Otonomy OTO-413 — Treatment of Hidden Hearing Loss

I actually think that FX-322 showing results may bring more money to the hearing space when investors see the market potential for hearing restoration. Same thing happens in other non-medical industries.

Problem is, Otonomy will need to get OTO-413 ahead in the pipeline.

 

Here are the definitions of "intent to treat" population vs "per protocol" as mentioned in the top line results:

https://www.clinfo.eu/itt-vs-pp/

 

What's further disappointing is that Otividex may have been a fantastic drug off label for acute acoustic trauma or even autoimmune disease. Maybe we can ask if they plan to look for other indications for this drug.

Since it's known that stress plays a role in Meniere's vertigo attacks and that they might be highly susceptible to placebo (which Otonomy ran into in their previous Phase 3 when their placebo patients got great results), maybe Otonomy should have considered whether or not IT steroids benefit that population in general.

Anyone know of any placebo controlled studies with regular IT Dexamethasone on Meniere's vertigo?

 

This is the only one I'm aware of where a placebo group was involved:

Dexamethasone inner ear perfusion by intratympanic injection in unilateral Ménière's disease: a two-year prospective, placebo-controlled, double-blind, randomized trial

The dosage was five daily injections though, so I'm not too sure whether one can call that regular.

All other studies seem to be retrospective in nature i.e. no placebo group.

 

Thanks for finding that!

I would have liked to see less than a two year follow up on that to match it with what Otonomy were trying to do but that's useful (unless it is in the full paper).

Fascinating that 57% achieved total vertigo control with placebo, though. That seems really high since the hearing symptoms had a much less response rate (between 10-20%). It does point to possibly some steroid effectiveness (at least over the long term) but also a really pronounced placebo effect.

I wish Otonomy didn't pick vertigo as their sole endpoint.

 

Wow, even in that study the placebo effect is really high. I wonder if just the act of doing the injection somehow helps relieve the symptoms of Ménière's. Maybe it helps some fluid leak out of the inner ear (which I've heard contributes to the disease). I wonder if the placebo effect would still be as high if the control group was given a sugar pill instead (and made unaware that the other group got an injection).

I also wonder if maybe Otonomy under-dosed Dexamethasone in Otividex. That seems to have been an issue in OTO-413 and OTO-313. Maybe they just don't have a good handle on how their extended release gel really works.

Anyway, I've read that a lot of drug miss getting approved because they can't beat the placebo effect. Thankfully that's something FX-322 won't really have to deal with (since hearing tests aren't subjective).

 

Even with the bad Phase 3 news, I'm still invested and willing to invest more in Otonomy.

 

Looks like the 6 month mark is when placebo and steroid start to differ appreciably.

This part also caught my eye:



So it seems for the first few months, Dexamethasone is no better than placebo but after about 6 months of treatment, it starts to be. Makes me wonder if two consecutive doses of Otividex would have met endpoints.

Probably wasn't the best decision regardless to make something like vertigo, being highly subject to placebo effects, the primary endpoint.

 

How does Pipeline Therapeutics' proposed synaptopathy drug PIPE-505 compare to OTO-413? Is it also a BDNF drug?

 

PIPE-505 is a gamma secretary inhibitor like Audion. However it must work very differently since it is primarily a synapse drug. Maybe it's a partial inhibitor only or less strongly inhibitory. I am extremely interested in their results and science.

 

Interesting - will be good to find out more about its mechanism of action. I really hope OTO-413 will pan out. I am always surprised that Decibel Therapeutics hasn't gone down the cochlear synaptopathy route with their pipeline, given that Charles Liberman is one of the founders.

 

This is probably exactly what has happened. However the same thing could happen with other treatments like FX-322 if they need to reformulate the medicine. I reckon that this is not a bad thing that they are doing this now because it will mean that the end product gives people the best chance of a positive and successful outcome possible.

I also think that Otonomy will also come out from the start with a bigger dose for their hair cell medicine so while this news is unfortunate and a set back it will have positive benefits to the trial processes.

 

Can someone kindly explain me the news in a nutshell?

Vertigo failed?
What about hearing loss and tinnitus?

 

The drug, Otividex, was designed to treat vertigo in Meniere's patients using a steroid delivered intratympanically. It got to Phase III but failed twice because it didn't show enough improvement over placebo on either occasion.

As they were only measuring vertigo as their primary endpoint (and not other things such as hearing recovery/tinnitus), it means they cannot take the drug to market for any condition, even if it helps with acute noise trauma/tinnitus, because they didn't test for those things. Had the drug been successful for Meniere's, it's possible it could have been used off-label for acute noise trauma, but that's no longer possible.

The bottom line is that this now means Otonomy will not be self-sustaining moving forwards. They cannot take any of their other drugs to Phase 3, such as OTO-413, without further investment, because they will not have the cashflow, unless they decide to trim their costs/staff/drop some drugs in their pipeline - but even that may not be enough to survive. They will at some point need more investment, and that's gonna be a hard task given Otonomy have a history of doubling down on a drug that ultimately failed on two occasions.

TL;DR: Meniere's drug failed. Otonomy desperately need good Phase 2 results for OTO-413/313, although I don't see OTO-313 doing much personally.

 

I'm no expert, but I read that the trials for tinnitus were successful last summer so they are focusing on that now.

 

Otonomy had a drug rarely discussed here called Otividex. It was an extended release steroid for Meniere's being tested for vertigo episodes. It did not meet its endpoints.

