Audion Therapeutics Trial

Case study: Lockdown no barrier to Sarah's research participation

This is about someone that participated in the Regain/Audion Therapeutics clinical trial. No mention about any improvements but she did state that they had a follow-up appointment with them in July. I still think they are not going to progress to the next stage with the information we received earlier but who knows.

 

I just found this. What do you think they mean by “positive” results?

It doesn’t say that they restored hearing, but that they had positive results in Phase 1.

Here is the link:

Audion Therapeutics and REGAIN Consortium Announce Positive Phase I Results in Patients with Sensorineural Hearing Loss

 

It says that it improved speech in noise.

“AUD1001 was shown to be safe and well tolerated, and provided early indications of efficacy in speech in noise, a key clinical outcome parameter. Importantly, the efficacy signals persisted a year after the treatment.”.

 

This article is from February 2019. So kind of outdated. Phase 2 results (at least some partial information) was released last year. Disappointing like that for FX-322. I think currently it's even not clear if they are still pursuing drug development or if they closed it once and for all.

 

I did not find any details of the Phase 2A results. Curious if somebody can post those. But around 30% of patients showed improvements if I remember it properly and further study was recommended. And look what I found here:

https://audiontherapeutics.com/development/

They are planning for a Phase 2B trial in H2 2021!

 

So are they saying the treatment improved people's hearing?

 

See:

https://cordis.europa.eu/article/id/415956-a-regenerative-therapy-for-hearing-loss

They are not that forthcoming. As far as I know we did not see more details.

Their drug is called AUD1001 (LY3056480). This drug converts supporting cells into hearing cells. So it is less elegant than FX-322 which first will activate progenitor cells that will result in new hair cells.

 

Wow, I was under the impression they had a failed clinical trial and abandoned the drug.

This is great news!

 

Holy shit. I thought this was a dead end but they said they are doing a Phase 2b so that must mean Phase 2a did well.

I remember last year, if you look back on the previous pages, the Phase 2a results were released by that EU website and we thought it was bad.

 

FYI AUD1001 (LY3056480) failed. Primary efficacy endpoints were not sufficiently met.

But don't expect a big announcement from the companies or entities involved. Apparently it's a touchy subject... which requires layer upon layer of positive spin and reframing to avoid triggering any negative public sentiment:

"Furthermore, the project has opened the way for others in the field seeking to introduce treatment to the hearing loss patient community."

Translation = yeah this thing failed but now other people can try other things and maybe learn from the thing we tried.

But if you look hard enough, you will eventually find the part about it failing. It's actually a great case study in propaganda and obfuscation.

 

If it failed, then why are they doing Phase 2b? Shouldn’t they have to repeat Phase 2a first?

I hope Audion/Regain try and complete these trials ASAP. They need to speed up the process because a year is way too long to complete for each phase.

I hope the follow-up appointments are up to Day 90 at the maximum.

 

At least they never shouted from the rooftops that they were god's gift to the hearing impaired. Unlike another outfit that begins with the letter F.

 

That's one heck of a great find @Coleoptere! Kudos from the other part of The Hague

 

Whoever told you the drug didn't work: the patients had a 35%-40% improvement, but this drug didn't shine due to the curse of FX-322 and the stock exchange.

 

Reading between the lines, they couldn't shift hearing thresholds either. Like Frequency Therapeutics, they're going for clarity.

 

We will not see a Phase 2b trial in the United States this year. As I said, this is a case study in propaganda and obfuscation. Phase 2b in U.S. this year = pure fantasy. When were the Phase 2 trial results supposed to be published or reported? How many times has that due date been pushed back? How many times have they missed the deadline? Has it been over a year since the last “due date”? Reason? Beware of post hoc adjustments to study design. How many endpoints were used? Why the shift to focus on “clarity”? Beware of any attempts to claim they have successfully identified a “responder group” — a supposed way to know who will or won’t benefit from this treatment, in advance, so they say... and beware of any plausible sounding explanations of the Phase 2 results that conveniently make a solid case for why more funding is warranted. For more Phase 2 trials. Look up data-dredging. Look up multiplicity problem. I would gladly untangle their Phase 2 results here, but they haven’t published them. So, all I can do is voice my concerns and suspicion. Understand I am typically optimistic and prefer to keep an eye on the upside, the best case scenario, the possibility of a big win. And yet I am highly suspicious of how this has played out.

Anyway, I will wrap this up by saying: I don’t know what the future holds. I could be wrong about all of this. But something is up with this one. Something afoot. Prove me wrong, Audion... prove me wrong. (Seriously.)

 

One thought I had on this is: the hearing test measure at distinct frequencies like 500 Hz, 1000 Hz, 2000 Hz, 4000 Hz, 8000 Hz. But what will happen if FX-322, AUD1001 or whatever stuff are repairing in between frequencies like 510 Hz, 1100 Hz, 2500 Hz, 4300 Hz, 7900 Hz? So then you will have patients who show improvements in their audiogram (coinciding with 500 Hz, 1000 Hz, etc) and patients who do not but have an improved audiogram but still hear better.

