Otonomy OTO-6XX — Hair Cell Regeneration

[Diesel]

Sorry for the drip-drip-drip of posts on this one, but news slowly keeps coming out.

They've updated their corporate slide deck and the slide on OTO-6XX is now:

View attachment 50207

This is pretty interesting. I wonder if the troubles of FX-322 helped shape this decision. Also, I wonder if part of the problem is how these regenerative drugs target cells to regenerate? It's always been unclear to me how a drug would know to replace a dead or damaged hair cell - or if it would even do so if a cell already existed. Maybe their animal studies were showing this to be the case?

I've sent them an email asking if we'll hear about the hair cell repair research anytime this year. I'll post here if they tell me anything. It's looking more and more likely that we'll see a future where we'll need to take multiple drugs to restore hearing (one for synapses, one for damaged hair cells, one to regenerate, one for tinnitus, etc etc).

Sounds to me that OTO-6XX is a long, long ways away.

 

[patorjk]

Sounds to me that OTO-6XX is a long, long ways away.

If they don't present anything this year, I think we're at least several years away from any kind of trial, if anything even comes to fruition. However, if they present something, I think OTO-6XX could be on the path to showing up soon. I think the most optimistic time-frame would be Phase 1/2 trials in 2024 - though that's if we see something this year. Otherwise it could be years.

Dr. Weber's quote from last November - "so there's more that we'll be coming forward with that we think is a very novel approach that really doesn't require the hurdles that regeneration does" - made me feel like they have something concrete though. It would seem odd to shift away from regeneration and cancel the Kyorin agreement if they didn't have something up their sleeve.

 

[Diesel]

If they don't present anything this year, I think we're at least several years away from any kind of trial, if anything even comes to fruition. However, if they present something, I think OTO-6XX could be on the path to showing up soon. I think the most optimistic time-frame would be Phase 1/2 trials in 2024 - though that's if we see something this year. Otherwise it could be years.

Dr. Weber's quote from last November - "so there's more that we'll be coming forward with that we think is a very novel approach that really doesn't require the hurdles that regeneration does" - made me feel like they have something concrete though. It would seem odd to shift away from regeneration and cancel the Kyorin agreement if they didn't have something up their sleeve.

I still don't get how OTO-6XX is intended to cause damaged cells to repair themselves. FX-322 activating progenitors isn't exactly new science, and cells are running native programs to begin with. Same with OTO-413, there is BDNF at higher levels in utero, so introducing cause a similar effect. But hair cells don't natively fix themselves in humans or in nature to my knowledge. Perhaps to a limited extent in humans when the parts of the stereocilia regenerate. In birds, fish, lower mammals, they basically do what FX-322 causes, a support cell dividing into a functioning daughter cell.

One bright note: The comment on OTO-6XX + OTO-413 being a complimentary set of treatments validates some of the speculation on this site that a synaptogenesis drug + cell regen; ex: OTO-413 + FX-322 will be the future of treatment.

 

[patorjk]

I still don't get how OTO-6XX is intended to cause damaged cells to repair themselves. FX-322 activating progenitors isn't exactly new science, and cells are running native programs to begin with. Same with OTO-413, there is BDNF at higher levels in utero, so introducing cause a similar effect. But hair cells don't natively fix themselves in humans or in nature to my knowledge. Perhaps to a limited extent in humans when the parts of the stereocilia regenerate. In birds, fish, lower mammals, they basically do what FX-322 causes, a support cell dividing into a functioning daughter cell.

One bright note: The comment on OTO-6XX + OTO-413 being a complimentary set of treatments validates some of the speculation on this site that a synaptogenesis drug + cell regen; ex: OTO-413 + FX-322 will be the future of treatment.

I have no idea either, though they're clearly working on something. Still no email back from them. They're usually super quick, though they may be getting sick of my emails.

 

[patorjk]

I listened to the H.C. Wainwright Global Investment Conference that was released this morning, no new info. Their only comment was that repair seems to be much easier than regeneration. I get the feeling the repair stuff is still in its early stages. I did some snooping around and found an article on hair cell repair. I'm thinking whatever they're working on will target certain types of damage (ex: stereocilia repair).

 

[Nobody19]

How excactly do repair and regeneration differ? Does the mean that a hair cell can be damaged, but not completely broken?

 

[patorjk]

How excactly do repair and regeneration differ? Does the mean that a hair cell can be damaged, but not completely broken?

For regeneration, a new hair cell is created that will replace an existing dead or damaged hair cell.

For repair there's an attempt to fix a damaged hair cell so that it doesn't die or so that it functions in an improved manner. Hair cells are complex and there's multiple parts that wear out over time. Besides the synapses, the stereocilia seem to degrade or thin out over time. There's even been some work done towards regenerating them. However, I'm not exactly sure what Otonomy is working on.

