Otonomy OTO-413 — Treatment of Hidden Hearing Loss

[FGG]

This was just published:

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224022

Sounds like they are testing monoclonal antibodies in rats for the next wave of these drugs (to be used with the neuropeptides).

 

[mrbrightside614]

I wonder if curing hearing loss/tinnitus will cure hyperacusis.

I know this was a year ago, but I doubt it. My hyperacusis came on a month before my tinnitus and is likely the cause of my tinnitus. Now, my hyperacusis has been settling down (save for when some dumbass purposefully drops a stack of weights because he's not strong enough to control it and left side nerves/muscles flare/spasm for 5-45minutes) and my tinnitus has not much at all. So in my case, there hasn't been a strong correlation between the two conditions apart from hyperacusis lending itself to causality of the tinnitus. One experience, at least.

 

[mrbrightside614]

https://europepmc.org/article/med/8724672
"BDNF was the most potent stimulator of neuritogenesis, NT-3 provided the strongest support for neuronal survival, while NGF supported limited neuritogenesis, and only at pharmacological levels. These findings suggest that both BDNF and NT-3 participate in the postnatal maturation of cochlear innervation and that NGF is most probably not involved in this process."
https://www.jneurosci.org/content/17/6/1959.short
"Elevated [K+]o has a biphasic effect on SGN survival; survival improves as [K+]o is raised to 30 mm (30K) and falls as [K+]o is further increased; SGN survival in 80 mm[K+]o (80K) is poor relative to survival in 30K."

"Ca2+]i elevated to 100–500 nm in a sustained or oscillatory manner permits SGN survival independent of exogenous neurotrophic factors. Higher [Ca2+]i is associated with cell death."

"By using a culture methodology that allows evaluation of single neurons, we determined that BDNF and neurotrophin‐4 (NT‐4), which both bind to the TrkB high‐affinity receptor, greatly enhanced neuron survival above control cultures. NT‐3, which acts via the TrkC high‐affinity receptor, also increased survival, but to a lesser extent. By testing a variety of neurotrophin concentrations and combinations, we observed that simultaneous activation of the TrkB and TrkC receptors synergistically promoted neuron survival compared to cultures that contained either neurotrophin alone at the same total concentration."​

Taking all of this into consideration, why on earth are we not using NT-3 and NT-4 in conjunction with BDNF? There are literally hundreds of easily available therapies to increase BDNF but absolutely none for NT-3.

It appears that BDNF itself may recover frequencies lost at the apex of the cochlea (see figure) while NT-3 would recover frequencies lost at the base of the cochlea.

 

[JohnAdams]

Taking all of this into consideration, why on earth are we not using NT-3 and NT-4 in conjunction with BDNF? There are literally hundreds of easily available therapies to increase BDNF but absolutely none for NT-3.

I agree. I think NT-3 and BDNF could be used together, on separate days though. There is also no good reason why we should have to wait years for such a thing. They are both safe when injected into the middle ear. We should be able to go to an ENT clinic right now and have them just give us shots of this as many times as needed, so long as we consent.

This may not cure tinnitus but very well give the types of improvements that I have experienced with my own.

 

[FGG]

Anyone know how we can get access to these Otonomy presentations from the Association for Research in Otolaryngology Annual Meeting:

• Characterization of OTO-413, an intratympanic sustained-exposure formulation of the neurotrophic factor BDNF, in preclinical models of cochlear synaptopathy" by Tsivkovskaia et al., on January 26.
• "Comparisons of single versus combinatorial strategies for hair cell regeneration in cochlear explants" by Uribe et al., on January 27.

 

[ajc]

Anyone know how we can get access to these Otonomy presentations from the Association for Research in Otolaryngology Annual Meeting:

• Characterization of OTO-413, an intratympanic sustained-exposure formulation of the neurotrophic factor BDNF, in preclinical models of cochlear synaptopathy" by Tsivkovskaia et al., on January 26.
• "Comparisons of single versus combinatorial strategies for hair cell regeneration in cochlear explants" by Uribe et al., on January 27.

