Otonomy OTO-313 — Treatment of Tinnitus

[ThomasF]

I'm still fairly new to Tinnitus Talk and the world of tinnitus, but it feels like there's a lot of potential treatments and there being a cure in the future doesn't feel absurd. If OTO-313 can quieten or silence the noise, then one of the regenerative treatments on the way might return people to normal hearing.

 

[Nick47]

We have Dr Susan Shore, XEN-1101, SPI-1005 and OTO-313, all completed Phase 2. Dr. Susan Shore will have the shortest timeline, I'd say followed by SPI-1005. That trial is already designed, only 200 participants with estimated completion of June 2023. Easier to get participants for a pill than for an injection through the eardrum!

Wasn't SPI-1005 for Meniere's but failed?

 

[ploughna]

It'll be very interesting to see if there's any difference between the <6 month and 6-12 month cohorts when results come out shortly. Since us longer term sufferers very much want to see what happens outside that window (assuming good results up to 12 months), I can't help but wonder what Otonomy might already know - wouldn't they be able to test long term efficacy with mice easily enough without the expense/time for human trials and if so, might not they have already done so?

Anyway, just thinking out loud...

 

[scotty03874]

It'll be very interesting to see if there's any difference between the <6 month and 6-12 month cohorts when results come out shortly. Since us longer term sufferers very much want to see what happens outside that window (assuming good results up to 12 months), I can't help but wonder what Otonomy might already know - wouldn't they be able to test long term efficacy with mice easily enough without the expense/time for human trials and if so, might not they have already done so?

Anyway, just thinking out loud...

Think out loud. The hearing loss community needs to think out loud.

 

[Geatly]

It'll be very interesting to see if there's any difference between the <6 month and 6-12 month cohorts when results come out shortly. Since us longer term sufferers very much want to see what happens outside that window (assuming good results up to 12 months), I can't help but wonder what Otonomy might already know - wouldn't they be able to test long term efficacy with mice easily enough without the expense/time for human trials and if so, might not they have already done so?

Anyway, just thinking out loud...

It will work for whatever tinnitus, if it is based in ear.

 

[Nick47]

True, but these numbers are not insignificant as far as I can tell. Or am I missing something? Yes, it's only in a cohort of people that have had tinnitus for less than a year, but still.

View attachment 48238

What is interesting is of the moderate amount that had a clinically meaningful response, 66% of them had a very large reduction in volume and TFI. As this is the only therapeutic for tinnitus in clinical trials, it is the main cause for optimism.

The statistical value p=<0.05 implies that there is only a 5% chance the results were just due to luck/probability.

I don't buy much into XEN1011 or the regeneration therapies as the former is speculation and the latter showing only small improvements in very early stage development. I'm not sure on the Dr. Shore device due to the long protracted wait on results and similarity with Lenire.

I think this product is the make or break at the moment and I am CAUTIOUSLY optimistic!

 

[Sam Marksmen]

Why are they only accepting patients with acute tinnitus? Does this mean they don't think it will work for long term sufferers?

 

[Nick47]

Why are they only accepting patients with acute tinnitus? Does this mean they don't think it will work for long term sufferers?

On the Tinnitus Talk Podcast Otonomy basically said it was the safest option for Phase 1. The theory that it may originate in the cochlea but become more centralised over time. They admitted they don't know yet. They said some of the good responders were 3-6 months though. This is really towards the chronic end... some say chronic tinnitus is at 3 months, some say 6 months.

Phase 2 is up to 12 months from tinnitus onset, so will be interesting to see those towards that end and how they respond.

For what it's worth, my theory is most tinnitus is cochlear and I don't subscribe 'fully' to the theory of it moving to become centralised, although maybe partially.

They also emphasise that Phase 1 was a single injection and are asking the questions;

1) What if non-responders had another injection?
2) What if a higher dose was used?

 

[AxEars]

I'm still fairly new to Tinnitus Talk and the world of tinnitus, but it feels like there's a lot of potential treatments and there being a cure in the future doesn't feel absurd. If OTO-313 can quieten or silence the noise, then one of the regenerative treatments on the way might return people to normal hearing.

Considering the trajectory of treatments in science, this tracks.

We'll start at repair. Once competitors can get their hands on this and reverse engineer it, improvements and alterations will be made. Science will continue its adolescent stage of regeneration into a more mature stage over the course of the next decade, and we'll have a treatment that can get people as close to 100% as possible.

Stem cells are returning rotator cuff injuries to normal. Sensory injuries are magnitudes more difficult than physical injuries, but we're not too far from one treatment becoming the domino affect to more treatments. In science, competition breeds more successful treatments.

It's a year away, but this is going to specifically go after tinnitus in a clinical trial next year. They're going after actual hearing loss first, then the noise that can accompany it.

