Otonomy OTO-313 — Treatment of Tinnitus

[Lucifer]

So the worse your tinnitus is, the better a responder you are? That's great.

If FX-322 does not get rid of your tinnitus completely, then you may need something like OTO-313 to permanently get rid of it.

 

[Tezcatlipoca]

Correct me if I'm wrong but doesn't this one have a very good chance of approval?

They don't need to regenerate anything, they just need to prove it relieves tinnitus above placebo.

 

[FGG]

Correct me if I'm wrong but doesn't this one have a very good chance of approval?

They don't need to regenerate anything, they just need to prove it relieves tinnitus above placebo.

Seems like it but a similar drug, AM-101, with the same mechanism of action failed.

Going by AM-101's ClinicalTrials page, they were much less selective about their participants/time frame.

Otonomy need to pick the right patient for this (and the right patient needs to apply) but they have the advantage of learning from Auris Medical's failure.

 

[kingsfan]

I'm not sure anyone knows for sure who this works for and why but the data so far is pretty interesting. In the first trial, they tested up to 6 months and 43% of people treated got improvements in tinnitus and 29% (4 patients) got a greater than 20 point TFI improvement (scroll up to see charts).

Interestingly, those 4 patients all had severe tinnitus.

It does seem that local cochlear NMDA receptor hyperexcitability (which is what the drug acts on) happens very acutely to everyone with cochlear damage (and the excitability gets propagated up the auditory channels) but that seems to be more variable long term when the central plasticity/"phantom cochlea" hyperexcitability may become a bigger part. This may be why it doesn't work for everyone and less than half of the participants responded.

However, it may be that people with *severe* tinnitus retain the local cochlear NMDA stimulation component of neural hyperexcitabilty longer. And actually studies have shown that the stress of severe tinnitus in and of itself can be somewhat self perpetuating, too, because of dynorphin release (which sensitizes the NMDA receptor further):

Endogenous dynorphins, glutamate and N-methyl-d-aspartate (NMDA) receptors may participate in a stress-mediated Type-I auditory neural exacerbation of tinnitus

In other words, this may work better in chronic cases when the tinnitus is severe. Which would be good news for the worst cases. Phase 2 would answer that better, though, obviously with a bigger sample size.

I've read the same about Ketamine - the worse the tinnitus, the better it may work.

 

[FGG]

I've read the same about Ketamine - the worse the tinnitus, the better it may work.

It's possible but Ketamine also acts on central NMDA receptors so it has even more variables. Some people do worsen on Ketamine and I wonder if it's because they get more cochlear blockage and their problem is more central (so you are reducing peripheral excitation but maybe temporarily reducing the overall auditory signal centrally).

I have only ever read Ketamine worsening being temporary, though, with short term use anyway, so that's good.

 

[Tezcatlipoca]

they were much less selective about their participants/time frame.

Good thing Otonomy is being very selective. Did AM-101 trials do as well as OTO-313 trials have?

 

[FGG]

Good thing Otonomy is being very selective. Did AM-101 trials do as well as OTO-313 trials have?

Well Phase 1 was just a safety study for AM-101 with no efficacy results so I'm not sure we can compare.

Here are published Phase 2 results, though:

Efficacy and safety of AM-101 in the treatment of acute inner ear tinnitus--a double-blind, randomized, placebo-controlled phase II study

Phase 3 was the study they failed.

 

[Tezcatlipoca]

Phase 3 was the study they failed.

Do you know why? Auris Medical states on their website that they are still working on it.

 

[FGG]

Do you know why? Auris Medical states on their website that they are still working on it.

Do I know why they didn't meet their end points? No, not sure.

I also just read this paper (didn't realize the full paper was free). Phase 2 had some interesting findings. The idiopathic hearing loss group didn't respond but the acute noise (within 3 months) and post otitis media group did. Seemed to work better in unilateral cases, too. They made the case for some types having more local NMDA receptor hyperexcitabilty than others.

One puzzling finding is that the MML did not change even when improvements were seen. They even speculates that the more "objective" measures of tinnitus don't seem to correspond with the subjective findings of improvement (they weren't suggesting it was psychological but questioned how useful MML was here).

I did also notice that their improvements took time (over a week), so I have to wonder if Otonomy's gel is a huge advantage here. Seems like extended release is the best strategy for IT injections, period.

Otonomy's exclusion criteria also states:

"temporomandibular joint disease (TMJ) associated with tinnitus perception"

Which makes me wonder if they suspect it doesn't work as well in somatic cases and Auris Medical may not have accounted for that?

Tl;dr: treating the cochlear NMDA receptor is complicated and they need to pick the right patients.

 

[Pero1234]

I received this email from Otonomy this morning:

Otonomy Announces Closing of Public Offering and Full Exercise of Underwriters' Option to Purchase Additional Shares

What does this mean?

