Otonomy OTO-413 — Treatment of Hidden Hearing Loss

[wwtsai]

I wonder what that means for OTO-413. Does Otonomy really have nothing in the pipeline now that their drugs have failed in the clinical trials.

This really sucks for Otonomy. I guess Frequency Therapeutics will be the only company that is ahead in the hearing loss regeneration game. I pray FX-322 will solve all our issues.

Otonomy has enough funding to at least get through the next set of trials for OTO-313 and OTO-413.

 

[spacehunter]

Considering the series of bad news from Otonomy: what are our alternatives of drugs curing already existing and chronic synaptic damage?

 

[nocticolor]

Well, that bodes poorly...

 

[Aaron91]

Jay Lichter, the founder of Otonomy and the Chairman of its board of directors, has sold all of his shares in the company over the last week:

https://investors.otonomy.com/node/9931/html
https://investors.otonomy.com/sec-filings

It really looks like he's bailing, like he's lost faith in the company. Either that or maybe he's just really upset that it will no longer have a drug for Ménière's (which he has).

I would be more inclined to believe the latter than the former. I'm actually wondering if we might see a resignation to follow, and whether this could be a less a case of him bailing and more a case of the board forcing him out.

Jay has been the face of Otonomy in pitching to investors for the now twice failed Otividex. As someone who has Meniere's he's probably pulled some heart strings in his pitching and in many ways was the perfect candidate for doing that. But moving forward, the company needs cash, and I think it would be difficult for investors to trust Jay knowing that his heart might be overriding his head in his decision-making (not saying this is the case, but it's certainly a plausible interpretation one could make). Otividex has failed twice now and they need someone that people won't associate with that track record: "Yes Otividex failed, but we have a new CEO now and <insert reasons for why you should invest your money here>"

Cash flow will be huge problem in 2 years from now and in reality they will probably need it well before then, otherwise other board members and employees might jump ship as well.

Here's another speculation. I wonder if Jay has had some legal agreements in place over the years that have allowed him to take Otividex himself to manage his own condition. If so, perhaps he really feels the drug works and can't understand why it's failed twice, and has maybe even pushed the board a third time to take Otividex to Phase 3. If so, I can't see how that would end well.

 

[FGG]

I would be more inclined to believe the latter than the former. I'm actually wondering if we might see a resignation to follow, and whether this could be a less a case of him bailing and more a case of the board forcing him out.

Jay has been the face of Otonomy in pitching to investors for the now twice failed Otividex. As someone who has Meniere's he's probably pulled some heart strings in his pitching and in many ways was the perfect candidate for doing that. But moving forward, the company needs cash, and I think it would be difficult for investors to trust Jay knowing that his heart might be overriding his head in his decision-making (not saying this is the case, but it's certainly a plausible interpretation one could make). Otividex has failed twice now and they need someone that people won't associate with that track record: "Yes Otividex failed, but we have a new CEO now and <insert reasons for why you should invest your money here>"

Cash flow will be huge problem in 2 years from now and in reality they will probably need it well before then, otherwise other board members and employees might jump ship as well.

Here's another speculation. I wonder if Jay has had some legal agreements in place over the years that have allowed him to take Otividex himself to manage his own condition. If so, perhaps he really feels the drug works and can't understand why it's failed twice, and has maybe even pushed the board a third time to take Otividex to Phase 3. If so, I can't see how that would end well.

I remember reading an interview where his desire to help Meniere's sufferers, in particular, and his connection with the suffering of those with the disease was cited as a reason for founding the company. You could really be onto something here.

 

[tequilaman69]

I would be more inclined to believe the latter than the former. I'm actually wondering if we might see a resignation to follow, and whether this could be a less a case of him bailing and more a case of the board forcing him out.