 

[patorjk]

Why are they only accepting patients with acute tinnitus? Does this mean they don't think it will work for long term sufferers?

The original research, Effects of extracochlear gacyclidine perfusion on tinnitus in humans: a case series, involved only patients with acute tinnitus (less than 7 months) and unilateral tinnitus. Since treatment was successful in this (human) research, I'm guessing Otonomy wanted to stick closely to it. Below you can see a chart of the results (side note: this study was not done by Otonomy).

If you read the case studies, 1 of the 2 non-responders actually responded during treatment, but it only lasted a few hours.

Patient 3, which is reported as a "relapse", had tinnitus that completely dissipated in the days after the treatment, though it was noted "Six weeks after the treatment the patient reported a slight increase in the intensity of her tinnitus; however, she also reported episodes when she could not hear the tinnitus at all."

Otonomy did some kind of special reformulation between OTO-311 and OTO-313 - it's been too long and I can't remember what they exactly did, but it was supposed to make the gacyclidine absorption better.

I'm guessing that in addition to sticking closely to the original study, Otonomy was probably also worried that many cases of bilateral tinnitus had an origin in the brain rather than the cochlea, however, I'm glad they're running a trial for bilateral tinnitus because I have a strong feeling that if it works, it'll work for bilateral tinnitus too.

Another aside - in one of their earnings calls Dr. Weber mentioned that they did not know if or when tinnitus moved to the brain. This tells me that they currently don't know if long term suffers will benefit, and they're playing things safely by focusing on acute tinnitus. If the 6-12 month group shows the same benefit as the 2-6 month group, I could see them expanding the time brackets for Phase 3. This is just my personal speculation though.

 

[AxEars]

The original research, Effects of extracochlear gacyclidine perfusion on tinnitus in humans: a case series, involved only patients with acute tinnitus (less than 7 months) and unilateral tinnitus. Since treatment was successful in this (human) research, I'm guessing Otonomy wanted to stick closely to it. Below you can see a chart of the results (side note: this study was not done by Otonomy).

View attachment 50987

If you read the case studies, 1 of the 2 non-responders actually responded during treatment, but it only lasted a few hours.

Patient 3, which is reported as a "relapse", had tinnitus that completely dissipated in the days after the treatment, though it was noted "Six weeks after the treatment the patient reported a slight increase in the intensity of her tinnitus; however, she also reported episodes when she could not hear the tinnitus at all."

Otonomy did some kind of special reformulation between OTO-311 and OTO-313 - it's been too long and I can't remember what they exactly did, but it was supposed to make the gacyclidine absorption better.

I'm guessing that in addition to sticking closely to the original study, Otonomy was probably also worried that many cases of bilateral tinnitus had an origin in the brain rather than the cochlea, however, I'm glad they're running a trial for bilateral tinnitus because I have a strong feeling that if it works, it'll work for bilateral tinnitus too.

Another aside - in one of their earnings calls Dr. Weber mentioned that they did not know if or when tinnitus moved to the brain. This tells me that they currently don't know if long term suffers will benefit, and they're playing things safely by focusing on acute tinnitus. If the 6-12 month group shows the same benefit as the 2-6 month group, I could see them expanding the time brackets for Phase 3. This is just my personal speculation though.

To piggyback on your comments - since clinicians don't know when tinnitus moves from the ear to the brain, it may be possible to think that if the ear is repaired, the brain could send less of a signal to the ear? Maybe that thinking is way too simplistic.

 

[Nick47]

The original research, Effects of extracochlear gacyclidine perfusion on tinnitus in humans: a case series, involved only patients with acute tinnitus (less than 7 months) and unilateral tinnitus. Since treatment was successful in this (human) research, I'm guessing Otonomy wanted to stick closely to it. Below you can see a chart of the results (side note: this study was not done by Otonomy).

View attachment 50987

If you read the case studies, 1 of the 2 non-responders actually responded during treatment, but it only lasted a few hours.

Patient 3, which is reported as a "relapse", had tinnitus that completely dissipated in the days after the treatment, though it was noted "Six weeks after the treatment the patient reported a slight increase in the intensity of her tinnitus; however, she also reported episodes when she could not hear the tinnitus at all."

Otonomy did some kind of special reformulation between OTO-311 and OTO-313 - it's been too long and I can't remember what they exactly did, but it was supposed to make the gacyclidine absorption better.

I'm guessing that in addition to sticking closely to the original study, Otonomy was probably also worried that many cases of bilateral tinnitus had an origin in the brain rather than the cochlea, however, I'm glad they're running a trial for bilateral tinnitus because I have a strong feeling that if it works, it'll work for bilateral tinnitus too.

