Otonomy OTO-6XX — Hair Cell Regeneration

[patorjk]

Why are OTO-313 and FX-322 so popular even though Hough Ear Institute's regenerating hair cell project is closer to commercialization?

OTO-313 is currently in Phase II trials. From what I gather online, Hough Ear Institute's pill hasn't entered Phase II:

https://houghear.org/tinnitus-study

This means OTO-313 is closer. I'm left with several questions though:

• Has it been demonstrated that the Hough Ear Institute's pill can cure tinnitus in humans? They say as much on that landing page, but looking closer all I see is a pre-clinical study they did on rats. Where is the data from this study?
• Why are they crowdfunding this? They could move things along a lot quicker if they got some investors. It seems almost scam-y to make big promises and raise money from people suffering from the condition. The only reason I see to do it this way is that they own their company completely when they go to market - but if there product works, they'll be rich no matter what, so there's no reason not to get investors if their product works.
• The Hough Ear Institute pill is a synaptopathy drug. If it works for tinnitus, why didn't Otonomy see any tinnitus improvement in their Phase I study of OTO-413?

There is real data behind OTO-313. Even though it's not a cure for the underlying cause, it's way more exciting as has solid science backing up its efficacy.

Little is known about OTO-6XX at the moment. Otonomy has 2 investor conferences this month, maybe they'll talk a little more at those but I don't know.

 

[tommyd87]

OTO-313 is currently in Phase II trials. From what I gather online, Hough Ear Institute's pill hasn't entered Phase II:

https://houghear.org/tinnitus-study

This means OTO-313 is closer. I'm left with several questions though:

• Has it been demonstrated that the Hough Ear Institute's pill can cure tinnitus in humans? They say as much on that landing page, but looking closer all I see is a pre-clinical study they did on rats. Where is the data from this study?
• Why are they crowdfunding this? They could move things along a lot quicker if they got some investors. It seems almost scam-y to make big promises and raise money from people suffering from the condition. The only reason I see to do it this way is that they own their company completely when they go to market - but if there product works, they'll be rich no matter what, so there's no reason not to get investors if their product works.
• The Hough Ear Institute pill is a synaptopathy drug. If it works for tinnitus, why didn't Otonomy see any tinnitus improvement in their Phase I study of OTO-413?

There is real data behind OTO-313. Even though it's not a cure for the underlying cause, it's way more exciting as has solid science backing up its efficacy.

Little is known about OTO-6XX at the moment. Otonomy has 2 investor conferences this month, maybe they'll talk a little more at those but I don't know.

- To be rational when it comes to the Hough Ear Institute pill, the initial trial was done with people who indicated that they did not have tinnitus etc. Essentially this demonstrates that it was not possible to determine whether the medicine had any benefit or not for tinnitus.

- Also wasn't it the case that the Otonomy OTO-413 trial did not test for tinnitus?

- Also to note that the trial outcomes from the recent work done by Hough Ear Institute has not been completed due to them apparently needing funding for the certification phase of this work.

- The biggest issue for Hough Ear Institute is the funding/finance raising. Really to date they have been very confusing and unclear with what they are trying to do with the funds raised, as well as why they need to fund through this manner. Most reasonable investors would not be interested in investing even if their work is positive because their case behind why people need to invest is unclear. There is most certainly something missing when it comes to the business side of their operations and if there isn't, there is something that needs urgent rectification.

 

[patorjk]

- Also wasn't it the case that the Otonomy OTO-413 trial did not test for tinnitus?

In a recent Tinnitus Talk Podcast @Hazel asked Dr. Webber and Dr. Foster if anyone reported any improvement in their tinnitus. They said no.

33% (1 in 3) of the trial's patients had tinnitus. 10 people got the full dose of the drug, 21 people got various smaller doses, and 8 people got the placebo. Yes, this is a small sample size, but I feel like someone would have said something if there was some kind of effect.

 

[tommyd87]

In a recent Tinnitus Talk Podcast @Hazel asked Dr. Webber and Dr. Foster if anyone reported any improvement in their tinnitus. They said no.