Jay has been the face of Otonomy in pitching to investors for the now twice failed Otividex. As someone who has Meniere's he's probably pulled some heart strings in his pitching and in many ways was the perfect candidate for doing that. But moving forward, the company needs cash, and I think it would be difficult for investors to trust Jay knowing that his heart might be overriding his head in his decision-making (not saying this is the case, but it's certainly a plausible interpretation one could make). Otividex has failed twice now and they need someone that people won't associate with that track record: "Yes Otividex failed, but we have a new CEO now and <insert reasons for why you should invest your money here>"

Cash flow will be huge problem in 2 years from now and in reality they will probably need it well before then, otherwise other board members and employees might jump ship as well.

Here's another speculation. I wonder if Jay has had some legal agreements in place over the years that have allowed him to take Otividex himself to manage his own condition. If so, perhaps he really feels the drug works and can't understand why it's failed twice, and has maybe even pushed the board a third time to take Otividex to Phase 3. If so, I can't see how that would end well.

Since I'm so invested in this (still) obviously I've given the Lichter sales a ton of thought. He's the founder and Chairman, he also owns a VC fund that invests in early stage biotechs. He dumped close to 2m shares after the P3 failure which is a terrible look, especially since there hasn't been any insider buys or sells in over 4 years by ANYBODY.

Obviously, not knowing how they raise funds or sell to institutions, Lichter is not the CEO, David Weber is. How responsible is he for the 2 failures? No-one really knows. I can't imagine though, Lichter selling his shares and staying on board as Chairman, however. I mean, he seems like a wealthy guy, did he need the money that bad, he needed to dump at this time, or is he jumping ship? I would assume the latter, which obviously for investors is pretty bad.

The whole thing is very confusing though, as they have such strong institutional ownership, almost 90%, which I rarely see for a "tiny" biotech like this... did they all get duped???

 

[Aaron91]

Since I'm so invested in this (still) obviously I've given the Lichter sales a ton of thought. He's the founder and Chairman, he also owns a VC fund that invests in early stage biotechs. He dumped close to 2m shares after the P3 failure which is a terrible look, especially since there hasn't been any insider buys or sells in over 4 years by ANYBODY.

Obviously, not knowing how they raise funds or sell to institutions, Lichter is not the CEO, David Weber is. How responsible is he for the 2 failures? No-one really knows. I can't imagine though, Lichter selling his shares and staying on board as Chairman, however. I mean, he seems like a wealthy guy, did he need the money that bad, he needed to dump at this time, or is he jumping ship? I would assume the latter, which obviously for investors is pretty bad.

The whole thing is very confusing though, as they have such strong institutional ownership, almost 90%, which I rarely see for a "tiny" biotech like this... did they all get duped???

Apologies, I have a bad habit of using the terms interchangeably!

I think all signs are pointing to Otonomy having made a very firm decision to focus on their other drugs, and I can imagine that given Jay's passion for Meniere's he would see no point in staying involved in the company any further. He wants a treatment for Meniere's and if he can't get that from Otonomy he will look for it elsewhere. I don't think we've seen the last of him.

On another note, I thought it was interesting that a tech company recently released a client video testimonial, and that client was Otonomy. Not sure how much one should read into this, but thought I'd share it anyway:



Otonomy have also released a March 2021 presentation where, in reference to Otividex, they have said:

"Analysis underway to understand difference observed between ITT and per protocol"​

Am I right in saying this means they're going to conduct some kind of post-mortem to see what happened?

 

[Tezcatlipoca]

Are there any other companies working on synaptogenesis?

 

[FGG]

Are there any other companies working on synaptogenesis?

Yes: Pipeline Therapeutics and Hough Ear Institute.

 

[Tezcatlipoca]

Yes: Pipeline Therapeutics and Hough Ear Institute.

How optimistic are you in their projects? I know HEI are really obtuse at the moment.

 

[Jrblovsky]

Hopefully Otonomy can test their other drugs. Would be a shame to see this company fail being I think OTO-413 will help. So will OTO-6xx.

 

[FGG]

Hopefully Otonomy can test their other drugs. Would be a shame to see this company fail being I think OTO-413 will help. So will OTO-6xx.

People are acting like OTO-413 is doomed and I don't get it.

OTO-413 actually worked at the high dose cohort. There is no reason an expanded Phase 1/2 set up to succeed no less will fail since the previous one met its endpoints.

