Otonomy OTO-413 — Treatment of Hidden Hearing Loss

Is this relating to OTO-413?

 

I wish the same thing as most of us don't have infinite resources to experiment in this manner. Finances for me are limited, and I'd hate to spend everything I have on for example FX-322 and find that I actually need PIPE-505, or OTO-413 instead.

 

I reckon you can get testing done for both speech in noise and an audiogram and see how your results come out. You might need both treatments. But basically if you have hair cell loss then I'd invest in FX-322 first because it is going to treat the synapse/cell component together. Then this will allow you to see if you still have speech in noise issues and/or tinnitus, then you can treat it utilising something like OTO-413.

 

On August 4th they mentioned they were almost done with enrollment [1]. The study takes 12 weeks, so the earliest they could be done is October 27th. For their OTO-313 drug, they announced completion in one of their news updates and said they were working on "conducting study completion activities". This took 3 weeks, and once they were done they posted the positive updates about the drug. So my guess is that ~4 weeks after October 27th we'll see an update from them regarding OTO-413, so probably at the end of November.

[1] https://investors.otonomy.com/news-...rts-second-quarter-2020-financial-results-and

For some odd reason Otonomy is targeting people with only mild hearing impairment for OTO-413. The FX-322 trial is open for people with moderately severe hearing loss though. However, if you're deaf, you're basically out of luck at this point as far as getting into a trial. It think these drugs will work nicely for that group though - but I think companies are avoiding them because it may be harder to get the results they need to show significance.

Also, as an aside, I was looking closer at the study page and it looks like patients will undergo "electrophysiological test of auditory brainstem response to auditory stimuli". This sounds very similar to the hearing tests that were given to guinea pigs that showed that BDNF improved hearing.

 

I am excited for the end of November.

 

This makes sense and is good info, thanks. I think they are testing people only with mild hearing issues is because it is the easiest way to get the medicine pass the regulatory approval process. I'm pretty sure it will help a wider range of people and Otonomy does too.

By using a mild hearing loss group they theoretically can show that the hearing thresholds can improve enough because they will probably get the best response from the treatment. People with moderate-severe hearing loss will get benefit from the treatment, however I also believe that they won’t improve as much as they will with taking this treatment in conjunction with OTO-6XX.

Otonomy also acknowledges this in one of their statements on the medicine and therefore I think that there tends to be a high likelihood that this will work more broadly than just for the those that are participating in the trial.

 

This is good and positive. It seems Otonomy is actually focused on assisting customers and also delivering them a positive experience too. Thanks for this Markku.

 

That's great to read! Not to volunteer, but it would be great to see a similar format as the Frequency Therapeutics interview, where @FGG did a follow-up segment.

 

Wait, were you wanting to do this? Because it looks like you live near @mrbrightside614.

 

Yesss, you know it's a good sign when companies accept the invitation because it means they're ready to get grilled.

 

I’m happy to help... but I’m volunteering you... nudge nudge .

P.S. I am in the 614... so probably not far!

 

I'm kind of wondering when Otonomy said that OTO-413 increased hearing in the lower frequencies, if that could have been related to TTTS, and that if you repair the synapses it stops the spasms/low tone drone noise, which helps with low tone hearing loss.

 

Yeah, this is majorly positive and also actually tells me that they have faith and also belief in their products.

 

I could be wrong but there is usually a rough improvement of 0-15 dB with a synapse medicine based off of what we have found out with other examples.

Hough Ear Institute has claimed similar results with their pill too.

The theory I have is that when you repair the synapses and actually connect stuff back together you'll get a more complete hearing process. Thus this means that you will improve by ensuring that the functioning hair cells have all got synapses connected with them then and thus sound goes through your ear in the normal way.

On the other hand, FX-322 will do the exact same stuff but it is going to regrow them all from scratch, so hence why you will get a bigger benefit from the hair cell medicine comparatively.

 

I don't think we can say for sure the 0-15 dB improvement was from synapse repair in Hough's case. It may be because of the anti-inflammatory results since the drug was also given within 6 months.

But the good thing is Otonomy might be answering this question with OTO-413.

 

https://investors.otonomy.com/static-files/5d9cb779-996b-49b3-b162-8285d00b6e71

In looking at the Before/After BDNF treatment (page 28). Two things stand out to me:

1. It appears there are MORE synapses after BDNF treatment than "Normal."

2. There is still some slight degradation in auditory function after BDNF treatment.

So,

1A. How could the synapse count be above normal?
1B. Would the extra synapses mean "extra" durability at the connection going forward?

