Otonomy OTO-413 — Treatment of Hidden Hearing Loss

We may never know now if continuing OTO-413 at the lower dose of 0.3 mg with more participants would have been a successful Phase 2b trial. I do hope either Spiral Therapeutics or Dompé continue with OTO-413 in some way or form. Best case scenario they continue with the Phase 2b trial with more participants to rule out if OTO-413 works or not. In the worst case scenario they bin the drug.

Let this be a lesson to other companies that are working on hearing restoration to never increase their dosage or do multiple doses in quick succession.

It makes me sad and angry to hear about Otonomy having to liquidate where the possibility of Spiral Therapeutics or Dompé continuing with the OTO-413 Phase 2a trial a slim chance and unlikely. This is what happens when these companies get too greedy. Otonomy should have been focusing on the 0.3 mg dosage trial first and getting that out before testing with a higher dosage.

 

I mean, sure, but unless there’s something particular about the cochlea we’ve discovered from this, to me it would still make plenty of sense to investigate higher doses. Stronger medicine typically yields a stronger response.

Both of Otonomy’s and Frequency Therapeutics’ drugs have been determined to not work on humans. I think that is the reason why we didn’t see improvement from multiple dosings.

 

@EkkoMusic, yea, I don't think it matters a hoot what dosage it is. They don't work and they know it!

 

I agree. I still think that the issue is how to get enough drug to the cochlea and make it survive to trigger the regeneration.

Damn, I wish that one of the companies could try it one more time.

I'm glad that other companies are pursuing the same with different approaches.

 

@patorjk, with the successful OTO-413 Phase 2a trial at the 0.3 mg dose, did they perform audiograms?

OTO-413 is the one that they should try again at the 0.3 mg dose with more participants to rule out if it works or not. We still do not know whether the higher doses did nothing or the drug doesn’t work. It doesn’t explain how the efficacy results for OTO-413 Phase 2a trial with the 0.3 mg did better than the higher dose cohort of 0.75 mg and 1.5 mg dose, and whether the Phase 2a results were a fluke or accurate with the 0.3 mg dose.

https://investors.otonomy.com/static-files/bb6f5503-6acc-4e39-acfa-3a1276ccf209

A proxy vote is going to happen on March 24th 2023 at 8:00am Pacific time.

Live meeting can be accessed here where you can submit questions as well:
www.virtualshareholdermeeting.com/OTIC2023SM

If anyone is available at this time and can listen to the live meeting, they could possibly ask Otonomy what the difference is between the sale of OTO-413 to Spiral Therapeutics and Dompé? Can either one of these companies continue with the OTO-413? If Spiral Therapeutics wants to continue with the OTO-413 trials, would they need to get permission from Dompé as they have bought the patent rights?

 

They did, but they didn't expect a response from them, they just did them for safety reasons. Here's what they told me when I emailed them back in 2021:

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.​

As for talking to Otonomy about the drugs they sold off, they'll probably just tell us to contact the companies that they were sold to.

I disagree on the bit about OTO-413 not working in humans. The whole reason Otonomy did the Phase 2a study was to verify that the drug worked, and with a larger pool of individuals it still showed efficacy. They had 2 trials with positive results:

• Phase 2a had 33 participants - 22 got the drug, 11 got a placebo.
• Phase 1/2 had 9 participants who got the 0.3 mg dose, and individuals in the lower groups apparently still saw some improvement (with the placebo group not showing any).

The higher dose trials actually had fewer participants (I can't find the numbers, but I think each cohort had around 10 participants). 0.3 mg was originally considered "high dose" in the Phase 1/2 trial. The problem was OTO-413's effect was weak. They would most likely have been better off trying a second dose a few weeks later, or taking a look at their delivery method - things I think Spiral Therapeutics may take a close look at (since they have their own delivery method). It may be that OTO-413 doesn't work in humans, drugs fail in Phase 3 all of the time, but the high dose studies failing doesn't mean the drug doesn't work, it just means it doesn't work at those doses.

These studies were more rigorous than FX-322's studies because they required that participants show improvement at 2 consecutive time points, rather than just 1. All of FX-322's studies were failures expect for the original Phase 1/2 study and their open label study. The Phase 1/2 had a lot of problems that we overlooked here, and the open label study had a lot of problems too (sadly I can't remember). I do think it's safe to say FX-322 doesn't work in humans though.

I remember arguing with people over the FX-322 studies and it being incredibly frustrating, so I don't want to be that way for the OTO-413 stuff. OTO-413 may legit be bunk. But I think it's throwing the baby out with the bathwater to disregard it because of the high dose studies failing. I hope Spiral Therapeutics takes a close look at it.

 

Great news everyone, the CEO of Spiral Therapeutics just tweeted that their plan is indeed to see if BDNF works with their delivery method. OTO-413 isn't quite dead yet.

He said this in a thread where he discussed why he thought FX-322 failed. I wonder if his company will try to acquire the rights to that too. It'd be pretty wild if all of these failures were due to drug delivery issues. I didn't notice this before, but apparently Spiral Therapeutics' leading drug candidate, SPT-2101, is simply dexamethasone with their drug delivery method. Otonomy's Otividex was simply dexamethasone with Otonomy's drug delivery method. It'll be really interesting to see if their Phase 2 trial for SPT-2101 (which is happening in Australia - I unfortunately don't know how to get info on it) shows positive data.