Novavax had *decades* of failures before they got a good product (Covid vax). Previous failure is not a deal breaker.

With good OTO-413 results, investors will keep coming in. Very worst case scenario (which I don't see as the most likely), they get bought out on the cheap and the drug comes out with a different name.

 

[FGG]

How optimistic are you in their projects? I know HEI are really obtuse at the moment.

Unlike some people here, I think the HEI pill works. Their complete lack of financial transparency makes people doubt them here though (which I get). I think the financial aspects keep them vague about the behind the scenes, not the drug itself.

Pipeline Therapeutics looks promising. They are still in Phase 1 and hopefully we can dissect results in the not too distant future.

Btw, I think OTO-413 will still be released.

 

[spacehunter]

How optimistic are you in their projects? I know HEI are really obtuse at the moment.

But do we really know for sure that the 'bomb blast' pill by HEI is also repeating/creating synapses? I have listened to the Tinnitus Talk Podcast, where they talked about it:

"Then, subsequently we found out that it might have some restorative capabilities and may have some efficacy for tinnitus. At least as we've seen in pre-clinical rodent models. It seems to regenerate the afferent nerve endings and synapses at the base of the inner hair cell, quite interestingly"​

"Yes, so this doesn't regenerate hair cells, but it regenerates a nerve ending. The injection technology regenerates hair cells. But with regard to the window there for the pill, we know it's effective if given shortly after the injury in animal models for sure. But we've done some delayed studies where it was administered four weeks later and there was regeneration of the nerve endings and reduction of tinnitus percept. So, it may work in chronic situations and we are submitting a grant to that effect right now to look more intently and intensely to see if they can reverse chronic tinnitus. But our pilot data suggests that it may."​

"I think the pre-clinical data for tinnitus are pretty strong and reproduceable and we have had an outside lab reproduce some of our data. So, I think the pre-clinical data for tinnitus are pretty strong. In addition to decreasing tinnitus percept, we see a number of file markers that are normalised that were previously abnormal from the noise exposure that are associated with tinnitus both in the cochlear and the brain stem and the auditory cortex so we see a correlation between re-grown nerve endings and normalisation of Wave 5 - Wave 1 ratio in the ABR Tracings and normalisation of these file markers that are thrown off that are associated with tinnitus. So, really the data are quite robust. All that being said, it's a big jump from small animals to humans. I think that the pre-clinical data are very strong for tinnitus. Hyperacusis, we haven't really looked at that too much. In theory I think it should be helpful, but we really haven't explored that to any degree at this point but would be willing to do so as we have funding and bandwidth."​

But for me it seems for now more like speculation whether it actually does regenerate synapses even for chronic tinnitus. The second problem is, that there is up to now not much progress going on. If one looks in the Hough Ear Institute's Hair Cell Regeneration Project thread, one can see, that so far nothing more than safety trials have been performed. The to be expected doses of HPN-07 mentioned in their patents are all over the place - ranging from 1,5 g per day in the safety trial up to 20 g per day IV...

 

[Lucifer]

People are acting like OTO-413 is doomed and I don't get it.

OTO-413 actually worked at the high dose cohort. There is no reason an expanded Phase 1/2 set up to succeed no less will fail since the previous one met its endpoints.

Novavax had *decades* of failures before they got a good product (Covid vax). Previous failure is not a deal breaker.

With good OTO-413 results, investors will keep coming in. Very worst case scenario (which I don't see as the most likely), they get bought out on the cheap and the drug comes out with a different name.

OTO-413 had good results but I am pissed that they are doing Phase 1 again. If they had done Phase 2 this year and Phase 3 in 2022 it could have been possible for it to come out in 2023. Guess I will suffer some more then.

