Otonomy OTO-313 — Treatment of Tinnitus

I agree with what you are stating. I really would have been better saying they may be a dead end. That is because if the other types of treatments for hair cells and synapses are successful stopping tinnitus, there may potentially be little or no benefit by using this treatment too.

The take that you have on FX-322 might be correct. Consequently choosing to use a treatment like OTO-313 might also assist as a in between if you have the ability to take FX-322 but no treatment for synapses is available. I still think that there will be a lot of people who will require both hair cell repair and synapse repair to resolve their tinnitus. So far evidence has proven that when a hearing device is used it does alleviate tinnitus, though there are people also with normal audiograms also experiencing tinnitus. This indicates it is caused by synapse damage. It will be very very intriguing to see really whether anyone after treating these two things still has tinnitus and hence then OTO-313 may be of further benefit. Otherwise obviously there will be questions around whether it is beneficial other than being a filler either before these treatments work or are available. Am still hoping and believing that the results thus far indicate that FX-322 and the treatment of synapses will be successful.

 

I think that this is the question which will need to be answered. At this stage hypothetically it could and probably would, although again although there has been promise and positive outcomes thus far in both the information around synapse recovery and FX-322. We will have to wait for a successful treatment then the answer will come about the tinnitus.

 

The evidence explains essentially that there is a real probability that 50% of the problem is hair cell restoration and 50% is synapses. So even though there may (conservative) be favourable help with tinnitus there may not be the full cure coming from using this.

There is no doubt tinnitus stems from hearing loss, however there is also the fact that we know some people have it yet do not have any hearing loss on their audiogram. There is research which indicate that synapse deficiencies do cause tinnitus, thus why groups like Hough have targeted this treatment.

Therefore while I think FX-322 will help with tinnitus I think that there will still need to be a treatment for synapses.

I also wonder whether the treatment of synapses might make better inroads into curing tinnitus. This could be the surprise of that medication much like FX-322 was when it surprised researchers and watchers when it showed ultra high frequency hair cells repairs led to good outcomes in deciphering speech.

 

It's a shame that Frequency is only targeting hair cell regeneration, if they had a synapse repair drug as well that could potentially increase their market share.

Won't frequencies approach repair cochlear synaptic damage as well as regenerate hair cells?

 

No, FX-322 only regenerates hair cells and their respective synapses. So if the cells are still alive but there's synaptic damage FX-322 won't do much to help you.

 

FX-322 only regenerates synapses in areas where there is hair cell loss. So if you are lucky that in some areas you have hair cell loss then it would be able to regenerate both hair cells and synapses.

 

As far as I know there are currently three options being researched for synapse repair:

Pipeline Therapeutics PIPE-505 (Phase 1/2 commencing)
Otonomy OTO-413 (Phase 1/2 results expected this year)
Hough Institute NHPN-1010

There’s also Rinri Therapeutics stem cell therapy for spiral ganglion neuron repair, but nobody’s ever explained to me its relationship to hair cells and synapses.

 

That is what scares me the most and what I always think with each new treatment. The definitive cure for acute tinnitus will be a life sentence for those of us who have chronic tinnitus.

 

Don’t you worry. They won’t forget about us. We’re a massive market that will pay handsomely to be fixed, and they’re aware of this.

 

I have only encountered literature on spiral ganglion neuropathy occuring in response to certain autoimmune conditions like MS and Guillian-Barre.

 

This is the question which will not yet have been completely answered. The information to date tells us that testing of FX-322 for speech in noise was done, however we have only seen that it targets the hair cells and thus there is no info on whether it targets synapses. The pill researched by Hough has demonstrated both the ability to improve hearing thresholds and synapse repair.

Thus the million dollar question is if you target one aspect (eg: synapses), if it also allows for improved hearing threshold and vice versa. I think that this is quite possible considering Frequency Therapeutics would not be testing speech in noise unless they knew or felt it had some benefit. Likewise with Hough we are yet to get told that the tablet targets cells only synapses. So seems that while the two treatments do not specifically target both areas needing recovery, there is some overlap in both hearing threshold and speech in noise when you improve synapses or cells with medicinal treatment exclusively.

 

Frequency said in their JP Morgan Q and A that if you repair a hair cell (implied IHC) it will re-synapse with the SGN. They said they are an synaptopathy drug only in areas where the hair cell reconnected in this way.

In other words, where you have (inner) hair cell loss, the synapses will be repaired too. And you should see speech in noise benefit. Where you have synapse loss without hair cell loss, FX-323 will not benefit.

 

And may I add something about synaptopathy from what I read recently.

The spiral ganglion neurons are much more with regards to the number of inner hair cells. But one spiral ganglion cell synapses with ONLY and only one inner hair cell. The inner hair cell can have a few synapses extending from different spiral ganglion cells through their ‘ribbons’ therefore when you lose your inner hair cells (died off and the synapses won’t survive) or synapses destroyed these spiral ganglion neurons will be silenced.