33% (1 in 3) of the trial's patients had tinnitus. 10 people got the full dose of the drug, 21 people got various smaller doses, and 8 people got the placebo. Yes, this is a small sample size, but I feel like someone would have said something if there was some kind of effect.

Thanks. I had not seen that tinnitus was commented on in the original trial results.

Can you show me where in the transcript it says this as I cannot see any mention of tinnitus in the OTO-413 section?

 

[patorjk]

Thanks. I had not seen that tinnitus was commented on in the original trial results.

Can you show me where in the transcript it says this as I cannot see any mention of tinnitus in the OTO-413 section?

Here's the text from the transcript: (page 21)

Hazel: Were there, so far that you are aware of any anecdotes amongst patients regarding tinnitus or maybe hyperacusis?
Alan: So no, and again, it was a fairly small study population, but no, we didn't receive any anecdotes of that kind. I think in the patient population, we had maybe one in three actually reported to some degree of tinnitus, so it was a fairly small number, so we wouldn't really expect to learn much from that.​

 

[tommyd87]

Here's the text from the transcript: (page 21)

Hazel: Were there, so far that you are aware of any anecdotes amongst patients regarding tinnitus or maybe hyperacusis?
Alan: So no, and again, it was a fairly small study population, but no, we didn't receive any anecdotes of that kind. I think in the patient population, we had maybe one in three actually reported to some degree of tinnitus, so it was a fairly small number, so we wouldn't really expect to learn much from that.​

Looking at the comments from Otonomy, it seems like they aren't able to comment and/or determine whether the medicine has any impact on tinnitus or not at this point.

 

[patorjk]

Looking at the comments from Otonomy, it seems like they aren't able to comment and/or determine whether the medicine has any impact on tinnitus or not at this point.

I quoted the numbers for the study above. 31 people were dosed with various levels of OTO-413. ~10 of these people had tinnitus and none of them reported back to their ENT that their tinnitus improved. FX-322 had a similarly small study and there were anecdotes of improved tinnitus. Obviously this isn't definitive, but it's 10 data points and that's interesting.

Now to go into speculation territory, Otonomy has this interesting chart in their corporate presentation that shows Inner Hair Cell loss and Auditory Nerve Fiber loss (synapse loss) as we age:

They also state that evidence suggests that cochlear synaptopathy occurs earlier than hair cell loss. Most older people don't have tinnitus, but they do have hearing loss. This leads me to think that cochlear synaptopathy is probably not a reason for tinnitus, otherwise a lot more people would have it.

I could be wrong, and future studies (especially Otonomy's extended Phase I/II OTO-413 study due out next summer) will be able to shed more light on this, but as things stand right now I'm very skeptical on cochlear synaptopathy drugs helping tinnitus - and thus skeptical on the Hough Ear Institute Pill.

 

[tommyd87]

I quoted the numbers for the study above. 31 people were dosed with various levels of OTO-413. ~10 of these people had tinnitus and none of them reported back to their ENT that their tinnitus improved. FX-322 had a similarly small study and there were anecdotes of improved tinnitus. Obviously this isn't definitive, but it's 10 data points and that's interesting.

Now to go into speculation territory, Otonomy has this interesting chart in their corporate presentation that shows Inner Hair Cell loss and Auditory Nerve Fiber loss (synapse loss) as we age:

View attachment 46485

They also state that evidence suggests that cochlear synaptopathy occurs earlier than hair cell loss. Most older people don't have tinnitus, but they do have hearing loss. This leads me to think that cochlear synaptopathy is probably not a reason for tinnitus, otherwise a lot more people would have it.

I could be wrong, and future studies (especially Otonomy's extended Phase I/II OTO-413 study due out next summer) will be able to shed more light on this, but as things stand right now I'm very skeptical on cochlear synaptopathy drugs helping tinnitus - and thus skeptical on the Hough Ear Institute Pill.

I have seen indications which suggest the opposite when it comes to tinnitus that it is often present in older people.

The Hough Ear Institute Pill is interesting. It apparently just doesn't solely have medicine for synapses alone according to what they have put out and while I think that there will be benefit from synapse regeneration, I don't think it will be as effective as a medicine like an FX-322 or similar which works with both.