 

I have seen two ENTs in London who helped in the Regain trial. The first one about one year ago, and this first ENT told me he could not disclose anything due to trial rules, but from facial expressions and reading between the lines I got the impression they were disappointed. I saw a second ENT recently and this second ENT told me that while I could not be told any detailed information, I should not have high hopes. This second ENT was more explicit and he definitely looked disappointed.

For obvious reasons I cannot give names.

From all this I deduce that the Audion drug in the current formulation does not work or works only very very marginally. This is consistent with the currently disappointing performance of FX-322 that in many respects is an hearing regeneration drug based on better science than Audion. My opinion (and it is just an opinion) is that while FX-322 may still be improved, Audion has kind of reached the limit of what can be achieved. I hope I'm wrong and that Audion can improve the drug into something more effective.

 

What is the difference between an increase in hearing threshold and clarity? If you can hear words better (clarity) doesn’t that mean there must be an increase in your hearing threshold?

 

Well if it failed then why move onto Phase 2b? I read that the participants were given 3 doses but am not sure how far apart those doses were given. Could be that the reason why it failed is because of multiple doses in quick succession like FX-322.

We need more details on what they are doing with Phase 2b.

 

Hearing threshold tends to refer to the volume that you can hear things. This tends to translate to what you see recorded on an audiogram.

Hearing clarity is how well you can hear words and doesn't show on something like an audiogram, although some include it on it as a supplementary test.

Thus the hearing thresholds refer to the functions of the outer hair cell, while the hearing clarity refers to the function of the inner hair cells.

Thus there are people who can have really high hearing thresholds (e.g., 70 dB) that tend to perform quite well with word recognition. This means that if they get the right volume, they can easily understand the words being said to them.

There are also people who have reasonable hearing thresholds (like 25 dB) but perform pretty poorly when it comes to word recognition too.

Thus this tends to be why the audiogram is not the be all and also the end all when it comes to hearing assessments. As a rule, this tends to be why some ENTs and audiologists have been roundly criticised for solely relying on audiogram outcomes when assessing people, because if it is the case that your hearing thresholds are bad but your word recognition or hearing in noise actually is good then you will significantly benefit from hearing aid.

Furthermore this is also why there has been a major reassessment of the criteria to meet for the CI. This is because those who work with these have identified that it is incredibly clear that you will and can benefit far more from having one even if your hearing loss doesn't fit into the profound category on the audiogram for example, especially when your word recognition and hearing in noise is poor.

 

Will you be seeing the same ENTs anytime soon? Would be nice to ask them why Audion/Regain are moving onto Phase 2b if they thought that the drug failed.

 

I'm not sure I'll have a follow up because these ENTs never take a proactive approach to try and treat progressing hearing loss and tinnitus. They just watch you go deaf or go mad with disabling tinnitus and then propose you a cochlear implant. I'm looking for ENTs who are willing to take a minimal risk and consider treatments also in presence of limited diagnostics, since the inner ear diagnostics is rubbish.

However, if I see this ENT again I will ask about Phase 2b. My impression is that they think something can be salvaged with the next phases, given there is absolutely nothing in the market, but the results are underwhelming compared to previous expectations. A little similar to what has happened with FX-322 but worse, as Audion has less margin for improvement.

 

Well, ENTs really can’t do anything at the moment so what do you want them to do?

 

Why do you say they can't do anything? Some forum members found solutions only after they insisted through many doctors. One saw their vestibular issues heal after a long course of antivirals, as in the papers by Gaceck, but no previous ENT they saw wanted to adopt that because it is unconventional. ENTs could definitely dare more to help patients but most of the time just watch their back. The diagnostics of the inner ear is very poor. This means you have to try treatments even in presence of circumstantial/incomplete evidence. If you suspect repeated viral attacks, administer a long course of antivirals, even if you are not sure (and you can't be). If you suspect AIED, perhaps try repeated courses of steroids, or other medications for autoimmune conditions.

Instead, what we get is sit there and wait for the patient to go deaf and then do a cochlear implant. Perhaps this is inevitable, but what would you have to lose in trying to save some hearing with the above approaches? If you are wrong on the viral attacks, you administered antivirals for nothing, a calculated risk that can be taken unless you are allergic/sensitive to that class of medications. But if you do have viral attacks and you do nothing but wait your hearing to be completely gone, that's even worse, you get a cochlear implant when you could have kept your hearing for longer through a medication protocol.

 

New trial (Phase 2) about to commence:

A Trial of LY3056480 in Patients With SNLH (VESTA)

What’s interesting is that they will use different dosage schedules. Once every couple of days, once weekly and once every two weeks, each schedule four injections. Learning from Frequency Therapeutics?

I do find it odd that speech in noise seems to be the only outcome measure. I think they’re basing this on the results of Phase 1. It’s the same as with FX-322; speech in noise improves a little, but nothing with regards to the audiogram.

 

Estimated Study Completion Date: March 2025

 

Commences September 2022.

 

This whole thing feels like someone's part-time project. I think with the lack of urgency you'd have to assume that the results have been unspectacular. Yet they mosey along...

I hope I'm left with egg on my face. Eventually.

 

3.5 years from now, assuming no delays from COVID-19 or other adverse events. It’s so far away in time that it doesn’t even excite me.