They are not online so I guess it's not possible.

 

[FGG]

They are not online so I guess it's not possible.

My finding as well but the conference is wrapping up so I will keep checking to see if it pops up later.

 

[Joeseph Stope]

My finding as well but the conference is wrapping up so I will keep checking to see if it pops up later.

Great to have some people on board such as yourself and HootOwl who understand all of this.
I wouldn't know a ribbon synaptopathy if it jumped up and bit me.

One small question. I recall reading way back that some patients suffer from hearing loss. Some suffer from tinnitus. Some suffer from hyperaccusis. Some suffer from one of these but not the other two. Some suffer from two of these but not the other one. And lastly some suffer from all three.
Can this be explained in terms of hair-cell, stereocilia, OHC, IHC damage... i.e. inner ear damage?

It's great to see so much movement on the research and clinical trial side of things. Some people on Wall Street must have scented something. The hearing aid business, the sign language side of things and the cochlear implant side together must have a world-wide turnover of Billions. An innovation here would be a big step forward for you, me and much of humanity but I think realistically that business that is one of the big drivers too.

Thinking outside the box here: is it possible to do a human cochlear transplant, say to a mouse? Probably a stupid question on my part. Betrays my low knowledge of medicine.

 

[FGG]

I just re-read the inclusion/exclusion criteria for this drug and most makes intuitive sense to me (e.g.. problem must have existed for more than 6 months, etc) but one of the exclusions is if you have ever had formal musical training (not just if you are a musician). Any idea why that would be an exclusion factor?

 

[FGG]

Great to have some people on board such as yourself and HootOwl who understand all of this.
I wouldn't know a ribbon synaptopathy if it jumped up and bit me.

One small question. I recall reading way back that some patients suffer from hearing loss. Some suffer from tinnitus. Some suffer from hyperaccusis. Some suffer from one of these but not the other two. Some suffer from two of these but not the other one. And lastly some suffer from all three.
Can this be explained in terms of hair-cell, stereocilia, OHC, IHC damage... i.e. inner ear damage?

It's great to see so much movement on the research and clinical trial side of things. Some people on Wall Street must have scented something. The hearing aid business, the sign language side of things and the cochlear implant side together must have a world-wide turnover of Billions. An innovation here would be a big step forward for you, me and much of humanity but I think realistically that business that is one of the big drivers too.

Thinking outside the box here: is it possible to do a human cochlear transplant, say to a mouse? Probably a stupid question on my part. Betrays my low knowledge of medicine.

They are still working out the details of the wheres and hows. Most everyone with tinnitus has hearing damage but not everyone with hearing damage has tinnitus.

I was reading last night about "thalmic gating." Apparently, if you have good "thalmic gating" it makes it harder to get tinnitus even with hearing damage. Regardless it is very unusual to get tinnitus without cochlear damage. It seems that anything that interrupts the normal signal can cause tinnitus. So that can mean any part: e.g.. OHC, IHC and synapse.

My own personal opinion is OHCs and Synapse are the most relevant parts to tinnitus. The reason I think this is that tinnitus seems to be related to Glutamate overstimulation at the synapse level. I need to find this paper again, but when you damage the cochlea, you release a lot of glutamate, which causes the terminals to actually store more glutamate because it "ran out" during excitation to try to restore the signal. So, in addition to neuroplasticity not being able to adjust to the lack of signal in the brain, the glutamate keeps stimulating the abnormal frequency/frequencies in the absence of stimulus to OHCs *and/or* because the synapse is damaged and the glutamate can't diffuse properly.

Loudness hyperacusis is a lot more mysterious to me. Why do some get central gain in response to hearing loss and others don't? Either way, I think restoring the hearing pathways should cause the brain to readjust. I tend to think it's more OHC related though (pure guess) because most ppl seem to do worse w high frequency sounds and high Frequency OHC damage is very frequent with noise and ototoxic damage is where synaptopathy speech in noise issues doesn't seem as confined to high pitched noises.