 

[star-affinity]

This leads me to think that cochlear synaptopathy is probably not a reason for tinnitus, otherwise a lot more people would have it.

Maybe not for everyone, but for some?

Tinnitus is definitely triggered in conjunction with hearing loss for some people. I'm one example of that – seems my pitch of tinnitus corresponds approximately to the hearing loss frequency. I actually heard the onset happen. My ear did a two, three second "warped chirp" that then immediately faded into to a high-pitched hiss/sizzle that's been going on for 4.5 months now.

Maybe there's also a difference to how the brain reacts to the synaptopathy if the synapse disconnects/dies gracefully of old age compared to if it's damaged or "disconnected somewhat" from auditory overstimulation?

Just a thought...

But I also hear from ENTs that there are people who hear the tones in a hearing test where their tinnitus is at, i.e. they don't have hearing loss (in a classical audiogram test), but do have tinnitus (like how my right ear seems to behave). It sure is confusing...

 

[Tau]

But I also hear from ENTs that there are people who hear the tones in a hearing test where their tinnitus is at, i.e. they don't have hearing loss (in a classical audiogram test), but do have tinnitus (like how my right ear seems to behave). It sure is confusing...

My case is like that. No threshold shifts larger than 10 dB, but I have cochlear neuropathy and blaring tinnitus sounds. I can hear all tones up to 18 kHz with my right ear and up to 16 kHz with my left ear. I do think synaptogenesis would help in this case.

 

[Gb3]

My case is like that. No threshold shifts larger than 10 dB, but I have cochlear neuropathy and blaring tinnitus sounds. I can hear all tones up to 18 kHz with my right ear and up to 16 kHz with my left ear. I do think synaptogenesis would help in this case.

You just have hearing loss that a standard audiogram can't detect.

 

[Silvio Sabo]

Maybe not for everyone, but for some?

Tinnitus is definitely triggered in conjunction with hearing loss for some people. I'm one example of that – seems my pitch of tinnitus corresponds approximately to the hearing loss frequency. I actually heard the onset happen. My ear did a two, three second "warped chirp" that then immediately faded into to a high-pitched hiss/sizzle that's been going on for 4.5 months now.

Maybe there's also a difference to how the brain reacts to the synaptopathy if the synapse disconnects/dies gracefully of old age compared to if it's damaged or "disconnected somewhat" from auditory overstimulation?

Just a thought...

But I also hear from ENTs that there are people who hear the tones in a hearing test where their tinnitus is at, i.e. they don't have hearing loss (in a classical audiogram test), but do have tinnitus (like how my right ear seems to behave). It sure is confusing...

I think most who consider tinnitus to be disconnected from hearing loss use an audiogram and think "I have no hearing loss, but I have tinnitus. Therefore tinnitus is not connected to hearing loss".

However it's not as simple as that. Audiograms are really blunt tools and hearing loss comes in many forms. Even when you have hearing loss in a certain frequency it's not 0% or 100%. It's gradual. People who have hearing loss in certain frequencies are seldom completely unable to hear sound in that frequency. If the sound is loud enough they will probably be able to hear it. So it's not just frequency. It's frequency AND volume. So you might be able to hear 20 db sounds at 4 kHz but it takes at least 60 db at 12 kHz for you to pick up the sound.

I strongly believe that tinnitus is connected to hearing loss in probably 99% of the cases. It's just that the hearing loss might be so slight or of a different kind that doesn't affect the ability to pick up pure tones and is therefore not picked up by an audiogram.

Oh, and most audiograms only go up to 8 kHz which is not even remotely close to the 20 kHz that the human hearing organ is normally capable of.

 

[Tau]

You just have hearing loss that a standard audiogram can't detect.

My extended audiograms are fine. I literally hear 16 kHz at 0-5 dB. It's synapses - I am not saying I don't have hearing loss, I do, I hear stupid beeping sounds over everyday noise and music sounds like trash, but I do hear all the instruments. Auditory brainstem response test show that I have neuropathy/synaptopathy. Maybe there's a dead hair cell here and there, but I don't have big threshold shifts. So I am hoping that BDNF or NT-3 injections can help.