 

Australian Clinical Trials - SPT-2101

Scroll down and you'll see:

 

Keep on pushing for better treatments or a cure!

 

There is a glimmer of light after all these failures! Maybe Spiral Therapeutics can get better results. Have they given any specific details about the delivery method?

 

I unfortunately can't find any info on it. I did find this press release though, which talks about the Phase 1 and Phase 2 studies of SPT-2101. Further digging shows they have around 18.5M in funding. Their website is really light on info though. I'm guessing they're just too early stage at the moment.

Also, it may make sense to sunset this thread in favor of the Spiral Therapeutics thread.

 

Be aware Spiral Therapeutics are looking to grab your money and start their own PR fooling machine.

Wait to see evidence of improved audiogram in humans that cannot be a fluke or natural variation. No speech-in-noise bollocks or 3D animal cochlears.

Their current drug candidate is for vertigo caused by Meniere's.

 

They did test audiograms for OTO-413, but I don’t think they mentioned if there were improvements after getting dosed with OTO-413 in Phase 1 & 2a using the 0.3 mg dose.

I wouldn’t give Spiral Therapeutics any money until they have success with at least 100 participants in the OTO-413 Phase 2b trial using the 0.3 mg dose.

@patorjk, did they mention any audiogram improvements after getting dosed with OTO-413 at the 0.3 mg dose?

 

Hugo Peris. Am I the only one who read it as Huge Penis? If Hugo Peris delivers the goods here, then in my mind he definitely has Huge Penis.

But I agree with @Nick47, some people are already falling for the Hugo character

 

As for what @Nick47 said, we need to set the bar higher. We need to have both audiogram and speech-in-noise improvements from OTO-413.

 

Perfect timing for Spiral Therapeutics to come out of the woodwork and capitalise on the community following Frequency Therapeutics' epic fail.

 

As I said in my previous post, their current drug candidate, SPT-2101, is dexamethasone - which is what Otonomy's Ovitidex was. If SPT-2101 shows improvements better than Otividex, then their drug delivery tech may be the real deal and there may be some real hope for OTO-413.

As for them trying to grab our money, I reached out to the CEO, and he was kind enough to answer me. They don't appear to be doing any kind of community outreach. If SPT-2101 is successful, they'll probably try to raise money from institutions. They're not going to go public right away. And if they do go public, we're all adults here and can make up our own minds. That said, I have seen quite a few stories of people investing all of their money in these hearing biotechs and then losing it and it's really depressing. I like to take small positions in them for fun (what I consider small), but if I lose, it's nothing to me. People should not invest significant amounts of money into these companies. I said it a lot previously and it fell on deaf ears. It's also important to note that not all of us are on the same level. I saw someone say they lost $40k but that they owned several businesses and it was no big deal. I saw another person say they lost $40k and it was their life savings.

I'm foremost interested in treatments/cures. Owning a piece of a company can be fun, but people get carried away.

They probably don't have the data yet. Also, I would agree that the bar needs to be higher for us to view what they do as a success. Rather than invest in them, I hope they do trials near me. If I qualify, I would definitely be interested in being a participant.

 

Hugo Peris reminds me of Justin De Moss but hopefully Hugo is the real deal.

If they do decide to try OTO-413 with the new delivery method, I hope the clinical trials don’t take too long. If only we could use the new delivery method for Phase 2b instead of going back to Phase 1, because the only thing we don’t know is whether the efficacy results will be the same with at least 100 participants.

We would probably have to wait a few years to see them get up to Phase 2b with the new delivery method. If they continue with the old delivery method, it would only be a year for the results depending on when Spiral Therapeutics starts.

Have there been any real life FDA cases where it was possible to change the delivery method, even though the dose and ingredients are the same?

I wonder what Hugo means when he talks about exploring alternative outcome measures? I assume this means testing to see if it also reduces tinnitus and hyperacusis?

I don’t think it would be easy to test. If they are going to test for tinnitus and hyperacusis, the participants should have at least had it for a year with no changes.

 

Elsewhere on Twitter he says (in regards to a hearing drug) "We’ve been testing a wide range of approaches in the lab. Might have something ready for the clinic in 2024" and "Biggest challenge is nailing the clinical application. What are relevant endpoints that lead to a reasonable study design (homogeneous patient population, happens relatively acutely, shows an meaningful effect, ...)?". He has to be referring to OTO-413/BDNF. They're way too small of a shop to have anything else. And when he talks about alternative outcome measures, he means measuring improvement by something other than a words-in-noise test (which could include tinnitus). I bet they're going to take a hard look at the audiograms.

Looking into them further, they were originally mentioned on Tinnitus Talk for their LPT99 drug, but that's not even listed on their website anymore. I guess that didn't pan out? Their new lead drug candidate is simply Otividex repackaged. I get the feeling LPT99 failed and they pivoted to drug delivery. When Otonomy imploded, they lucked out and were able to pick up most of their pipeline.