 

[FGG]

But do we really know for sure that the 'bomb blast' pill by HEI is also repeating/creating synapses? I have listened to the Tinnitus Talk Podcast, where they talked about it:

"Then, subsequently we found out that it might have some restorative capabilities and may have some efficacy for tinnitus. At least as we've seen in pre-clinical rodent models. It seems to regenerate the afferent nerve endings and synapses at the base of the inner hair cell, quite interestingly"​

"Yes, so this doesn't regenerate hair cells, but it regenerates a nerve ending. The injection technology regenerates hair cells. But with regard to the window there for the pill, we know it's effective if given shortly after the injury in animal models for sure. But we've done some delayed studies where it was administered four weeks later and there was regeneration of the nerve endings and reduction of tinnitus percept. So, it may work in chronic situations and we are submitting a grant to that effect right now to look more intently and intensely to see if they can reverse chronic tinnitus. But our pilot data suggests that it may."​

"I think the pre-clinical data for tinnitus are pretty strong and reproduceable and we have had an outside lab reproduce some of our data. So, I think the pre-clinical data for tinnitus are pretty strong. In addition to decreasing tinnitus percept, we see a number of file markers that are normalised that were previously abnormal from the noise exposure that are associated with tinnitus both in the cochlear and the brain stem and the auditory cortex so we see a correlation between re-grown nerve endings and normalisation of Wave 5 - Wave 1 ratio in the ABR Tracings and normalisation of these file markers that are thrown off that are associated with tinnitus. So, really the data are quite robust. All that being said, it's a big jump from small animals to humans. I think that the pre-clinical data are very strong for tinnitus. Hyperacusis, we haven't really looked at that too much. In theory I think it should be helpful, but we really haven't explored that to any degree at this point but would be willing to do so as we have funding and bandwidth."​

But for me it seems for now more like speculation whether it actually does regenerate synapses even for chronic tinnitus. The second problem is, that there is up to now not much progress going on. If one looks in the Hough Ear Institute's Hair Cell Regeneration Project thread, one can see, that so far nothing more than safety trials have been performed. The to be expected doses of HPN-07 mentioned in their patents are all over the place - ranging from 1,5 g per day in the safety trial up to 20 g per day IV...

Their histology indicated the synapses did regrow. As for whether there is a chronicity related "time limit" on this, I couldn't say for absolute sure but 4 weeks seems reasonably far out in rodent studies for it not to be just a "preventative" imo.

 

[Jrblovsky]

OTO-413 had good results but I am pissed that they are doing Phase 1 again. If they had done Phase 2 this year and Phase 3 in 2022 it could have been possible for it to come out in 2023. Guess I will suffer some more then.

I'm not sure why there are so many on this site who just assume a drug is going to ultimately be released. The drug may never make it past trials. A lot of people are upset about timelines when it's not known whether the drug even works or not. It's the same for FX-322. People want it out now, which I totally understand, but if it doesn't work then why bother. I hate this condition as much as anyone being I am disabled by it but no point of releasing a drug to only be disappointed by the results.

 

[Zugzug]

I'm not sure why there are so many on this site who just assume a drug is going to ultimately be released. The drug may never make it past trials. A lot of people are upset about timelines when it's not known whether the drug even works or not. It's the same for FX-322. People want it out now, which I totally understand, but if it doesn't work then why bother. I hate this condition as much as anyone being I am disabled by it but no point of releasing a drug to only be disappointed by the results.

Personally, there are two big, thematic reasons why I am optimistic about their (FX-322 and OTO-413) eventual release. Will they actually help me is unclear.

1) The science is 100% real and proven. The questions are more along the lines of dosage, correct formulations, engineering techniques to maximize absorption, etc.

2) Many of the bad unknowns in 1) are made up for by the fact that there is currently nothing.

Just take FX-322, for example. It has to work, but it doesn't have to cure hearing loss to pass clinical trials. In fact, the goal, as stated by Carl LeBel, doesn't even include eliminating hearing aids. This is the mindset they are going into this. The bigtime investors know this.

Honestly, I don't totally understand why Otonomy is repeating Phase 1/2 for OTO-413 other than a (justified or not) freak out over the two failed OTIVIDEX Phase 3 trials at the finish line.

 

[FGG]

Personally, there are two big, thematic reasons why I am optimistic about their (FX-322 and OTO-413) eventual release. Will they actually help me is unclear.