And FX-322 regrows those inner hair cells with their synaptic ribbons which will help to improve hearing.

But if the inner hair cell is there with some broken synapses then that is where FX-332 is not going to work.

 

There appears to be a contradiction between what FGGand you have written. FGG stated that the synapses will regrow right in conjunction with FX-322 treatment. You say that if the synapse is broken, it will not regrow.

 

No, he said that if the hair cells are still intact, FX-322 won't "reconnect" them. Only newly created hair cells attach themselves.

 

Let me try to make this simple:

Synapses refered to here are between the inner hair cells and the SGN.

If you are missing an inner hair cell and a new one regrows in its place in response to the drug, the new hair cell will form new synapses.

If your inner hair cells are all normal but you have broken synapses (e.g. you have "cochlear synaptopathy" without inner hair cell loss), then this drug does not target those synapses.

Edit: there is a lot more info about this in the Frequency thread.

 

Very easy to understand. Cheers. Currently would this mean those with broken synapses and no hair cell loss would be looking at either the OTO-413 or Hough pill?

 

How can you know if you have broken synapses or loss of hair cells?

Do you have to try FX-322 and see if it works?

 

And if the hair cells are damaged, but live, with damaged synapses... will the hair cell and the synapse recover? Let's see if it will be better to have them lost and regenerate than a little damaged and not regenerate or fix...

 

Or PIPE-505.

 

If you have a lot of speech in noise problems but otherwise normal hearing, that can be a clue. But really, it seems like diagnostics will lag behind treatments until they catch up at some point. It may end up being a trial and error thing for many people.

 

Unless there have been updates on imaging you'd have to go through dissection of the ear preferably during an autopsy.

FMRI techniques might provide an imaging solution though it will take minimum 6-20 years to improve to that level.

 

Agree with the first part but I think flexible scopes the width of a hair are already being designed to fit through the round window and will likely be more useful than fMRI. The tricky part will be gathering enough data through autopsy studies to correlate gross lesions with likely microscopic findings.

 

It is something which will be blatantly more helpful however I have a feeling that the current criteria for testing tends to be a sufficient source of diagnosing dose requirements for an individual.

For example the theory of what is insufficient in a person (either hair cells, synapses or both) is already determined and identified. If you have sound/speech in noise trouble then synapses and an audiogram decline is hair cells. Thus for people such as myself who have both issues the prudent course would be to have FX-322 first, then the treatment course runs through, then test again. If you then fail the speech with noise section again at this point it is obviously necessary to take the synapse treatment now.

So some improvements in pictures provided through imaging is going to mean a benefit to specialists and patients in terms of instant identification of issues in an ear. However having the knowledge of the anatomical effects on hearing and also how these relate in testing terms mean most likely that this won't be necessary. We are all extremely fortunate in this regard.

 

Thanks for clarifying @FGG and @Sloth Yes, that’s what I meant. You can maybe test for synaptopathy or at the very least inner hair cell function through acoustic reflex, but I’m not extremely certain about this.

 

I don’t know where they are with hearing in noise tests that cochlear synaptopathy might be diagnosed with. Other than that... a super advanced MRI might be able to tell at some point, but they still have ways to go with that.

 

@FGG Can you clarify what it means when the clinical trials include "Phase I/IIa" in the title, such as when I was searching for PIPE-505 clinical trials.

https://clinicaltrials.gov/ct2/show/NCT04462198

Are they testing for both phase 1 and phase 2a? What is the focus on this? Both safety and efficacy? I thought they had to go through in steps.

 

It's just as it sounds. A combination safety and efficacy. Usually they would then do a larger efficacy phase 2 (phase 2b) with a dose they determined in this combined phase.

 

I've wondered how to diagnose synapse vs hair cell loss?

• I do have hair cell damage, as evidenced by notches on my audiogram
  
  
• I experience (temporary) residual inhibition around the same frequencies of my hearing loss
  
  
• However, amplifying lost frequencies (recently trialled a hearing aid capable of amplifying above 8 kHz) made no difference to my tinnitus whatsoever
  
  
• So, would I assume that my tinnitus is largely synaptic (hearing loss long before tinnitus, but only tested to 8 kHz so unsure if losses above this were present pre-tinnitus)?

 

Are you able to match your tone to a particular frequency? Hearing aids that help over 8 kHz go to just over 10 kHz.

As to your question, if you have notches you have hair cell damage but you could also have synapse damage (or IHC damage), which is not easy to diagnose.

Diagnostics are still very crude, unfortunately. People with a lot of speech in noise problems have cochlear synaptopathy but that would apply to synaptopathy in a certain range and may not apply to say, ultra high frequency synaptopathy. I would get an extended audiogram if you haven't though other than that I'm not sure what else you could do to diagnose.