2A. Could the slight degradation in auditory function imply damage/wear to the stereocilia of the hair cells?

As it relates to the outcomes of the OTO-413 trial:

If OTO-413 does succeed in "synaptogenesis" as intended, wouldn't some of the re-synapsing occur with already worn cells? Wouldn't that also cause a fairly large variance in performance (audiogram, word score, etc) after treatment?

I am certainly looking forward to this drug working, just curious if the results will be as statistically significant as FX-322, since some of the reconnected parts are presumably "worn" already.

 

I think it's more likely that the high frequency OHC loss just isn't accounted for after they induced the hearing loss with noise:

"Using ABR wave I amplitude as an indicator of synaptopathy is further complicated by the fact that high frequency OHC loss also reduces ABR wave I amplitude by decreasing the contribution of high frequency AN fibers to the ABR generation (e.g., Lewis et al., 2015;Verhulst et al., 2016). "

 

That is a plausible point, however I had read that the treatment of synapses does do some restoration of hearing ability from an audiogram perspective although I could be wrong too. I totally agree about the OTO-413 giving us an answer to this question though.

 

Looks like Otonomy is getting hammered this morning (-8% at the moment). Frequency Therapeutics is also down (-4%), so some of the drop may just be the market right now, but I wonder if the larger drop for Otonomy has anything to do with the news update they posted today:

On the surface that doesn't look bad, but I wonder if people are fearful that OTO-413 isn't going to have good results. Also, what kind of Corporate Update could be announced next week? My thoughts:

* An announcement about the results of OTO-413.
* An announcement about the end of the OTO-413 study. As I mentioned previously, October 27th is the earliest it could have ended, and this is only if they were able to fill the remaining spots the day they posted their update.
* An announcement about OTO-6XX.
* An announcement about future study plans for other Otonomy drugs.
* Some kind of deal they've made with another company.

 

This Quarter-End update they posted is completely boilerplate. The market/stocks are almost always volatile leading up to a US Presidential Election. Add COVID-19 news, and stocks are going to nosedive. My expectations are a brief update on the trials in-progress or ending soon.

 

Personally, *especially* on days with IBB drops, I don't assign significance.

 

There is nothing even indicating that results are going to be reported next week for any medicine that Otonomy is working on.

The analysis about volatility leading into the US election is very valid, as even I had one of my online trading support guys ring me to let me know about some stuff they could offer me to help me avoid risks associated with volatility in the lead up to the US election.

Essentially I don’t see these price drops in the stock as bad, especially when there has been a flat across the board fall in not only the NASDAQ but the biotech sector as a whole too.

 

Looks like they closed 2% up today, so the negative swing really was nothing.

It looks like it's standard for them to give a week's notice before posting their financial results, so no real story here. My guess is it'll follow a similar pattern to previous updates. I don't think the OTO-413 results will be ready (whether positive or negative) by the 4th.

 

fwiw, actually completely retraced the loss and finished up 2%. Makes no sense but I'll take it.

 

It is incredibly likely it is just daily volatility that is being caused by a mixture of things that include COVID-19, the economy generally, and also the election. Essentially I expect that we will widely continue to see fluctuations both up until the time that the treatment results come out and even after a treatment is successful.

These fluctuations are almost always guaranteed with shares anyway regardless of the time it is.

 

Otonomy’s financial results will be poor anyway regardless because they have only one functional medicine at the moment that can be purchased and they are having to pump heaps of cash into things like the trials. Thus there is unlikely to be positive positions taken on Otonomy’s financial reporting by the market and/or investors until they get more medicines out for sale or they get success with one of their medicines which are going to generate more significant sales like the OTO-6XX.

I also agree that the trial results are not likely to be out soon. In fact I would think that there is a possibility that this mightn’t be till December.

 

Otonomy had a conference call today to talk about their treatments and about their financial results.

These are some of the main points:

FINANCIAL:

Otonomy stated that they are in a suitable financial position to fund their costs and operate for the next two years.

TREATMENTS:

OTO-104/Otividex for Meniere’s Disease

- They have had more patients enroll the trial, required by the FDA. This is beneficial because they can still demonstrate a strong patient cohort was dosed and are also able to account for the inevitable dropouts which they may have during the trial.

- The patient cohort is highly motivated and as a result this shall help with outcomes because it will assist compliance with the trial requirements and also mean participants will complete the trial.