 

[GBB]

I received this email from Otonomy this morning:

Otonomy Announces Closing of Public Offering and Full Exercise of Underwriters' Option to Purchase Additional Shares

What does this mean?

Sounds like they did a follow-on offering to raise more money by offering additional shares to the public, though I didn't read beyond what you wrote (e.g. did not google it). It's not unusual for a company to either issue debt or additional shares to raise funding, though it sucks for existing shareholders whose shares are diluted in value.

 

[Jack V]

I've read the same about Ketamine - the worse the tinnitus, the better it may work.

As a side note, Gacyclidine, the molecule in OTO-313, is similar to Ketamine.

 

[VeryUnfortunate]

I don't think anyone has posted this video yet but this is pretty interesting (you can use any name/company and email to sign up):

https://wsw.com/webcast/needham107/otic/2250710

Some things to note:

• They have enough funding until Mid-2023 apparently
• Q2 2021: Initiate OTO-413 Expansion Study
• Mid-2021: OTO-825 Program Update (Congenital Hearing Loss)
• Mid-2022: OTO-313 Phase 2 Results
• Mid-2022: OTO-413 Expansion Study Results

They also talked about how their drug differs from AM-101 at the end, and how their drug is more specific. And how their trial design differs from other companies because they will not make the same errors other companies have.

 

[Tezcatlipoca]

I don't think anyone has posted this video yet but this is pretty interesting (you can use any name/company and email to sign up):

https://wsw.com/webcast/needham107/otic/2250710

Some things to note:

• They have enough funding until Mid-2023 apparently
• Q2 2021: Initiate OTO-413 Expansion Study
• Mid-2021: OTO-825 Program Update (Congenital Hearing Loss)
• Mid-2022: OTO-313 Phase 2 Results
• Mid-2022: OTO-413 Expansion Study Results

They also talked about how their drug differs from AM-101 at the end, and how their drug is more specific. And how their trial design differs from other companies because they will not make the same errors other companies have.

Does the 2023 date take into account the recent sale of shares that @Pero1234 talked about?

 

[VeryUnfortunate]

Does the 2023 date take into account the recent sale of shares that @Pero1234 talked about?

So I am not really well versed with the implications of your question, but one thing I can say is the video I linked took place on the 13th of April and the share thing happened earlier today. Hopefully someone else can answer your question but based on the video they emphasized that they have a good amount of funding and that the trials should go through no problem.

 

[AfroSnowman]

Initiate OTO-413 Expansion Study

What is an 'expansion study'?

 

[FGG]

I don't think anyone has posted this video yet but this is pretty interesting (you can use any name/company and email to sign up):

https://wsw.com/webcast/needham107/otic/2250710

Some things to note:

• They have enough funding until Mid-2023 apparently
• Q2 2021: Initiate OTO-413 Expansion Study
• Mid-2021: OTO-825 Program Update (Congenital Hearing Loss)
• Mid-2022: OTO-313 Phase 2 Results
• Mid-2022: OTO-413 Expansion Study Results

They also talked about how their drug differs from AM-101 at the end, and how their drug is more specific. And how their trial design differs from other companies because they will not make the same errors other companies have.

My ears are too sensitive to listen right now. Do you remember what they said about how their trial design differs?

 

[Tezcatlipoca]

So Frequency Therapeutics is sitting on some $200M, how much does Otonomy have?

 

[VeryUnfortunate]

My ears are too sensitive to listen right now. Do you remember what they said about how their trial design differs?

Sorry for the late response. I am going to basically paraphrase what Dave Weber said in the video. I think there is a lot of technical stuff throughout the whole video that you can probably understand better than me. If you can manage to watch it yourself there is a lot of juicy stuff after 30 minutes in. In the beginning he talks about OTO-313, then talks about the other products in Otonomy's pipeline.

So let's get started:

• He talked about how his team thought the mechanism of action used in other previous tinnitus trials wasn't really applicable. I believe he directly called out Auris Medical when he talked about another company that previously tried using an NMDA receptor antagonist.
• He said OTO-313's formulation is very valuable, from a single administration it shows prolonged results compared to what others have tried from multiple injections. He said the issue with multiple injections is that you don't really get sustained concentration at a high level, and that you cannot "drive" a drug through the ear.
• He emphasized trial design, and how the lead-in will be rigorous for this trial. He talked about how in previous trials (I believe he was talking about AM-101) there was no consistency in the level of tinnitus people had, so the minimum level of tinnitus varied a lot. He said that there were people with mild tinnitus in the trial, and that he wouldn't expect to see those people improve anyway. He also thinks there were issues with how people were followed after the trial. He said OTO-313's trial is different from this because he wants to ensure stability of disease and a strong lead in phase along with rigorous follow up. He emphasized that he thinks the trial design for OTO-313 and OTO-413 is very strong.
• Phase 3 OTIVDEX data was mentioned, they are analyzing what occurred in the trial. They are trying to understand if anything went wrong and if it did go wrong, there MAY be discussion with the FDA about what happened. The results of the analysis will come out within the next two months. They will see what they can find, and he said he does not think they will pursue more clinical trials on OTIVIDEX but again they are looking through all the data across all trials to see what happened and if anything significant is there there may be discussion with the FDA.

