Frequency Therapeutics — Hearing Loss Regeneration

[Diesel]

This could unfortunately explain their emphasis on "clarity" in recent online media.

This differentiates FX-322 from hearing aids and cochlear implants. Neither provide clarity; and how they're using it, they mean how sensitive regenerated biology is to sounds / words / music / filtering noise / etc.

 

[Diesel]

I'm not well read on this, but is that assuming the progenitor cell starts at zero divisions? My point being, do we know how many times a progenitor cell in the cochlea has already divided by the time we're born (before they eventually deactivate)?

It starts at 1. The first time it divided while we were in the womb to copy itself and create the daughter hair cell we have (or don't have) today.

 

[Aaron91]

Thanks for the reply; I have suspected similarly. Thoughts added:

a) I suspect this as well. I think though in the marketing, since they don't have hard data to back up anything beyond the Phase 1/2, this is why they're hitting on the EHF in the marketing comms. You'll notice they don't talk about age-related loss at all, even though a Phase 1B is currently going on (and it is now believed that age-related hearing loss is basically SNHL).

b) I'm not sure if this is considered a reformulation. Considering FX-322 is two separate molecules, I don't know if if from an FDA standpoint it is considered a reformulation to dial either molecule's concentration/volume up or down per injection. Technically for the two Phase 1B programs, they could test a higher dose of FX-322, since they are new safety trials. At one point I saw them call those studies "FX-322.02" or something along those lines in a presentation; can't find it now.

c) It's likely we are.

Something else has just occurred to me, and perhaps we are missing something really obvious.

Wouldn't there be some kind of relationship between absorption rate relative to where OHC loss is most prominent?

We know/suspect that OHC loss is much more prominent in the EHF areas, so is it possible that that is why we are seeing a massive drop-off in both drugs so quickly?

This could explain then why Frequency Therapeutics have opted for multiple doses in the first place, because once regeneration has occurred in the EHF areas, the drug will simply travel through to the next frequency regions without having already been absorbed.

 

[Diesel]

Something else has just occurred to me, and perhaps we are missing something really obvious.

Wouldn't there be some kind of relationship between absorption rate relative to where OHC loss is most prominent?

We know/suspect that OHC loss is much more prominent in the EHF areas, so is it possible that that is why we are seeing a massive drop-off in both drugs so quickly?

This could explain then why Frequency Therapeutics have opted for multiple doses in the first place.

That is what I am hoping is the case. Since CHIR/VPA are supposed to target those progenitor support cells specifically. First, that fresh new OHC/IHC is regenerated after PCA takes place, covering the new progenitor support cell. The next "wave" of CHIR/VPA would pass over that new "patch" and be absorbed further into the cochlea where there are exposed progenitors.

Carl LeBel mentioned in the January webcast that they couldn't validate this in an animal model. So, perhaps they managed to do it with donated cochlea.

@FGG and I swapped a couple threads about this many moons ago before this was released. Don't know what she thinks about it today?

Edit: It's possible that explains the week gap. They know it takes slightly more than a week for the OHC/IHC to fully regrow. So FX-322 isn't being wasted on progenitors in-progress.

 

[serendipity1996]

Are you talking about the Hayflick limitation? If so, that's 70 times or so and hopefully no one needs that even over their lifetime.

I presume so - this was just my musing based on a brief google search lol. It certainly seems like this won't present much of an issue.

 

[FGG]

I'm not well read on this, but is that assuming the progenitor cell starts at zero divisions? My point being, do we know how many times a progenitor cell in the cochlea has already divided by the time we're born (before they eventually deactivate)?

I don't think very much considering mice in utero can regenerate some hair cells (and when they are just born) but humans can't.

 

[FGG]

Thanks for the reply; I have suspected similarly. Thoughts added:

a) I suspect this as well. I think though in the marketing, since they don't have hard data to back up anything beyond the Phase 1/2, this is why they're hitting on the EHF in the marketing comms. You'll notice they don't talk about age-related loss at all, even though a Phase 1B is currently going on (and it is now believed that age-related hearing loss is basically SNHL).

b) I'm not sure if this is considered a reformulation. Considering FX-322 is two separate molecules, I don't know if if from an FDA standpoint it is considered a reformulation to dial either molecule's concentration/volume up or down per injection. Technically for the two Phase 1B programs, they could test a higher dose of FX-322, since they are new safety trials. At one point I saw them call those studies "FX-322.02" or something along those lines in a presentation; can't find it now.

c) It's likely we are.