I could be way off base. Would love to hear other theories.

 

[DaveFromChicago]

To FGG:

Perhaps the rigorous discipline of such formal musical training creates indelible, permanent neuronal pathways in the brain's circuitry.

I have heard from musicologists that music is actually an application of a type of mathematical development, and perhaps these entrenched, learned systems are difficult to neutralize (and might block various treatments).

Just speculation.

 

[FGG]

To FGG:

Perhaps the rigorous discipline of such formal musical training creates indelible, permanent neuronal pathways in the brain's circuitry.

I have heard from musicologists that music is actually an application of a type of mathematical development, and perhaps these entrenched, learned systems are difficult to neutralize (and might block various treatments).

Just speculation.

I wonder if it's because musical people know how to "listen" better so might have worse synaptic damage than their "speech in noise" test suggests. Also pure speculation.

 

[serendipity1996]

Might be relevant to post this here. New article on Hidden Hearing Loss and Brain Changes from Ototoxic Drugs by Richard Salvi, published in Feb 2020 edition of The Hearing Journal

https://journals.lww.com/thehearing...en_Hearing_Loss_and_Brain_Changes_from.8.aspx

 

[FGG]

Might be relevant to post this here. New article on Hidden Hearing Loss and Brain Changes from Ototoxic Drugs by Richard Salvi, published in Feb 2020 edition of The Hearing Journal

https://journals.lww.com/thehearing...en_Hearing_Loss_and_Brain_Changes_from.8.aspx

Cisplatin toxicity is among the worst. I hope the preventatives for it in trial don't stop research to help them as they have their own unique otologic problems including widespread support cell loss and platinum stored in the cochlea acting as an anti mitotic.

 

[serendipity1996]

Cisplatin toxicity is among the worst. I hope the preventatives for it in trial don't stop research to help them as they have their own unique otologic problems including widespread support cell loss and platinum stored in the cochlea acting as an anti mitotic.

Would the loss of support cells mean that potential treatments like FX-322 would be ineffective?

 

[FGG]

Would the loss of support cells mean that potential treatments like FX-322 would be ineffective?

I imagine it would have to be a substantial loss of them, but probably it would in those cases.

There are other people working on regenerating support cells, though (Chen at Harvard and it is ambiguous but possible the new LATS pathway Decibel just bought the rights to for development may help here, too). It's just a bit further out.

 

[TuxedoCat]

@FGG

OK if I PM you sometime this weekend? Thanks, TC

 

[FGG]

@Joeseph Stope , I'm revising my speculation about loudness hyperacusis a bit. Maybe it is the synapses, after all but they might not be as commonly in the speech range.

Has there ever been a study of the range of frequencies people with loudness hyperacusis tend to react worse to?

 

[lapidus]

Has there ever been a study of the range of frequencies people with loudness hyperacusis tend to react worse to?

Based on patient testimonals from forums and such over the years, I'm pretty sure the general consensus is that high frequency sounds are worse than lower ones for us with H. Not sure if there is some official data on this but maybe the CoRDS hyperacusis survey from some years back shine a light on it, I don't remember.

 

[FGG]

https://investors.otonomy.com/news-...y-present-two-upcoming-investor-conferences-1

 

[KyleM]

I had the chance to participate in the OTO-413 but I decided against it. For one Tinnitus was indeed an exclusionary criteria. Now I easily could've lied about having tinnitus but it felt like doing so would only be shooting myself in the foot.

Another reason I did not proceed (with lying) was @ChrisBoyMonkey experience with the other OTO trial. He had a pretty adverse reaction and I didn't want to put myself in the same situation. yes perhaps this drug would be different but by roll the dice on a clinical trial?

Finally and probably the two biggest reasons- they only inject into one ear, and I'd have no idea if I got the real thing or not. What's the point of attempting to try a drug I might not even get and would only be in one ear regardless? Just felt like too much uncertainty.

 

[FGG]

I had the chance to participate in the OTO-413 but I decided against it. For one Tinnitus was indeed an exclusionary criteria. Now I easily could've lied about having tinnitus but it felt like doing so would only be shooting myself in the foot.