 

[star-affinity]

Auditory brainstem response test show that I have neuropathy/synaptopathy.

Wow, can you conduct a test to figure out if you have synaptopathy? I didn't know that. Would be interesting to know how I fare on that.

 

[Tau]

Wow, can you conduct a test to figure out if you have synaptopathy? I didn't know that. Would be interesting to know how I fare on that.

I probably have lost more synapses than the classic 'can't-hear-in-noise' person because I have clear sound distortions. After my initial trauma ABR showed nothing, a month after - clear neuropathy (with no additional trauma - strange). I am lucky to have an experienced otologist who ran custom ABR tests, not just a standard 2 kHz click, or whatever it is. After my MRI I have clearly lost even more synapses, but she did not want to do another ABR for fear it might cause more damage as I have moderate hyperacusis now. I will get retested before my stem cell secretome treatment to establish a baseline.

To sum up, if you have speech-in-noise difficulty and that's it, an ABR test will most likely not show anything unless you do suprathreshold tests, but almost no otologist can do that.

 

[patorjk]

I probably have lost more synapses than the classic 'can't-hear-in-noise' person because I have clear sound distortions. After my initial trauma ABR showed nothing, a month after - clear neuropathy (with no additional trauma - strange). I am lucky to have an experienced otologist who ran custom ABR tests, not just a standard 2 kHz click, or whatever it is. After my MRI I have clearly lost even more synapses, but she did not want to do another ABR for fear it might cause more damage as I have moderate hyperacusis now. I will get retested before my stem cell secretome treatment to establish a baseline.

To sum up, if you have speech-in-noise difficulty and that's it, an ABR test will most likely not show anything unless you do suprathreshold tests, but almost no otologist can do that.

Can you explain what a suprathreshold test is? If it measures synaptopathy then it's kind of odd that Otonomy isn't using it. From my understanding the ABR test is like an audiogram test. A few months ago when I asked Otonomy about data from these tests (the preclinical and audiograms from Phase I), they told me:

Thanks for the question. We are still doing standard audiograms as part of the safety assessment. For preclinical studies, we used auditory brainstem response (ABR's) because that's the only way to measure hearing function in animals. Since the primary mechanism of action of OTO-413 (BDNF) is repair of the neuronal connection, this is best assessed by evaluating speech-in-noise tests. That is why we focused on these tests in reporting a therapeutic effect in our proof-of-concept trial and why we are focusing on these tests going forward. We will report the audiogram results from a safety perspective.​

 

[Tau]

@patorjk:

Hidden hearing loss, a disorder with multiple etiologies and mechanisms

"The auditory defects associated with HHL have been demonstrated in animal models by detection of changes in neural responses to sounds with intensities above hearing thresholds (suprathreshold sounds) in the absence of changes in sensitivity (threshold shifts). Early studies in mice indicated that moderate noise exposures that induce temporary threshold shifts (TTS) do not induce hair cell death, but rather result in decreased responses to suprathreshold sounds that persists after thresholds recover. The observation that the decreased amplitude in the response to suprathreshold sounds correlates with the loss of a subset of synaptic connections between IHCs and AN fibers in the cochlea led to the notion that noise-induced synaptopathy causes HHL (Kujawa and Liberman 2009)."

Some info here, too:

Hidden versus Not-so-Hidden Hearing Loss

The problem is that none of these are completely reliable yet.

 

[patorjk]

@patorjk:

Hidden hearing loss, a disorder with multiple etiologies and mechanisms

"The auditory defects associated with HHL have been demonstrated in animal models by detection of changes in neural responses to sounds with intensities above hearing thresholds (suprathreshold sounds) in the absence of changes in sensitivity (threshold shifts). Early studies in mice indicated that moderate noise exposures that induce temporary threshold shifts (TTS) do not induce hair cell death, but rather result in decreased responses to suprathreshold sounds that persists after thresholds recover. The observation that the decreased amplitude in the response to suprathreshold sounds correlates with the loss of a subset of synaptic connections between IHCs and AN fibers in the cochlea led to the notion that noise-induced synaptopathy causes HHL (Kujawa and Liberman 2009)."