 

[VeryUnfortunate]

What is an 'expansion study'?

So I am not entirely sure what it is either, but I did a little bit of googling so I am going to try my best to answer this, hopefully someone else can chime in as well. Here's what I found: "These trials consist of two phases: the usual dose escalation phase that aims to establish the maximum tolerated dose (MTD), and the dose expansion phase that accrues additional patients, often with different eligibility criteria, and where additional information is collected".

So I assuming they are going to enroll more patients with different eligibility criteria than the other studies, to further see how the drug is tolerated or how it works against different populations. Again, I am not 100% on this so hopefully someone else can chime in if I am wrong.

 

[VeryUnfortunate]

So Frequency Therapeutics is sitting on some $200M, how much does Otonomy have?

So I am not really good with knowing how companies operate and stuff but I think I have a rough idea of what's going on here. I believe they had $86 million in cash on hand, then earlier this month they secured another $30 million in financing, and I think another $15 million on top of that?

In the video he states:

"We have the runway to get not only past the mid 2022 readouts for OTO-313 and OTO-413, but well into 2023, there is no financing overhang here, we have the cash to run our programs and advances those programs clinically as well as the other programs discussed"

Here is a screenshot I pulled from the video:

 

[Tezcatlipoca]

He said the issue with multiple injections is that you don't really get sustained concentration at a high level, and that you cannot "drive" a drug through the ear.

@Frequency Therapeutics.

There are now 2 Pharmaceutical Companies that have identified multiple injections as detrimental to the therapy itself.

@FGG, @Diesel, what do you make of this?

 

[r34d1ng]

He said OTO-313's formulation is very valuable, from a single administration it shows prolonged results compared to what others have tried from multiple injections. He said the issue with multiple injections is that you don't really get sustained concentration at a high level, and that you cannot "drive" a drug through the ear.

Shots fired

 

[weab00]

Shots fired

Definitely a call out to Frequency Therapeutics.

 

[Diesel]

@Frequency Therapeutics.

There are now 2 Pharmaceutical Companies that have identified multiple injections as detrimental to the therapy itself.

@FGG, @Diesel, what do you make of this?

Armchair quarterbacking.

 

[FGG]

@Frequency Therapeutics.

There are now 2 Pharmaceutical Companies that have identified multiple injections as detrimental to the therapy itself.

@FGG, @Diesel, what do you make of this?

Well, Otonomy is going for the extended release approach and so far so good.

 

[VeryUnfortunate]

Okay, so I was thinking about OTO-313 and then I realized that OTO-313 isn't really a cure, it seems like it mostly just improves symptoms for people by reducing their TFI score.

As far as I know there hasn't been a total remission of tinnitus for those who have received OTO-313.

I believe it mostly just reduces the severity of tinnitus or it just reduces the volume of it.

What do you guys think?

 

[FGG]

Okay, so I was thinking about OTO-313 and then I realized that OTO-313 isn't really a cure, it seems like it mostly just improves symptoms for people by reducing their TFI score.

As far as I know there hasn't been a total remission of tinnitus for those who have received OTO-313.

I believe it mostly just reduces the severity of tinnitus or it just reduces the volume of it.

What do you guys think?

There has not been a total remission in anyone treated with OTO-313 so far. It reduces severity and volume in 43% of those given the drug, in 29% of those given the drug it reduced TFI by 20 or more points. The loudness and annoyance charts matched pretty closely.

 

[Tezcatlipoca]

Okay, so I was thinking about OTO-313 and then I realized that OTO-313 isn't really a cure, it seems like it mostly just improves symptoms for people by reducing their TFI score.

As far as I know there hasn't been a total remission of tinnitus for those who have received OTO-313.

I believe it mostly just reduces the severity of tinnitus or it just reduces the volume of it.

What do you guys think?

It could still help us very very much, even if not a cure, if it reduces the intensity/severity, we could cope better.

 

[VeryUnfortunate]

There has not been a total remission in anyone treated with OTO-313 so far. It reduces severity and volume in 43% of those given the drug, in 29% of those given the drug it reduced TFI by 20 or more points. The loudness and annoyance charts matched pretty closely.

I wish OTO-313 could lead to total remission. Well, I'll take whatever I can get. Any improvement is better than nothing. I wonder as more time goes on after receiving OTO-313 if it would lead to further improvement or return to baseline. I'm just glad that there is some success at least.