Another reason I did not proceed (with lying) was @ChrisBoyMonkey experience with the other OTO trial. He had a pretty adverse reaction and I didn't want to put myself in the same situation. yes perhaps this drug would be different but by roll the dice on a clinical trial?

Finally and probably the two biggest reasons- they only inject into one ear, and I'd have no idea if I got the real thing or not. What's the point of attempting to try a drug I might not even get and would only be in one ear regardless? Just felt like too much uncertainty.

The results of this drug are set to come out in a few months, anyway (but maybe they would provide an update at the two upcoming conferences they are attending). You'd have a lot more info on results and side effects then if you wanted to pursue a further trial later.

As far as I know, they only ever do one ear in any of these trials, not just Otonomy.

 

[Ben S]

Hi @ChrisBoyMonkey, can I ask what adverse effects you had from this?

 

[FGG]

Hi @ChrisBoyMonkey, can I ask what adverse effects you had from this?

He took OTO-313, not this drug.

 

[mrbrightside614]

I had the chance to participate in the OTO-413 but I decided against it. For one Tinnitus was indeed an exclusionary criteria. Now I easily could've lied about having tinnitus but it felt like doing so would only be shooting myself in the foot.

Another reason I did not proceed (with lying) was @ChrisBoyMonkey experience with the other OTO trial. He had a pretty adverse reaction and I didn't want to put myself in the same situation. yes perhaps this drug would be different but by roll the dice on a clinical trial?

Finally and probably the two biggest reasons- they only inject into one ear, and I'd have no idea if I got the real thing or not. What's the point of attempting to try a drug I might not even get and would only be in one ear regardless? Just felt like too much uncertainty.

Damn. Your apprehension is understandable, and if I'd been able to get to @ChrisBoyMonkey before he made his decision I would've indeed advised against OTO-313 since 3 months is WAY too long to expect an NMDA antagonist to reverse damage IMO.

IT BDNF is a different story though. Would've been cool to have an anecdote to work from.

Regardless, I'm glad Otonomy is actually trying to do something for us.

 

[KyleM]

IT BDNF is a different story though. Would've been cool to have an anecdote to work from.

Regardless, I'm glad Otonomy is actually trying to do something for us.

Yeah I agree, maybe down the road things will be different.

 

[FGG]

Anyone else listen to today's investor conference call and the Q and A (it's on their website now)? Nothing really new except:

--Ovidex seems amazing for Meniere's vertigo (some on this site have that so that's good news).

--Dr. Weber specifically said that measures such as TFI are useful to determine if the drug (in this case, OTO-313) lowers tinnitus loudness because he said degree of distress is directly related to loudness (take that, Jastreboff). Basically also said the drug is for acute tinnitus of cochlear origin (which we knew).

--They are not completely sure how long it will take to fully recruit for OTO-413 but they think/hope they should still get results by end of year.

--OTO-6xx is going to be a great synergistic drug with OTO-413 for broad treatment of "severe" hearing loss. This is the first compound I am aware of targeting "severe" loss. He didn't say more, unfortunately.

Anything I missed?

The questions were call in questions but you had to be with a financial institution to ask them, unfortunately.

 

[Joly]

I feel like all the treatments cure acute tinnitus, not chronic. It's a shame and I don't understand because even if the number of tinnitus sufferers increase, there are many chronic tinnitus sufferers who have suffered for years.

 

[FGG]

I feel like all the treatments cure acute tinnitus, not chronic. It's a shame and I don't understand because even if the number of tinnitus sufferers increase, there are many chronic tinnitus sufferers who have suffered for years.

Which treatments do you mean? Only OTO-313 is in trial for acute tinnitus.

 

[Joly]

Which treatments do you mean? Only OTO-313 is in trial for acute tinnitus.

The Hough pill is also for acute tinnitus. It is apparently easier to repair acute tinnitus.

What I don't understand is the difference between acute and chronic tinnitus in the ear and the brain?