Some info here, too:

Hidden versus Not-so-Hidden Hearing Loss

The problem is that none of these are completely reliable yet.

I'll have to dig into this deeper later on, thank you for the links! One interesting aside was this bit:

However, more recent findings indicate that other causes of HHL exist, including cochlear demyelination (Wan and Corfas 2017, Choi, Seok et al. 2018) and possibly mild or persistent hair cell dysfunction (Hoben, Easow et al. 2017, Mulders, Chin et al. 2018)​

So hidden hearing loss can be caused by more than just synapses dying off. Unless I'm reading something wrong there doesn't seem to be a way to tell synaptopathy from these other two types of damage. This isn't great news for Otonomy, though I'm guessing most HHL is due to synapse damage.

Assuming OTO-413 works, next year we'll have a better idea on if repairing synapses does anything for tinnitus.

 

[evrmre]

@patorjk, although it would be great for Otonomy to treat most hearing loss, they really only need to demonstrate consistent reproducible results of hearing regeneration in a subset of hearing loss sufferers to be successful. If they can greatly improve hearing in people with hair cell dysfunction but not synapse damage, that will still be one of the greatest medical breakthroughs of the century and most certainly secure them more funding. They have plenty of time to investigate why their treatments succeed in some and fail in others. It's succeeding in anyone that is the first big step.

 

[Diesel]

@patorjk, although it would be great for Otonomy to treat most hearing loss, they really only need to demonstrate consistent reproducible results of hearing regeneration in a subset of hearing loss sufferers to be successful. If they can greatly improve hearing in people with hair cell dysfunction but not synapse damage, that will still be one of the greatest medical breakthroughs of the century and most certainly secure them more funding. They have plenty of time to investigate why their treatments succeed in some and fail in others. It's succeeding in anyone that is the first big step.

Signed in just to give you a quick winner. Glad to see someone else on this forum "gets" how drugs come to market. Talk to you all later.

 

[tommyd87]

You just have hearing loss that a standard audiogram can't detect.

This isn't necessarily true. A lot of people have hearing loss from the audiogram perspective and no tinnitus.

 

[patorjk]

I listened to the latest Piper Sandler interview from Otonomy and they gave a short but interesting update on OTO-6XX. They mentioned that it's geared towards repairing the damage to the hair cells and that it won't regenerate hair cells. Dr. Weber finished up his brief words on OTO-6XX by stating "so there's more that we'll be coming forward with that we think is a very novel approach that really doesn't require the hurdles that regeneration does".

So whatever they're working on sounds very different from what Frequency Therapeutics and Decibel Therapeutics are working on. Dr. Weber also mentioned that they were doing some "gate keeping" to maintain focus (this was in reference to OTO-510). I'm guessing if they can get some wins under their belt with OTO-313 and OTO-413 they'll then move forward with OTO-510 (which sounds like it's ready) or OTO-6XX (which sounds like it's still being worked on but maybe is getting closer to be ready?).

 

[Diesel]

"gate keeping"

That's business speak for ... "we can't afford to do it all right now."

The update on OTO-6XX is interesting. What exactly gets repaired at this point? The stereocilia? Isn't that still technically regeneration since they don't self-regrow?

It's an interesting idea to position more drugs to treat different stages of acquired hearing loss, and probably a good one from a business standpoint. So now there's a potential future state for synaptopathy (OTO-413), repairing "heavily worn" cells (OTO-6xx), and if they're gone completely (since you can't regrow synapses or fix damage), FX-322/345.

 

[patorjk]

That's business speak for ... "we can't afford to do it all right now."

The update on OTO-6XX is interesting. What exactly gets repaired at this point? The stereocilia? Isn't that still technically regeneration since they don't self-regrow?

It's an interesting idea to position more drugs to treat different stages of acquired hearing loss, and probably a good one from a business standpoint. So now there's a potential future state for synaptopathy (OTO-413), repairing "heavily worn" cells (OTO-6xx), and if they're gone completely (since you can't regrow synapses or fix damage), FX-322/345.

Yeah, I was thinking the same thing when he said that. OTO-825 has been ready for a while now and the only reason to put its IND in 2023 is to make sure there's money for it. OTO-510 also looks like it's been ready for a while now too.