All I know is that they worked for 2 years on Kyorin's regeneration drug and were unable to make good progress. Early last year they started talking about "hair cell repair" in their OTO-6XX slides, which showed that they were actively looking into that area. Then earlier this year they dropped the Kyorin drug and decided to exclusively focus on hair cell repair.

 

[Nobody19]

For regeneration, a new hair cell is created that will replace an existing dead or damaged hair cell.

For repair there's an attempt to fix a damaged hair cell so that it doesn't die or so that it functions in an improved manner. Hair cells are complex and there's multiple parts that wear out over time. Besides the synapses, the stereocilia seem to degrade or thin out over time. There's even been some work done towards regenerating them. However, I'm not exactly sure what Otonomy is working on.

All I know is that they worked for 2 years on Kyorin's regeneration drug and were unable to make good progress. Early last year they started talking about "hair cell repair" in their OTO-6XX slides, which showed that they were actively looking into that area. Then earlier this year they dropped the Kyorin drug and decided to exclusively focus on hair cell repair.

Frequency Therapeutics still seems to be miles ahead when it comes to actual regeneration then.

 

[patorjk]

Otonomy just answered my email. I was worried that I'd irritated them with how many questions I send in, but we still seem to have a friendly rapport:

Sorry for the delayed response, I didn't see the message until yesterday. We believe that we're one of the first companies working on this approach to treating severe hearing loss so will be careful about the timing and extent of our disclosures on this work so as to not tip-off potential competitors.

That response coupled with Dr. Webber's quote from last November ("so there's more that we'll be coming forward with that we think is a very novel approach that really doesn't require the hurdles that regeneration does") leave me very intrigued. The tone is also very different from well over a year ago when I emailed them about OTO-6XX and they responded pretty flatly that they'd "provide an update when we have substantive new information to report".

It's still probably far away, but it sounds like they're onto something good. Whatever the case, it's good that these different companies are attacking the problem in different ways. There probably won't be one solution that fixes or restores everything for everyone.

 

[Eliot Martin]

I believe they are taking a risk by focusing on repair of hair cells. Since many people with significant / severe hearing loss could have either damage or hair cell death. And if patients with hair cell death participate in their trials, this drug will definitely fail.

 

[star-affinity]

I believe they are taking a risk by focusing on repair of hair cells. Since many people with significant / severe hearing loss could have either damage or hair cell death. And if patients with hair cell death participate in their trials, this drug will definitely fail.

Isn't the whole point to create a new hair cell to replace the dead one? Or is that not possible once a hair cell dies entierly?

I mean how does it work in fish and birds? Isn't the difference compared to us mammals that they have active progenitor cells next to the hair cells that kick in when needed and ours for some reasons are at a constant slumber after creating their first and only hair cell?

 

[Diesel]

I believe they are taking a risk by focusing on repair of hair cells. Since many people with significant / severe hearing loss could have either damage or hair cell death. And if patients with hair cell death participate in their trials, this drug will definitely fail.

The majority of hearing loss patients have acquired (Noise, SNHL) losses that are between mild and moderate. Severe or profound makes up the furthest edge of the hearing loss population. In the bulk of the mild-moderate cases, there is a combination of hair cell damage of varying levels, particularly wear to the stereocilia, and synaptopathy. If this drug were to be effective, it might be doing something to cause the stereocilia to repair/regenerate to a more like-new fashion. Speculating, of course.

If this were the case, FX-322/345 PCA drugs won't provide a benefit to this population of hair cells anyway.

This would be very valuable to those mild-moderate cases where they haven't experienced as much wholesale damage to the hair cells.

 

[CW Dragon]

Isn't the whole point to create a new hair cell to replace the dead one? Or is that not possible once a hair cell dies entierly?

I mean how does it work in fish and birds? Isn't the difference compared to us mammals that they have active progenitor cells next to the hair cells that kick in when needed and ours for some reasons are at a constant slumber after creating their first and only hair cell?

This might be where the answer lies: teeth.

Teeth come in two sets since adult teeth are too large to fit a baby's jaw. It appears the roots of the baby tooth dissolves at the same time the new adult root forms. What stimulates the new adult teeth creation to take place by the stem/progenitor cells? Does the baby tooth release a chemical that signifies its time is up and that the body needs to replace it, or the body just "knows" when to start forming the adult tooth root? It would seem that teeth are probably a lot easier to study in a living person (i.e. child going through the tooth fairy phase) than the super-hardened cochlea.

I know the cochlea stops growing after birth and retains its pea size till death so that does counter this theory sadly. I would like in the future for odontology and those in hearing to work together to figure this out. Might be one large piece of the puzzle for hearing cell regrowth and also producing another fully-forming adult tooth naturally, instead of implants.