1) The science is 100% real and proven. The questions are more along the lines of dosage, correct formulations, engineering techniques to maximize absorption, etc.

2) Many of the bad unknowns in 1) are made up for by the fact that there is currently nothing.

Just take FX-322, for example. It has to work, but it doesn't have to cure hearing loss to pass clinical trials. In fact, the goal, as stated by Carl LeBel, doesn't even include eliminating hearing aids. This is the mindset they are going into this. The bigtime investors know this.

Honestly, I don't totally understand why Otonomy is repeating Phase 1/2 for OTO-413 other than a (justified or not) freak out over the two failed OTIVIDEX Phase 3 trials at the finish line.

Agree, except there are two potentially good reasons for Otonomy to want to repeat OTO-413 apart from being conservative due to the Otividex trial:

1) They want to start with a different dose. The improvements seen in the last trial were all with the 0.3mg dosing (the highest dose) cohort. They may want to increase the dose more for the next trial to see if they can get even stronger results.

2) It seems from the results that not all the speech in noise tests were equal (this would support what Carl LeBel said about high frequency hearing being part of the speech in noise equation by the way, as the synaptopathy part may be better tested for with one test over another). They may chose to use the best responding speech in noise tests for their next trial to ensure the best results over larger sample sizes later.

 

[Tezcatlipoca]

Personally, there are two big, thematic reasons why I am optimistic about their (FX-322 and OTO-413) eventual release. Will they actually help me is unclear.

1) The science is 100% real and proven. The questions are more along the lines of dosage, correct formulations, engineering techniques to maximize absorption, etc.

2) Many of the bad unknowns in 1) are made up for by the fact that there is currently nothing.

Just take FX-322, for example. It has to work, but it doesn't have to cure hearing loss to pass clinical trials. In fact, the goal, as stated by Carl LeBel, doesn't even include eliminating hearing aids. This is the mindset they are going into this. The bigtime investors know this.

Honestly, I don't totally understand why Otonomy is repeating Phase 1/2 for OTO-413 other than a (justified or not) freak out over the two failed OTIVIDEX Phase 3 trials at the finish line.

Exactly, the science works, and we're at the dawn of regenerative medicine.

Even if Otonomy itself is a bust their science isn't. By the time FX-322 is released the entire medical community will realize the potential of this field (some companies already have) and buy the Otonomy science.

 

[Jrblovsky]

Exactly, the science works, and we're at the dawn of regenerative medicine.

Even if Otonomy itself is a bust their science isn't. By the time FX-322 is released the entire medical community will realize the potential of this field (some companies already have) and buy the Otonomy science.

Hopefully. They can cure 100 different kinds of cancer, but we're stuck in the stone age with hearing loss. Still relying on hearing aids from the 50s and cochlear implants from the 80s. The field is sad. I wish I could figure out how to function so I could research more.

 

[wwtsai]

Agree, except there are two potentially good reasons for Otonomy to want to repeat OTO-413 apart from being conservative due to the Otividex trial:

1) They want to start with a different dose. The improvements seen in the last trial were all with the 0.3mg dosing (the highest dose) cohort. They may want to increase the dose more for the next trial to see if they can get even stronger results.

2) It seems from the results that not all the speech in noise tests were equal (this would support what Carl LeBel said about high frequency hearing being part of the speech in noise equation by the way, as the synaptopathy part may be better tested for with one test over another). They may chose to use the best responding speech in noise tests for their next trial to ensure the best results over larger sample sizes later.

Otonomy presented today at the Cowen 41st Annual Health Care Conference. Starting around 19:38, Dave Weber talks about their decision to conduct the exploratory trial rather than moving onto the Phase 2. It looks like the reasons are because they want to look at Speech-in-Noise (SIN) more as a primary outcome and that they're trying to figure out which of the three SIN tests would provide the most compelling data going forward. Again, I don't see how they couldn't have moved on to Phase 2 with the trial data already have, but clearly they want to strengthen their results before moving on.