This is separate from their hearing loss and tinnitus drugs.

 

How does a drug like Otividex show positive results in Phase II and negative results in Phase III?

Hope that doesn't happen with FX-322.

 

Because vertigo in Meniere's is extremely subject to the placebo effect. In one study that @Aaron91 posted, 57% had full remission for a year with placebo. Vertigo episodes were Otividex's only endpoint.

Hearing regeneration doesn't have that issue so I don't think any comparisons there are apt.

 

Can you explain how vertigo can be so much subject to placebo? How can placebo treat vertigo? Weird.

 

My theory: it probably doesn't help vertigo from other causes, but in Meniere's specifically elevated intracranial pressure seems to be related to hydropic attacks and stress can elevate intracranial pressure.

Full rotational vertigo attacks are enough to give anyone PTSD and I think if you felt that you had a medication that might help, it would drastically reduce this fear/chronic stress.

 

Very accurate overview, and I'm hurting because of it $$$ . With that said, don't you think their balance sheet of almost $85m gives them enough working capital to make a go at their other pipeline drugs?

 

After reading about all of this stuff regarding OTIVIDEX, I am interested in what the criteria was for someone to be excluded from the per protocol (PP) group. The p-value was 0.031 in this group, while it was 0.312 in the intent-to-treat (ITT) group. That seems like quite the difference. Generally, ITT performance matters more (why the study failed) because it's more conservative and doesn't account for the people that, for example, dropped out of the study or became loosey-goosey with study guidelines because it wasn't working. The sample drop from ITT to PP was n=148 to n=136. I wonder what those 12 people did and how bad it really was.

Honestly, I'm also really confused as to why this drug was restricted to unilateral Meniere's vertigo symptoms. I get that it's too complicated to have a study with unilateral Meniere's, bilateral AIED, Meniere's with varying levels of hearing loss, etc.

But just as a layman speaking, this drug sounds like it has higher potential for AIED, ISNHL, SSNHL than it does just for vertigo. Maybe they had to pick one study direction and picked wrong? I'm not sure.

Hindsight is 20/20. Maybe no one had any idea that vertigo was so prone to the placebo effect. I really like @patorjk 's question about whether or not the actual injection played a role in upping the performance of the placebo group.

 

Not sure why everyone is worried about Otonomy not having enough cash.

From:

Otonomy Announces Top-Line Results for the Phase 3 Clinical Trial of OTIVIDEX® in Patients with Ménière's Disease

"We expect that our existing cash balance will permit us to achieve these clinical readouts as well as advance our preclinical hearing loss programs including OTO-825, a gene therapy for congenital hearing loss."

Unless people think they are lying, they also have enough cash to initiate OTO-825 as well as maintain their current trials.

Also, it's not a blockbuster but they do have an approved drug already for swimmer's ear: OTIPRIO so they do have some revenue.

 

I think people are scared of their ability to keep taking hits. If OTO-413 is a booming success (thankfully, the first Phase 1/2 was really positive so the next one probably will be as well), there's less to be worried about, but what if they have to redo a deeper phase (much like OTIVIDEX)?

I know little about investor relations, but I would guess that if OTIVIDEX failed two Phase III trials and OTO-413 also failed one, things would start looking a bit shaky.

I guess zooming out and removing emotions, most drugs fail so making it to Phase III is still promising. I'm not sure if investors would view it that way or not.

 

Very good points, and the failure in this latest Phase 3 is a real head scratcher. After looking at the latest 13F's (institutional investment) they really "piled on" in the last quarter, so there were many believers they would crush Phase 3. I think what's going to be very important to keep these institutions from losing faith and heading for the hills would be as you pointed out the ITT vs PP assessments. This will allow the company to identify if it was only a few patients that drove the ITT vs PP results or was it all 12 patients. My thought is if there are logical explanations, it may allow them to save faith and maintain investor confidence that they are able to finally execute successfully.

 

Well, they're saying they have enough cash balance to achieve clinical readouts, but for which phases?

Their cash balance as of December 31, 2020, is $86.3 million and their operating expenses are just under half that ($42.6 million), meaning that, as things stand, they have enough cash for two more years' worth of operations. I'm not saying they're lying, but the numbers certainly don't lie. So bottom line, two years from now means Otonomy should just about scrape a Phase 2 readout of OTO-413 given they're re-running Phase 1 with a readout in 2022. Which is why I've said several times now, even if Phase 2 results for OTO-413 are promising, they won't be able to go to Phase 3 unless they find cash from somewhere else. Let's also not forget that Phase 3 trials tend to be a lot more expensive to run than previous phases.

 

Bad news about Otividex trial failing again, I really hoped it would pass because this makes me nervous for SPI-1005 as I kind of understand they are for similar purposes although different drugs.

Could the placebo effect also be similar for the SPI-1005 Meniere's trial? It's a pill rather than an injection but it would still be giving the candidate the effect of having received a form of treatment. SPI-1005 is a drug I am really hoping gets approved.

Is Otividex likely to enter further trials or is it binned now?

 

Well, you can assume with favorable Phase 2 readouts, more cash investments will be made. Without favorable readouts, though, they don't have drugs anyway.

 

The relationship between CSF pressures and inner ear pressures in hydrops suggests that intra-aural fluid pressures are elevated in the hydropic ear.

(PDF) The Meniere attack: An ischemia/reperfusion disorder of inner ear sensory tissues (researchgate.net)