Another aside - in one of their earnings calls Dr. Weber mentioned that they did not know if or when tinnitus moved to the brain. This tells me that they currently don't know if long term suffers will benefit, and they're playing things safely by focusing on acute tinnitus. If the 6-12 month group shows the same benefit as the 2-6 month group, I could see them expanding the time brackets for Phase 3. This is just my personal speculation though.

I think there are plenty of valid points speculated on in your post.

One key point representatives from Otonomy continually make is that the key to their success is their drug delivery system. It seems they have a method of delivering the drugs in a sustained and time released way. They believe this allows a continuous perfusion through the round oval window.

 

[Gb3]

They don't know if tinnitus moves from the ear to the brain at all. It's just an assumption.

 

[Nick47]

They don't know if tinnitus moves from the ear to the brain at all. It's just an assumption.

Agree. I would think it is only processed in the brain. All senses are. If you lose an eye in an accident and can't see, you wouldn't say it's a brain problem.

 

[ThomasF]

Agree. I would think it is only processed in the brain. All senses are. If you lose an eye in an accident and can't see, you wouldn't say it's a brain problem.

I've always been agreeable to the thought of damaged or dead hair cells not transmitting signals to the brain and the brain creating a phantom sound in response. The relationship being similar to phantom limb syndrome. It makes sense as both are responses to lack of nerve stimuli and signals.

 

[Pharz]

How can tinnitus "move" to the brain...?

The problem happens in the ear and stays there, the brain receives signals and reacts. Just like chronic pain, the pain doesn't move to the brain.

Am I missing something here?

 

[Diesel]

How can tinnitus "move" to the brain...?

The problem happens in the ear and stays there, the brain receives signals and reacts. Just like chronic pain, the pain doesn't move to the brain.

Am I missing something here?

Classic observations of the brain by researchers of tinnitus patients have led to this conclusion. It's the "best" explanation provided thus far, especially with tinnitus where progression of the disorder is a one-way street — it only gets worse.

What's interesting is that neurological researchers like Dr. Thanos refute this claim by stating that a healthy/normal brain is fairly elastic, and doesn't deteriorate in a way that would cause "tinnitus in the brain." They point directly to the peripheral sensory being the culprit, and it's the brain's "programming" not able to handle the level of damage, lack of output, or overactive output received by the brain. IE: Cochlear in origin.

Other top hearing researchers also note that nearly every patient they see with tinnitus reliably have some detectible hearing loss. Therefore, even they point to the peripheral sensors likely being the root cause. IE: Cochlear in origin.

I think it stands to reason that the most modern research may be disproving the idea that tinnitus is "in the brain." It's possible that in a few more years, this will be understood by the medical community as a myth or legacy science. Unfortunately for this community, this classic idea will continue to be repeated because it cannot be refuted until treatment proves otherwise.

 

[Nick47]

Classic observations of the brain by researchers of tinnitus patients have led to this conclusion. It's the "best" explanation provided thus far, especially with tinnitus where progression of the disorder is a one-way street — it only gets worse.

What's interesting is that neurological researchers like Dr. Thanos refute this claim by stating that a healthy/normal brain is fairly elastic, and doesn't deteriorate in a way that would cause "tinnitus in the brain." They point directly to the peripheral sensory being the culprit, and it's the brain's "programming" not able to handle the level of damage, lack of output, or overactive output received by the brain. IE: Cochlear in origin.

Other top hearing researchers also note that nearly every patient they see with tinnitus reliably have some detectible hearing loss. Therefore, even they point to the peripheral sensors likely being the root cause. IE: Cochlear in origin.

I think it stands to reason that the most modern research may be disproving the idea that tinnitus is "in the brain." It's possible that in a few more years, this will be understood by the medical community as a myth or legacy science. Unfortunately for this community, this classic idea will continue to be repeated because it cannot be refuted until treatment proves otherwise.

Added to that, it's known hearing aids reduce tinnitus for some people. As do cochlear implants often, although not always. OTO-313 points that for many under 6 months it stems from the cochlear. We wait to see for those up to 12 months.

Exciting times, hey?

 

[Gb3]

@Diesel, don't the majority of cases progressively get better?

 

[Sam Marksmen]

How would OTO-313 work if hair cells were damaged and glutamate keeps getting produced? NMDA receptor uptake would be limited but the glutamate is still being produced as hair cells are still damaged. If OTO-314 repairs hair cells, then what's the point of OTO-313?

 

[Diesel]

@Diesel, don't the majority of cases progressively get better?

It depends by the term "better." Based on this site, and on those who joined due to a noise injury, in the short-term (let's call that a year), it appears to be a combination of inflammation reducing and habituation. In the long-term, again, based on the long-haulers on this site, tinnitus does slowly get worse. But, it seems that most of the time, there's been some level of habituation, so it's much easier to adapt to an increased baseline.

