Otonomy OTO-413 — Treatment of Hidden Hearing Loss

My understanding is the order of operations won't matter much here. Susan's device is targeting neurons misfiring in the brain which can happen whether your tinnitus is caused by acoustic trauma or something else. For people with acoustic trauma, taking a regenerative therapy and also doing Susan's therapy, regardless of order, should long term restore hearing and reduce tinnitus. Susan's device won't help regenerated hair cells rewire back to normal. That will likely be a natural process or one progressed by another treatment.

 

Simple. You just regenerate the cochlea, the brain will then take care of rewiring itself. It's just like if you close your eyes and don't have light input, you'll see blue and red "noise." You restore vision input and the noise goes away. All that needs to be done is regenerating the cochlear damage, that will restore lost input. Same way with how tinnitus began for most, with the physical damage from noise and others to hearing structure, which then results in lost auditory input, and a need for the brain to increase its auditory gain.

 

If only regenerating the cochlea were that easy friend. I actually agree with you that the brain may adapt and fix precious maladaptive tendencies.

 

My main concern with this (which I think others have also pointed out at various times) is, the cohort of people that have cochlear damage, dodgy audiograms etc etc, and yet still don't suffer from tinnitus.

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I believe (and it's only speculation) that in us tinnitus sufferers there's something else further upstream in the brain's audio processing system, (my own simple analogy has me likening it to a flawed electrical component), that has failed, or is in the process of failing.

It may be that in tinnitus patients there is a genetic predisposition within such components for them to fail (I think of this in the same way I think of say, capacitors and resistors that one finds in a basic radio set (tinnitus ears), compared to those one finds in aircraft electronics (non-tinnitus ears). The manufacturing tolerances between these ostensibly similar two sets of components are entirely different.

The reason I've used the phrase 'in the process of failing' is because if our ears undergo a destructive event like cochlear damage, the mechanics of which lead to a 'cooking' of the upstream system (resulting in tinnitus) but not a toasting, then it makes perfect sense to me that repairing the cochlear damage downstream very well may result in normality returning to our hearing system.

If this scenario has worth then the bigger problem to me is, what happens if the cochlear damage results in a permanent component damage upstream - a toasting? In that situation I don't believe any hearing regeneration drug at the cochlear will address the tinnitus precept, however, I do believe there's still light at the end of the tunnel.

My analogy for these upstream electrical components has been born out of what I've read about the KV7 gating channels. I could be completely wrong but it's the explanation of their function that is the only thing that has ever really made sense to me when trying to consider tinnitus as an overall issue rather than one with a single point of focus. Regardless, the good news as we know is that Thanos Tzounopoulos and other researchers are working on pharmacological solutions to KV7 gating problems, and we have at least seen some people here who had good results after going down that particular pharmacological path.

If both options were currently available my path would be, regeneration first, followed by pharmacology if the regeneration failed.

Just to put it out there: I personally don't believe the Shore device will address the underlying issues, however, absent a full on cure I do believe it will bring a massively beneficial dampening of the symptoms, which would be great while we wait for regeneration etc to work their way along the pipeline.

Soz for the long post. My posts are getting longer it seems

 

Does anyone know if damage to synapses can also affect thresholds? Has there been any research showing this?

 

It's been debated. However, Otonomy has not observed improvements in audiometric thresholds with OTO-413. HOWEVER, Otonomy indicates that OTO-413 affects HIGH FREQUENCY hearing loss where there is a hearing-in-noise deficit. So, it's possible that the audiometry isn't measuring into the Extended Frequency Range, where they might see an effect. It's not been disclosed to this detail by Otonomy.

 

During Otonomy's earnings call on Monday February 28th, the President said the following:

"We have completed patient enrollment in the OTO-313 Phase 2 trial in tinnitus ahead of schedule with top-line results for all time points expected in mid-2022. We also fully enrolled the OTO-413 Phase 2a cohort in hearing loss earlier than planned and moved up the timing for top-line results to early in the second quarter of 2022."​

That's sometime in the next 10 weeks.