- Using a negative binomial regression model to conduct statistical analysis of the results.

- Right now Otonomy are on track to complete current phase 3 trial in Q1 of 2021.

- If this final trial turns out to be successful then an application will be filed with the FDA to obtain approval at some point in Q3 of 2021.


OTO-313 for Tinnitus:

- Positive results in the phase 1/2 trial after the dosing period.

- Improvements have seemingly been maintained even after the trial.

- Single dose of the medicine was well tolerated and delivered better treatment outcomes and fewer adverse effects when compared to the placebo.

- Filed for the Type C Meeting with the FDA for approvals to proceed with a phase 2 trial. The 75 day deadline which the FDA has to respond to this request has not been met yet and as a result Otonomy is still waiting for an answer.

- Otonomy is looking to commence the phase 2 trial as early as possible next year.

- Possibly evaluating changes to criteria for participation to expand eligibility (eg: longer tinnitus onset time) in order to get a better understanding of the benefit of this medicine.

- Looking at gaining FDA approval for a bigger dose to be used in phase 2, since the medicine is well tolerated and fairly safe.

- OTO-313 will hopefully be used with OTO-104 (Otividex) to assist Meniere’s patients as tinnitus is a byproduct.


OTO-413 for Hidden Hearing Loss

- First time BDNF has been used as a treatment for synapses and according to Otonomy’s understanding it will assist at maintaining and also actually reconnecting synapses.

- Current phase 1/2 trial is happening now, with results to be completed and released by the end of this year.

- Doses are a mixture of volumes of the medicine and a placebo group. The large dose group got 15 participants enrolled in it.

- Otonomy is not just wanting to see that the big dose group had improvement but is hoping that all groups who got OTO-413 show improvement. It was stressed though that this is a safety trial and thus the safety of the treatment is the primary purpose of the trial.

- Otonomy stated that most people in the current trial have normal/near normal hearing according to the audiogram although this is for trial purposes.

- Otonomy said that there is no recognised testing method for speech in noise testing like there is for tinnitus with the TFI. Thus they have come up with relevant tests to test the benefit of the medicine.

These tests include speech and numbers in noise and they strongly believe that these will certainly demonstrate the benefits of the medicine to the FDA. Patients will also keep a log to note their personal perceptions of improvements in their normal routines.

- Otonomy hopes to proceed to a phase 2 trial next year if the current trial turns out to be successful.


OTO-510 for Cisplatin-Induced Hearing Loss:

- Simply stated what this treatment is for (hearing loss caused by Cisplatin in cancer treatments) and that they have moved forward in the preclinical phase and will be looking to get this to a position where they can conduct trials.


OTO-6JB2 for Genetic Hearing Loss:

- Have selected the compound for this medicine and it is an AAV treatment.

- This is for one of the most common genetic hearing loss causes.


OTO-6XX for Hair Cell Regeneration:

- Entered into their agreement with Kyorin to purchase the license for the compound contained in the medicine.

- Will work with the treatment of severe hearing loss.

- Stated that OTO-6XX is to be used in conjunction with OTO-413.


Other Comments made by Otonomy in the Q&A (some have been addressed in the medicine information above):

- Otonomy was asked about how they and their treatment differed from another company with massive investment currently undergoing a phase 2 trial (Frequency Therapeutics).

Otonomy did not say much about anything relating to the medicine they are working on nor about anything to do with the medicines Frequency Therapeutics are working on either.

Essentially what Otonomy did say are the two ways which they stand out from their perspective are:

- That they are working across all relevant treatment areas and are hoping to and intending to provide a treatment to all ear matters.

- Otonomy believes their drug delivery method is superior. They believe that they can get their treatments covering all areas of the ear and that this will mean that they can deliver a comprehensive treatment.

Furthermore they believe that the effectiveness of the dosing will mean that they can get better outcomes from a single dose of any treatment. This means that the patient will benefit because they will get better outcomes from the medicine and also will hopefully require fewer visits to complete a treatment course.

 

Phase 1/2 results are supposed to come out at the end of the month, right? I know the Tinnitus Talk Podcast is coming soon and I figure it will be done after they break the news. Hopefully they have some good stuff to present.

 

Here's a bit more from what he said about the drug delivery (specifically in response to the question about Frequency Therapeutics):

I wish he would say more about how deep they're able to get in the ear. I feel like they've said it before, and I would assume they can reach far down, but it would be huge if they can show they're able to treat the lower frequencies.