 

[FGG]

Otonomy presented today at the Cowen 41st Annual Health Care Conference. Starting around 19:38, Dave Weber talks about their decision to conduct the exploratory trial rather than moving onto the Phase 2. It looks like the reasons are because they want to look at Speech-in-Noise (SIN) more as a primary outcome and that they're trying to figure out which of the three SIN tests would provide the most compelling data going forward. Again, I don't see how they couldn't have moved on to Phase 2 with the trial data already have, but clearly they want to strengthen their results before moving on.

Thanks! So reason number 2.

Does that mean they definitely aren't increasing their dose at the same time?

 

[wwtsai]

Thanks! So reason number 2.

Does that mean they definitely aren't increasing their dose at the same time?

I can't say for sure, but I'd expect them to keep the dosing consistent to support their Phase 1 data. A few seconds after the timestamp I mentioned, Weber does say that they have gotten very long term exposure from a single dose of both OTO-313 and OTO-413.

 

[FGG]

I can't say for sure, but I'd expect them to keep the dosing consistent to support their Phase 1 data. A few seconds after the timestamp I mentioned, Weber does say that they have gotten very long term exposure from a single dose of both OTO-313 and OTO-413.

Sorry to ask about things on the link but my ears are really sensitive at the moment and can't listen :/.

 

[wwtsai]

Sorry to ask about things on the link but my ears are really sensitive at the moment and can't listen :/.

Oh, no worries! I was just trying point out where in the presentation he mentions the effectiveness of their drug delivery system. I actually tried to edit my post right after I submitted it, but it wouldn't let me for some reason. I didn't mean to come off that way and apologize if I did.

 

[Zugzug]

Agree, except there are two potentially good reasons for Otonomy to want to repeat OTO-413 apart from being conservative due to the Otividex trial:

1) They want to start with a different dose. The improvements seen in the last trial were all with the 0.3mg dosing (the highest dose) cohort. They may want to increase the dose more for the next trial to see if they can get even stronger results.

2) It seems from the results that not all the speech in noise tests were equal (this would support what Carl LeBel said about high frequency hearing being part of the speech in noise equation by the way, as the synaptopathy part may be better tested for with one test over another). They may chose to use the best responding speech in noise tests for their next trial to ensure the best results over larger sample sizes later.

I'm going to have to get reacquainted with OTO-413. I learned a ton about FX-322 over the past couple of weeks, but it would be nice to learn more about the others such as the Hough Pill, SPI-1005, PIPE-505, OTO-413, OTO-313, etc.

I also think Dr. Thanos Tzounopoulos's Retigabine is flying way under the radar because we have tunnel vision on the hearing regeneration drugs.

You're probably right that there's probably some smart reason for repeating Phase 1/2. Maybe synaptopathy is less known to people so the market requires irrefutable evidence? I still think it's surprising since there isn't anything out there already.

 

[Tezcatlipoca]

I'm going to have to get reacquainted with OTO-413. I learned a ton about FX-322 over the past couple of weeks, but it would be nice to learn more about the others such as the Hough Pill, SPI-1005, PIPE-505, OTO-413, OTO-313, etc.

I also think Dr. Thanos Tzounopoulos's Retigabine is flying way under the radar because we have tunnel vision on the hearing regeneration drugs.

You're probably right that there's probably some smart reason for repeating Phase 1/2. Maybe synaptopathy is less known to people so the market requires irrefutable evidence? I still think it's surprising since there isn't anything out there already.

Wasn't Retigabine effective but also rat poison?

 

[Jcmc]

I also think Dr. Thanos Tzounopoulos's Retigabine is flying way under the radar because we have tunnel vision on the hearing regeneration drugs.

He has money to put in FREQ stock and disappear.

 

[spacehunter]

Their histology indicated the synapses did regrow. As for whether there is a chronicity related "time limit" on this, I couldn't say for absolute sure but 4 weeks seems reasonably far out in rodent studies for it not to be just a "preventative" imo.

Can you maybe provide me some sources for this? So far I have not found any clear statement for it (I did not find any so far - except for the podcast), so I would really like to get a more in depth answer...