Otonomy OTO-413 — Treatment of Hidden Hearing Loss

DEFCON LEVEL 5 BOYS

Exactly.

Screw Otonomy. I stand for Frequency Therapeutics and Dr. Susan Shore.

 

I'm awaiting to see if there were any adverse reactions/side effects to the increased dosage since I didn't see anything related to safety in the press release. Phase 2 studies are designed to care more for clinical safety than for effectiveness apparently.

Looking back on it, I mean they had some success with their two previous trials, Phase 1/2 and Phase 2a, with the lower 0.3mg dosage so they can't just throw that all away? Honestly, with Otonomy on its last legs, could they go straight into the pivotal trial if possible? The average cost of a Phase 3 clinical trial appears to be about 20 million, but I'm not sure how their balance sheet is looking since they haven't released 3rd quarter financials yet.

From FDA's Clinical Research Guidelines:

 

The previous results still stand though?

“In light of challenging financing environment, we intend to explore strategic options to advance and realize value from our pipeline including both OTO-413 and OTO-825, our gene therapy program for congenital hearing loss.”​

I think this means they're going to try to sell their IP.

 

Just a non-medical thought on this, based on how our bodies react to any other drug, chemical, etc., is it really surprising that too much could be bad or that it would undo the positive results from smaller doses?

I mean I think our bodies need a bit of salt, but if we drink salt water we go insane and die.

Am I completely oversimplifying things/creating bad analogies?

 

Why didn't they include a fourth arm with 0.3 mg in this trial?

 

I really hope that this doesn’t delay in starting Phase 2 trials with the smaller dose of OTO-413 if they end up not having enough money to complete it. They better find a potential buyer soon.

 

@CW Dragon, do you reckon that there will be a delay in releasing the Q3 financial report? They usually release the reports a month after the quarter ends.

 

I think the key learning here is small Phase 1 trials can throw up signals that are not there. Once a bigger group is included, it sorts the men out from the boys.

In order to get excited about something coming to market, you need to see big improvements in most participants in the intervention arm.

In a small Phase 1 study 40% responder rate can account for ~6 people. You get flukes and chance results when there is really not much there. The chance of repeating that result (if it's not effective or very mildly effective) disappears once you ramp up the number of participants.

 

Didn’t they also get positive results with the Phase 2a trial using the lower dosage as well?

So that is 2 positive trials with the lower dose. I still think their best bet is to continue with OTO-413 but using the lower dose which was successful in previous trials. If they can achieve that same success, but with more participants, then we will know whether it really works or not.

 

The Phase 2a with 0.3 mg had favorable outcomes. It was the high dose cohort evaluation (0.75 mg + 1.5 mg) that did not show improvement. This is why they are evaluating how to proceed with OTO-413. They could proceed with a Phase 3 trial designed around the 0.3 mg dose. They also note having a lot of data about the patients that received OTO-413.

This is very similar to the FX-322 Phase 2b. They eliminated multi-dose as an path to Phase 3, and instead focused in a trial design that intends to demonstrate efficacy with specific patient groups.

As expected, there's a lot of immediate reaction without reviewing the context. It's not dead yet.

 

I didn’t realise they could move onto Phase 3 after this but, since they got positive results at 0.3 mg for Phase 2a, as long as the FDA approves the results for Phase 2a and allows them to commence Phase 3, that would be good.

Only issue is the financials. The report will come out either end of this month or early next month. We will know more then if they have enough money to start Phase 3 of OTO-413.

If the results had been positive for the higher dose, they would have to repeat Phase 2 again but since they weren’t, then this would a chance to move onto Phase 2b/3 with 0.3 mg.

 

Otonomy fiscal year is calendar-based so really we should be seeing quarterlies by End of Month. Their 2nd quarter 10-Q was filed on July 25, so we'll see it in a couple of weeks.

I noticed they filed a 8-k today which mentioned they as of September 30, 2022 have $40MM left, I have no idea how much is tied up to their liabilities or what their net assets would be after taking out the liabilities.

https://investors.otonomy.com/sec-filings

 

That’s good that they have $40 million left.

Hopefully they don’t have a lot of liabilities. That seems enough for them to conduct a Phase 3 trial for OTO-413.

 

They have already stated multiple times that they will do a full Phase 2 first.