 

[Diesel]

How would OTO-313 work if hair cells were damaged and glutamate keeps getting produced? NMDA receptor uptake would be limited but the glutamate is still being produced as hair cells are still damaged. If OTO-314 repairs hair cells, then what's the point of OTO-313?

Patient: Complaint of tinnitus following loud noise exposure.

Doctor: Administers OTO-313 to get tinnitus under control and reduce long-term damage / likelihood of long-term tinnitus. HIGHLY likely that hearing is damaged to some degree. Sets follow-up at 6-months.

Patient: Returns at 6-months. Tinnitus is reduced due to early application of OTO-313. Now complains of hearing-in-noise difficulties.

Doctor: Administers OTO-413 to address hearing in noise challenges. Sets follow-up at 1 year to determine if hearing improvements have stabilized or if another treatment is required.

What they're doing is creating an administration pipeline by treating parts of the overall condition.

 

[ThomasF]

Patient: Complaint of tinnitus following loud noise exposure.

Doctor: Administers OTO-313 to get tinnitus under control and reduce long-term damage / likelihood of long-term tinnitus. HIGHLY likely that hearing is damaged to some degree. Sets follow-up at 6-months.

Patient: Returns at 6-months. Tinnitus is reduced due to early application of OTO-313. Now complains of hearing-in-noise difficulties.

Doctor: Administers OTO-413 to address hearing in noise challenges. Sets follow-up at 1 year to determine if hearing improvements have stabilized or if another treatment is required.

What they're doing is creating an administration pipeline by treating parts of the overall condition.

Not to mention the potential application of OTO-6XX or some of the formulae from FREQ perhaps.

 

[Nick47]

How would OTO-313 work if hair cells were damaged and glutamate keeps getting produced? NMDA receptor uptake would be limited but the glutamate is still being produced as hair cells are still damaged. If OTO-314 repairs hair cells, then what's the point of OTO-313?

OTO-413 does not repair hair cells. It repairs synapses.

 

[DimLeb]

Patient: Complaint of tinnitus following loud noise exposure.

Doctor: Administers OTO-313 to get tinnitus under control and reduce long-term damage / likelihood of long-term tinnitus. HIGHLY likely that hearing is damaged to some degree. Sets follow-up at 6-months.

Patient: Returns at 6-months. Tinnitus is reduced due to early application of OTO-313. Now complains of hearing-in-noise difficulties.

Doctor: Administers OTO-413 to address hearing in noise challenges. Sets follow-up at 1 year to determine if hearing improvements have stabilized or if another treatment is required.

In some parallel universe...

 

[Diesel]

In some parallel universe...

It's called a "Future State."

 

[Champ]

OTO-413 does not repair hair cells. It repairs synapses.

Then perhaps tinnitus is more related to how well the synapses are functioning, not the hair cells. Improving the hair cells may help hearing, but if your synapses are having issues, then they would need to be treated to alleviate tinnitus. Just a guess of course, I know the brain can adapt and change (for the positive) so perhaps this is just one way of dealing with the issue.

 

[Nick47]

Then perhaps tinnitus is more related to how well the synapses are functioning, not the hair cells. Improving the hair cells may help hearing, but if your synapses are having issues, then they would need to be treated to alleviate tinnitus. Just a guess of course, I know the brain can adapt and change (for the positive) so perhaps this is just one way of dealing with the issue.

We will not know unless the patients enrolled in the OTO-413 trial have tinnitus.

 

[Sam Marksmen]

So it's OTO-313, then, OTO-314, then OTO-6XX? I also thought they had a gene editing one in the pipeline.

When they say synapses with OTO-314, is that the one that limits uptake of glutamate via NMDA receptors? I thought that was what OTO-313 did.

Frequency Therapeutics lost a lot of their finances after their synthetic stem cell treatment failed. It would be interesting to see if Otonomy tried this approach.

 

[patorjk]

So it's OTO-313, then, OTO-314, then OTO-6XX? I also thought they had a gene editing one in the pipeline.

When they say synapses with OTO-314, is that the one that limits uptake of glutamate via NMDA receptors? I thought that was what OTO-313 did.

Frequency Therapeutics lost a lot of their finances after their synthetic stem cell treatment failed. It would be interesting to see if Otonomy tried this approach.

OTO-825 is their gene therapy drug, it's for congenital hearing loss.

OTO-413 regenerates synapses. It doesn't deal with glutamate or NMDA receptors (that's OTO-313).

OTO-6XX was originally going to work like FX-322. Otonomy licensed a drug from Kyorin that worked in a similar fashion, however, after about 2 years of research they scrapped it and instead decided to focus on a hair cell repair drug they'd been working on (OTO-6XX represents a whole program of research). They said that regeneration had a number of hurtles that repair didn't have (according to their research) and that it seemed to be the more fruitful approach. They're playing it pretty close to the chest though, so until they reveal more we don't really have much to go on.