They didn't really mention anything else specific about how OTO-6XX would work. They did state that they have looked into regeneration pretty deeply and that they believe it's a complex issue that would involve more than just using a small molecule (which to me seemed like an FX-322 reference, but I may be reading too much into his wording?). Hopefully they'll spill the beans on what they're doing in the coming months, but I have a feeling they won't be doing that until they've passed some of their upcoming milestones and raised some more money.

 

[Nobody19]

That's business speak for ... "we can't afford to do it all right now."

Their failed Meniere's drug probably hit them pretty bad financially.

 

[Eliot Martin]

When is this drug entering clinical trials? Anyone have any idea about this? If this drug is complementary to OTO-413, they should be working on OTO-6XX instead of OTO-510 and OTO-825.

People like Bill Gates and Elon Musk should fund Otonomy so they could speed up the process of their drug development.

 

[Exit]

When is this drug entering clinical trials? Anyone have any idea about this? If this drug is complementary to OTO-413, they should be working on OTO-6XX instead of OTO-510 and OTO-825.

People like Bill Gates and Elon Musk should fund Otonomy so they could speed up the process of their drug development.

My understanding is that they've put it on ice because it's a very complex problem to regenerate the hair cells and they need many more years to get it working well.

I salute them for being honest and serious.

Although it's not what I like to hear...

 

[patorjk]

I haven't listened to the conference call yet, but I found this in the Form Q-10 document they released today:

Our OTO-6XX program is focused on developing a treatment for severe hearing loss. In July 2020, we entered into an exclusive license agreement with Kyorin Pharmaceutical Co., Ltd. (Kyorin) that provided us with worldwide rights to develop, manufacture and commercialize a novel compound from Kyorin that demonstrated initial potential for hair cell regeneration in preclinical models. After further evaluation, we notified Kyorin in March 2022 of our discontinuation of the development of this compound and intent to terminate the license agreement. Our focus for the OTO-6XX program going forward is centered on the repair of damaged hair cells for the treatment of severe hearing loss.

I figured something was up when I saw milestone payments were due to Kyorin upon completion of certain tasks (like getting it working in a preclinical environment) weren't occurring. They've also been a little coy in previous conference calls and indicated that regeneration has a lot of problems and that repair seems like a better approach. Speaking of which, the addition of the word "repair" to their slides last year was also another clue that something was up, as it seemed to signal they were approaching things from a different angle.

Anyway, it's sad the Kyorin chemical didn't work out, though hopefully whatever they're doing for repair will bear fruit. I haven't yet listened to their conference call today so I don't know if this is talked about.

 

[patorjk]

As a follow-up, I just finished listening to their Q1 Earnings Conference call and OTO-6XX wasn't mentioned. They focused on OTO-413, OTO-313, and OTO-825. The questions from the analysts and investors were all in regards to OTO-413 and OTO-313, probably because these drugs will make or break them and they don't care about stuff that's 5-10 years out (and if OTO-313 fails, I'm guessing Otonomy will too).

It's interesting they slipped the OTO-6XX news into the Q-10. I'm guessing they didn't want to draw any attention to it if they didn't have to. The repair mechanism sounds interesting though, I'm guessing its still in the early stages though (it's first mention in the slides was last March). Hopefully we'll hear more about it later this year.

 

[patorjk]

Sorry for the drip-drip-drip of posts on this one, but news slowly keeps coming out.

They've updated their corporate slide deck and the slide on OTO-6XX is now:

This is pretty interesting. I wonder if the troubles of FX-322 helped shape this decision. Also, I wonder if part of the problem is how these regenerative drugs target cells to regenerate? It's always been unclear to me how a drug would know to replace a dead or damaged hair cell - or if it would even do so if a cell already existed. Maybe their animal studies were showing this to be the case?

I've sent them an email asking if we'll hear about the hair cell repair research anytime this year. I'll post here if they tell me anything. It's looking more and more likely that we'll see a future where we'll need to take multiple drugs to restore hearing (one for synapses, one for damaged hair cells, one to regenerate, one for tinnitus, etc etc).