Here's a link to transcript.

 

All that is good but they say earlier than planned, yet I read those dates last year...

Creative souls in PR?

 

From the Feb 2022 Investor Pres:

 

Original date was mid 2022.

 

Have they said more about the audiometric data? I tried getting that info out of them last year but all they would say was that they'd report that data "from a safety perspective". Their corporate presentation used to have a slide that said even small dB improvements (like 3 dB) could lead to hearing improvements, which made me think that maybe they'd seen a small bump. When BDNF was injected into pigs' ears the pigs had an 11 dB improvement in hearing. Although hearing in noise is separate from loudness/clarity, I think all of these components have some effect on each other.

Also, the 4 cases studies in their corporate presentation seem to show uniform improvement in hearing rather than just high frequency hearing. Though I vaguely remember them talking about this in the last investor call.

I went ahead and shot their IR team an email asking about these, though I haven't heard anything back yet (I'll report if they say something). Usually they're super quick, though when they've taken their time usually it's a sign they can't answer my questions (I'll get an answer when the info is released). Though I've also emailed them 8 times in the last year, so I'm also starting to wonder if maybe they're getting a little sick of me (I am an investor, albeit a small one).

 

I believe the CEO made a comment re: OTO-413 similar to Frequency's CEO about FX-322, that audiometry doesn't tell the whole story / illustrate improvement in hearing. Note that the 4 cases on page 25 all say "high frequency hearing loss" which is often associated with speech-in-noise difficulty. They don't indicate anywhere that OTO-413 is providing robust coverage of the cochlea. The 3 dB they've referred to is an improvement in SNR, not pure-tone.

 

Nothing new from IR, basically just saying what they've said before:

I take it from this that they didn't see improvements in audiometry, or if they did it was small. Though it sounds like they're not even looking at it for efficacy. I suppose we'll know more next month when they have more data to churn through.

As an aside, a week or so ago I asked them for more information on their dose escalation cohorts for OTO-413. The current Phase 2a (formally the extended trial) uses a dose of 0.3 mg. The first high dose trial uses 0.75 mg (2.5 times as much). I asked the following:

Is there more than one dose escalation cohort planned? If so, is there a limit to how high the dose will go? Yes, as we’ve stated publicly, we will evaluate “at least one higher dose” of OTO-413 so will escalate to an even higher dose if safety results for 0.75 mg are supportive. We have not disclosed the dosing above 0.75 mg.​

I find this very interesting. I assume 2.5 times as much medicine (especially when slowly released) is going to have a bigger benefit. Who knows what the next escalation will be. This means if they see good results next month that it's not the whole story, since they're still adjusting the dose for maximum efficacy (I also asked if they were doing the words-in-noise tests for these cohorts and they said yes).

These mini-trials may also act as a safety net if the current Phase 2a trial doesn't pan out well. I've probably said it here before, but I believe that Otonomy may have underdosed Otividex and/or didn't fully understand how slow their slow release gel worked (I'm just a random guy on the internet though so take that will a grain of salt). I have high hopes for the new high-dose mini trials for OTO-413 and OTO-313.

 

I’m glad that OTO-413 timeline is around the same as FX-322. Hopefully, if OTO-413 Phase 2 goes well, they can go to the pivotal phase next, like FX-322.

@patorjk, with OTO-413, are they also doing audiogram tests?

 

Yes, though they haven't released any data related to them and they say they're doing them just for safety purposes (ex: to ensure the drug isn't damaging hearing).

 

So would that mean when Phase 2 trial finishes for OTO-413, they won’t mention anything about audiogram improvements? It would be nice to compare OTO-413 with FX-322 in terms of words in noise, words in quiet and audiogram improvements between the 2 drugs.

