centre where i had am 101 ...only one person out of 10 got better....

So, we have seen the statistics of improvement no better than chance....e.

For me the injections caused eustachian tube dysfunction, my ears click everytine i swallow now(for some reason i fell like swallowing since the injections as the pressure regulation seems to be messed up).....could someone in the forum advice me what i can do next....as Auris Medical to fix my eustachian tube dysfunction at there expense?

 

Such a heartbreak.

Meanwhile I still have my smug site coordinator begging me to return. Fat chance after all this.

 

My tinnitus is worse after 2nd round and I have gone from mild high frequency hearing loss above 4k (that I did not really notice) to severe deafness such that I cannot understand reliably what somebody is saying to my face. This is a personal tragedy for me. I hope there are not many others left in such a state.

 

Do you have your audiograms from before and after? That sucks. How long has it been since your last injection? Having fluid still in your ears can cause temporary (conductive) high frequency hearing loss.

 

I definately got some relief after the double-blind injections, so i guess that is all due to natural healing when reading about these results. I am glad i did not participate in the open label round, although this was mainly due to the incomptence at my facility, where the trial coordinator and doctors just 'went on holiday' in june.. The hospital in general was really crappy overall.
I do wish the people from AM all the best and hope they will continue the search for viable treatments.

 

Hi cheerears, yes for me it is also a tragedy and I am sure that we are not alone. I would think that safety end point is not reach as well (except if for Auris safety is when you do not loose much more than 20db or if you do not become deaf). In addition worsened T is not count as safety.Good luck cheerears. I hope you will get improvement soon.

 

@attheedgeofscience believed this injection drug would be successful, he was wrong

 

It may have been successful if injected within 4 days of onset........it only worked for rats for the first 4 days, after that it had NO effect....but the assumption was 3 man days = 3 rat months, I think that is where the problem lies.

 

So that's a flop as well then.
Well, in tinnitus land, shit happens daily.

 

Evidence that blocking NMDA receptors was not effective after 4 days of onset in rats.

http://www.ncbi.nlm.nih.gov/pubmed/18301716

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246076/figure/fig4/

I wish they had given it to people within 4 day window..........I think if Tinnitus stays for 2 days, its unlikely to go anyway....so it should be fine to take at day 3.....anyway this is the end of road for AM 101.

 

Yes, I knew this going in, but still had to hope for something. It is true that changes in rats and humans happen at different rates, how long that translates out to nobody knows. AM 101 did seem to cure my fleeting tinnitus, which wasn't even factored in because I didn't consider it a "different tone" because it only happened a few times a week, but did nothing for my most bothersome baseline tinnitus. I wouldn't say 2 days, maybe more like 2 weeks.

I wonder what's going to happen now with OTO-311 seeing that it works by the very same mechanism as AM-101. I wonder the same with AM-102.

I knew AM-101 was a hit and miss, but I'm not feeling very optimistic about the future of tinnitus research at the moment, this is the closest an actual treatment has come to approval, and look how many years it took.

 

Yep. My pessimism is a 10 of 10 again.

It had dropped to a 9.5.

 

Yes it is sad and dissapointing that this drug did't work. From the company things looked very optimistic.
I wish one company is able to find some cureable treatments, raise a lot of money with it and invest more in other hearing related projects.
After the out of Autifony it's really a good question what's next.

 

I had some fleeting optimism, but it went away after a couple of seconds

 

From this http://endpts.com/auris-shares-are-crushed-as-tinnitus-drug-fails-phiii-test/ article about the AM-101 trial failure:

Here’s Leerink’s Joseph Schwartz from a note this morning:

“Although we continue to expect the confirmatory portion of this study
to mirror the results of TACTT2, this EU-based study includes an additional
300 patients being enrolled in Stratum B with post-acute stage of tinnitus of
3-6 months onset that will provide an additional shot at efficacy in a different
patient population. The completion of a prespecified futility analysis in Stratum B
based on 50% of the planned total enrollment in post-acute stage (3-2 months from onset)
was assessed by the Independent Data Monitoring Committee (DMC) and led to the
recommendation for continued enrollment, which is encouraging. Ultimately it
remains to be seen how the FDA/EMA would consider Keyzilen if TACTT3 is successful
in light of today’s negative TACTT2 results, as we expect that two successful
pivotal trials are necessary for approval.”​

A couple of things stand out. First, this biopharma analyst expects TACTT3 Stratum A to have the same result as TACTT2. This is not a surprise, but it is of course bad.

Second, the futility analysis of Stratum B was positive enough that they are continuing to enroll people in the "post-acute" phase. Of course this doesn't mean they will ultimately find a beneficial effect. It only means that the DMC believes that there is enough of a chance of finding an effect that it is worthwhile to continue to enroll people. This is important because it was a similar futility analysis that resulted in the halt of the AUT00063 trial.

What is odd about this is, based on the proposed mechanism of action, AM-101 should be more effective the sooner it is given so you would think the results of Straum B should be worse than the results of TACTT2. Of course the results may ultimately show this.

Third, he raises the possibility that two successful Phase III trials may be required for approval. It's unclear what might happen if TACTT3 Stratum A fails but Stratum B succeeds. In that case you have 1 successful Phase III trial but for the post-acute group.

It may even be unclear what happens if both succeed since they target different populations. Would FDA/EMA require a second Phase III trial for one or both populations or would those two count as two successful trials even though they are in different populations? My guess is that they would require an additional trial.