Right now it's a waiting game. They need to do some work with OTO-413/BDNF to see how it works with their platform. Though that said, the guy is really accessible on Twitter. He seems to answer any question tweeted at him. If anyone has any questions I would just shoot him a tweet (though be nice - he's doing us a huge favor in continuing Otonomy's work).

 

@patorjk, I do hope when Hugo Peris mentioned “Might have something ready for the clinic in 2024” that he was referring to OTO-413. You’re right, I don’t think it could be anything else. I don’t think they are talking about the Phase 2 for their Meniere’s drug as they are starting that this year.

As I mentioned in the Frequency Therapeutics thread, I wonder if Hugo Peris would take some patients that were dosed with a single dose of FX-322 to see if OTO-413 is the missing piece to hearing regeneration. Highly unlikely, but I would like them to compare the results between those getting dosed with FX-322 and those not.

If the improvements in audiogram and speech-in-noise are greater when OTO-413 is combined with FX-322, then FX-322 might not be completely dead.

EDIT:

I just saw you mention in the Frequency Therapeutics thread about Spiral Therapeutics not considering testing FX-322 out with their own delivery method.

They probably saw that the OTO-413 results showed more efficacy compared to FX-322 and it wasn’t worth it for them to test it out.

I do hope OTO-413 combined with Spiral Therapeutics’ delivery method can show much better efficacy.

 

For those interested, Spiral Therapeutics has patents on their slow release gel. It's a chemically crosslinked polymer - you mix PEG esters with trilysine amines and can control the crosslinking reaction by adjusting the pH. This gel is more durable than a P407 gel (Otonomy and Frequency Therapeutics gels) as those do not have polymers linked to each other chemically.

 

Where is this information from?

 

Literally their patents.

 

I’ve seen Spiral Therapeutics announce the purchase of OTO-413 inventory and clinical trial information but Dompé hasn’t announced the purchase of OTO-413 patent rights even though Otonomy have stated that Dompé has successfully bought the patent rights to OTO-413. Should this concern anyone?

I have no problem with Dompé buying the patent rights of OTO-413 as long as they allow other companies, such as Spiral Therapeutics, to conduct future OTO-413 trials without limitations due to patent rights being bought by Dompé.

I would like to hear from Hugo Peris, the CEO of Spiral Therapeutics, if there are any limitations on them starting the OTO-413 trials, like them having to pay a fee to Dompé to use OTO-413 in their trials (or if they can do it free of charge).

 

Is there no news at all regarding OTO-413 and Spiral Therapeutics? It´s been half a year without any information whatsoever.

 

I've been following this and other research news for some time and, like others, I am disappointed.

Just some thoughts on this for whatever it's worth.

Reading the literature suggests there is an issue of maintaining quality drug release into the cochlea. I remember a specific paper that used bisphosphonates with a nootropic just to sustain release. Another research paper by the same group did an experiment to demonstrate drug distribution by diffusing a drug via the RWM into the perilymphatic fluid vs. intra-cochlear delivery which was significantly different as one might suspect. RWM's from person to person can differ and it's possible it impacted the trials.

Spiral Therapeutics have an interesting technology they are coining "Spiral’s MICS" - minimally-invasive cochlear system. In the paper I mentioned above the best option to deliver the drug into the cochlea was to pump the drug through the RWM (intra-cochlear delivery). However, that is quite invasive and carries more risk. I wonder why they coin it minimally invasive. I will be reading into it more.

If we had a delivery vehicle/mechanism proven to work over months, and if shown to distribute into all sections of the cochlea in humans, I think it would be a pretty major game changer in the field, drugs aside for a moment. Good on Spiral Therapeutics for focusing on this only as it's a significant piece to the problem. Think back to Frequency Therapeutics where they tried to adjust their formula to target deeper into the cochlea, but had too many issues for them to handle in a small trial window (delivery and drug).

Threads in Research News generally talk about a) recovery (anti-inflammatories, compounds that help with recovery, etc.), otoprotective (preventative or for recovery), and b) regenerative, which we still don't know definitively if it's possible and hence is a bigger gamble for any company to take through clinical trials.

Recovery has good clinical data to show it works well in humans using e.g., Cinnarizine, anti-inflammatories such as Dexamethasone, Prednisolone etc. So having sustained release of whatever a) is, is a great thing vs. alternatives i.e. oral or intratympanic steroid injections without sustained release mechanisms.

I'm not sure what stage Spiral Therapeutics is at but I think it's a great move to tackle one issue at a time rather than both and I'm surprised no one has actually done it yet. If they can meet their end points (I personally would like to see drug distribution), it can be licensed to whoever wants to take residence in this space because they have a proven technology. Good drug distribution in humans will be hard to prove. It's potentially easier with cadavers because there is no need for hearing loss as a pre-requisite.

I wonder how they'll do this in humans, maybe fluoresce dye that lights up on an MRI or CT (assuming resolution is high enough) or like one of the papers I mentioned in the beginning (however, it requires dissection and raises ethical concerns). I do wish they'd give an update on their pipeline and share more details.