 

My guess is they'll only mention it if they see an improvement or if there's an issue with safety. When tested in pigs, there was an 11 dB improvement, so there's some hope that higher doses will yield an audiogram benefit. Speaking of which - I just checked out the slides for their R&D day that took place 2 days ago (I haven't listened to the event yet, I just haven't had time) and on slide 70 they reveal what the second dose escalation of OTO-413 will be:

• Started with 0.75 mg and escalated to 1.50 mg (5x dose used in Phase 1/2 efficacy cohort)

To me this seems to imply they saw no safety issues with 0.75 mg (which was 2.5 times the dose in Phase 1/2). If OTO-413 works, I have to imagine 5x the dose will super charge it. Next month we should see the results of the Phase 2a trial. If the results are good, we should hopefully be in for even better news later this year.

 

When you say even better news later this year, are you talking about the possibility of OTO-413 going into the next phase and then completing that trial near the end of the year?

Hopefully if Phase 2a goes well, they mention something about the next phase being pivotal, similar to what Frequency Therapeutics suggested if the Phase 2 results were successful.

 

The two small dose escalation studies will help decide the dosage for their Phase 2 efficacy trial that begins at the end of this year. With the current dosage they're seeing 20-30% hearing improvement. With 5 times the dosage they might see significantly better results (probably not 5 times as good, but maybe we'll see 50-60% improvement). This is what I mean by even better news. At this dosage we may also see other benefits like tinnitus improvements too - but that's pure speculation on my part (so far there have been no improvements in this area). In my email to their IR team they said they'd only escalate up from 0.75 mg if it was shown to be safe, which it apparently has since they're now trying 1.5 mg. The Phase 2a trial which we'll see results for next month is using 0.3 mg as its dosage.

 

How do you know that they are seeing 20-30% hearing improvements?

 

I really hope increasing the dosage doesn’t affect the regrowing process like FX-322 but that was because of multiple injections whereas OTO-413 is still using single dosage but adding more mg in their dose.

So when did the 0.75 mg and 1.50 mg dose trial start and what month are they expecting for those results?

 

They talk about it in their latest corporate presentation (see slides 20-33):



It's probably more correct for me to say 20%+ improvement in speech intelligibility since OTO-413 deals with hearing-in-noise improvements.

I think they must have already done the 0.75 mg trial, or at least gotten far enough for them to determine it was safe. They talked about starting it in December. The trial length is 3 months, with 12 people taking part in each trial. Results for both of these escalated dosage trials will come in the second half of this year.

 

Audiometry is difficult because you're trying to discern what is essentially a continuous spectrum. If your hearing loss (or tinnitus) is in a very narrow band -- like say 5789-5812 Hz, there's a good chance no audiologist on earth will find the precise band because they'll either be playing beeps, which are too narrow band, or trying to find a broadband masker that is far too broad a band. Could be wrong, I don't actually know the precision of human hearing.

 

I feel like it's half a victory when we have better diagnostic tools. This audiometry and TFI/THI trash needs to go.

 

I think TFI is decent, but as most of us know, volume is what matters, not the psych-obsessed garbage. I don't know if that's a contentious opinion on here, but I've had it so loud it vibrates my head and let me tell you meditation and the like ain't gonna cut it.

 

What would you say the frequency of the tinnitus is that vibrates your head? Low or high?

 

Volume definitely matters. There does seem to be this notion that on bad days, you’re just noticing it more. For me, that is definitely not the case. I can do a level match comparison, and my actual perception of volume is louder on bad days. And bad days are much more bothersome. For me, it’s not louder because I’m more bothered. I’m more bothered because it’s louder.

 

It doesn't literally vibrate my head, obviously, but I mean that it's so horrifyingly loud that it fills every inch of my awareness in the way that excruciating pain does-----somehow it feels like vibration. Frequency comes and goes. I've been in the midst of a horrible noise/stress induced spike since last year with complete remission and then relapse after an additional noise event.

 

Sorry, I understood you meant a sensation of vibration and not actual vibration. I experience this too now from a very low frequency tinnitus that recently developed in the past month. When it ramps up really bad, it feels like my head and body are vibrating. That’s why I was asking what frequency it was.

 

Oof, insider selling.

Actually, yes! Now that you mention it, the frequency that feels like it jumps from CN VIII to one of the facial nerves (literally feels physical) is a lower pitch ringing.