That said, since there is no FDA approved treatment for tinnitus, it is possible that one positive Phase III trial may be enough if TACTT2 hit some of the secondary endpoints. The argument would be that a marginally effective drug is better than no drug.

Potential Impact on Funding for Auris

The failure may have consequences for funding beyond the fall in stock price. In July it was announced that Auris had secured at $20 million loan, but $7.5 million was contingent on hitting the co-endpoints in TACTT2 (https://www.thestreet.com/story/136...ecures-loan-facility-of-up-to-20-million.html) so it isn't clear if that additional money will be forthcoming. As of now Auris is saying that they have funds to get through 2017.

Effect on Otonomy/OTO-311

It turns out that Otonomy has been free-riding off AM-101 a bit. (http://us11.campaign-archive2.com/?u=f8609630ae206654824f897b6&id=072d002c61O) This makes sense since OTO-311 and AM-101 operate on the same principles. It sounds like Otonomy won't move on to Phase II of OTO-311 until they see Auris's results in TACTT3. They want to attempt to discern whether it appears that NMDA receptors just aren't a good target or whether there is an issue with AM-101's trial design or patient population. It will be interesting to see the patient population of TACTT2 because earlier AM-101 trials have had some odd sample issues.

If it's the case that NMDA receptors just aren't a good target, then killing OTO-311 due to AM-101 results is a good outcome because it saves Otonomy time and money. If it isn't clear what the problems are and Otonomy decides to halt OTO-311, then it's potentially a bad thing. Regardless, don't expect a Phase II trial on OTO-311 before the top-line results from TACTT3 are known - and, if the results are negative, perhaps not until the detailed results are known assuming Auris decides to make them public.

 

Okay, so I have been checking in with TinnitusTalk a little more often than I would have under normal circumstances. Given the nature of the subject, my previous role in certain matters, and the fact that my name has been mentioned, I guess some kind of response is indicated.

It is correct that I assumed that AM-101 would ultimately prove to be successful (despite a less conclusive phase-II trial). There are a number of reasons for this, but, I do not wish to turn this into a whole essay, and so, I will limit myself to a few snapshots of my line-of-thinking in this. But firstly, I would like to mention that the full trial is not over yet (TACTT3 stratum A + B still awaits) - so to say that I am wrong is a little premature (but then again, accuracy of statements has never been the forté of the average member here). I should also mention that there are "other people" than just tinnitus sufferers reading this, and so, that is another reason why I do not wish to be too clear and exhaustive in my wording.

So what's the deal here? Well, I attended the two latest conference calls hosted by Auris Medical (the last one being the one held this past Thursday where the TACTT2 news were released). I also attended the latest conference call by Otonomy (for their Q2 2016 results). Given that they are both publicly listed companies, the presentations they make follow essentially the information released via their website (see attachment pdf-file).

Back in 2014, Prof. Marlies Knipper was part of a symposium hosted by Auris Medical. There were several different speakers; she was one of them. She brilliantly covered the science on cochlear tinnitus and the assumed mechanism of action of NMDA receptor antagonists (incl. details such as to how there is a difference between inner ear- and outer ear- hair cells; tinnitus being caused by inner ear hair cells - or so it is thought). In that presentation (which is about 15 minutes long), there is a "controversial" moment where she mentions that the animal studies conducted - and where efficacy was observed during a time window of days - would translate into the same drug being efficacious for up to several months (in humans). How that was determined, I do not know.

As for phase-II vs phase-III, I assumed that an improvement in terms of demonstrated efficacy would be shown - in part - because:

• The inclusion criteria (= the study population) would be better targeted (in phase-III vs phase-II which included idiopathic cases of tinnitus).
• Larger sample size (allowing for a better spread of various variables - including time of treatment after onset i.e. a better potential to have really early onset candidates).
• The phase-III study "survived" an interim assessment.

However, it turns out that in phase-III, a two week screening period was introduced. My understanding of this is that this essentially adds an additional two weeks to every candidates time of treatment (vs. onset). Clearly if tinnitus is time sensitive to treatment, then introducing a like-for-like two-week delay (vs. phase-II) is a pretty impactful variable (at least, in my opinion). This topic was touched upon (slightly) during the conference call:



So it is possible that the study failed to show efficacy not because of the science, but, because of the study design.

Now, I could go on and on about "this and that" and some other thing. But let's assume for a minute that the study actually will not pass (in the end). What then tinnitus community - what will you do? Back in October last year, when the AUT00063 QUIET-1 study failed, an announcement was made here on the forum:



Those who pay attention will notice that the info-sheet was downloaded an incredible +50,000 times. Compare that with the average attachment which typically is downloaded - on average - 10, 20, 30, or perhaps 50 times. Suppose back then that every person who downloaded the info sheet had also clicked our Trobalt campaign (which I was very much part of devising) or some other initiative - think about the massive amount of awareness there would now be. Well, opportunities come and go. And for the tinnitus community, they seem to mostly go.

All the best to everyone. And, on a very final note: many many thanks to Auris Medical for being a pioneer in the emerging field of inner ear otology.

 

Come on people, enough of the pity party. So AM101 failed so what? Do you honestly believe that the scientist who worked on this is just going to shrug and give up? No there will be more research and development of potential cures for T in the future. Sure this sucks but medical technology improves fast these days, bell if my company can develop liquid Biopsy then a T cure can be made. It isn't going to happen over night people so enough with the sobbing and crap, buckle down and wait for new developments.