 

I thought Phase 3 OTO-413 trial with the 0.3 mg dose would be their next step since they already did a Phase 2 with 0.3 mg dose which showed meaningful improvements.

Otonomy should do everything they can to speed up their trials because right now they are on a lifeline. They need to go all in on OTO-413.

 

Or give it to another company that knows what they are doing.

 

If they do that, I really hope that it doesn’t delay the trial. Right now Otonomy has $40 million left before their net liabilities. If they have around $20 million left, that should be enough to complete a Phase 3 OTO-413 trial themselves which they should do as soon as possible if they want to recuperate their expenses from the higher dose trial which failed.

 

If you would actually read Otonomy's press releases, you would have known this is not the case:

Otonomy intends to initiate a dose-ranging Phase 2 efficacy trial in hearing loss patients expected to start in the first quarter of 2023

Otonomy Reports Second Quarter 2022 Financial Results and Provides Corporate Update

 

People also seem to have forgotten they did a Phase 1 earlier this year, not a Phase 2. This was a first Phase 2 primarily for safety and a Phase 2b trial was planned for next year. Given they looked at the efficacy, it may be they don't pursue it at all.

 

This was before the disappointing results.

From the newest report:

“In light of the challenging financing environment, we intend to explore strategic options to advance and realize value from our pipeline including both OTO-413 and OTO-825, our gene therapy program for congenital hearing loss.”​

I think their only choice is really partnering up with another company, or Otonomy will probably go bankrupt before getting any product to market.

 

If they had to choose between OTO-413 or OTO-825, they should go all in on OTO-413 Phase 2b trial with the 0.3 mg dose if they have any money left to complete.

Wait until they get some more money from another company or positive Phase 2b results with the 0.3 mg dose before starting OTO-825 trial.

 

I would love for Otonomy (or Frequency Therapeutics) to try multi dosing further apart, like a dose every 6-10 weeks for 3 doses, just to see what happens. Obviously overloading with too much at once is cancelling out any improvements.

 

I think if they were going to try multi dosing again, it would need to be done after the single dose trials finish as I don’t want these companies to delay releasing their drug out in the market which is currently happening with FX-322 and a bit with OTO-413 with trying to use a higher dose.

They should have around 90 patients in total split into 3 groups with 4 doses each per patient: dose every month, dose every 2 months, dose every 3 months. Then within those 3 groups at least 10 patients will receive placebo so making it a 2:1 ratio.

 

Good point

 

I want to look into these words-in-noise tests. I wonder if they throw in words that rhyme with lots of other words like 'lime' or 'frog,' or if the words they use cannot be mistaken for something else easily, like 'banana' or 'restaurant.' And then the background noise - like is it static-y (like the Mimi iPhone app) or other words in the background? Music? I feel like I saw something previously about it in a thread but can't find it...

But then again thinking about it, the testing procedures, it would be the same they used in lower dosage trials that had success

 

When I did my word-in-noise tests, the background sounds were like a noisy restaurant with lots of people talking (of course with no actual words). The actual words I don’t remember exactly but I think they definitely use a lot of words that could be misheard.

 

Can someone please explain to me why word tests are so important? I'm extremely dumbfounded as to why they even matter...

 

Understanding the words people say is probably the most important part of regaining hearing. Not being able to understand what people are saying is the biggest issue for most people with hearing loss.

 

It’s called hidden hearing loss. People who get normal audiograms that turn out fine but they can’t understand speech, especially when there’s background noise is a sign of cochlear synaptopathy (synapse damage). Synapse damage can also be the cause of tinnitus and hyperacusis. OTO-413 aims to regenerate those synapses which could help many people here.

 

It may even help with your noxacusis, the Type 2 afferent nerves that signal cochlea damage. Ignore the PIPE-505 below.



Remember safety of the high dosage OTO-413 was the primary outcome, I didn't see Alan Foster say anything about negative adverse reactions, but just a simple phrasing "complex dose relationship with BDNF." Whatever exactly that means, who knows (except Otonomy - perhaps not even them yet). They did the standard SIN & ABR follow-up tests, so we don't know other effects. Maybe the higher dosage had a positive effect on tinnitus, hyperacusis (and noxacusis). That "Patient Global Impression of Change" outcome leaves me with high hopes that I don't want to dash just yet.