There is an abbreviated trial you can run to reformulate (lasts about a year on average) once a drug is released. Companies do it a lot when they later release "extended release" versions of their drug but it can be used for something like this too.

It's better for the company to release "as is" now and focus on the high frequencies (and "clarity").

But multiple dosing should at least help even if it doesn't do the full range without extra supplemental VPA.

 

[Olive27]

So are we now saying/speculating that FX-322 will only work at high frequencies in the hidden hearing loss range?

Sorry, my science knowledge is minimal, so above is hard to follow!

 

[FGG]

Something else has just occurred to me, and perhaps we are missing something really obvious.

Wouldn't there be some kind of relationship between absorption rate relative to where OHC loss is most prominent?

We know/suspect that OHC loss is much more prominent in the EHF areas, so is it possible that that is why we are seeing a massive drop-off in both drugs so quickly?

This could explain then why Frequency Therapeutics have opted for multiple doses in the first place, because once regeneration has occurred in the EHF areas, the drug will simply travel through to the next frequency regions without having already been absorbed.

I have brought that up before and I agree that it's a possibility but I would think guinea pig studies would shed some light on this (I'm assuming they did pharmacokinetics in normal guinea pigs too).

 

[FGG]

So are we now saying/speculating that FX-322 will only work at high frequencies in the hidden hearing loss range?

With one dose, yes. They are testing multiple doses now.

 

[Keith Handy]

So the big question is, do healthy hair cells absorb the molecules and do nothing, or do they resist absorbing the molecules?

 

[Diesel]

So the big question is, do healthy hair cells absorb the molecules and do nothing, or do they resist absorbing the molecules?

According to Frequency Therapeutics, FX-322 will not work where a healthy hair cell is present. That is all we know.

 

[FGG]

So the big question is, do healthy hair cells absorb the molecules and do nothing, or do they resist absorbing the molecules?

My guess is the progenitor cell activator binds specifically to the LGR5+ cells. As for VPA, not sure. It is a pretty small molecule: 144.21 Dalton so I think more of it just diffuses into the perilymph quicker in addition to maybe less selective absorption.

 

[serendipity1996]

New Interview Alert.

There was a recent podcast interview with Carl LeBel - the transcript and audio is available here.

What is notable is that he says that: "We believe that we can see FX-322 being approved sometime in the mid 2020s. So it's not too, too far off. We still have several years to go."

I presume that he is still erring somewhat on the conservative side but I think it's interesting that he has modified his timeline from 'within a decade' to 'mid 2020s'. It seems like they have ever more confidence in bringing their product to market.

 

[Guywithapug]

So the big question is, do healthy hair cells absorb the molecules and do nothing, or do they resist absorbing the molecules?

That is a very good question, maybe so much so that it will determine whether a reformulation is needed to penetrate beyond 8 kHz.

 

[Diesel]

New Interview Alert.

There was a recent podcast interview with Carl LeBel - the transcript and audio is available here.

What is notable is that he says that: "We believe that we can see FX-322 being approved sometime in the mid 2020s. So it's not too, too far off. We still have several years to go."

I presume that he is still erring somewhat on the conservative side but I think it's interesting that he has modified his timeline from 'within a decade' to 'mid 2020s'. It seems like they have ever more confidence in bringing their product to market.

Yes. Totally playing it conservative. Still... Mid-2020s to me is like 2023-2027... Which is about what many are projecting here.

 

[Olive27]

Pretty disappointed with that interview, on both the timescales and the fact the they don't see FX-322 being able to eliminate hearing aids!

 

[Keith Handy]

I'm betting that the extended audiogram will be the star performer in this round of trials. Tinnitus might be hit and miss, especially if people's tones aren't ultra high pitched.

 

[Diesel]

Pretty disappointed with that interview, on both the timescales and the fact the they don't see FX-322 being able to eliminate hearing aids!

Carl LeBel can only speak to data that is known from the Phase 1/2 clinical trial. So based on that, they only saw improvements above 8 kHz. If outcomes start to look more like they're deeply penetrating the cochlea and creating improvements at frequencies that compete with hearing aids... the narrative will definitely shift.

 

[FGG]

I'm betting that the extended audiogram will be the star performer in this round of trials. Tinnitus might be hit and miss, especially if people's tones aren't ultra high pitched.

Agree. Without tone matching tinnitus frequencies first, it's definitely not going to be universally effective.

 

[ThomasRobert]

Pretty disappointed with that interview, on both the timescales and the fact the they don't see FX-322 being able to eliminate hearing aids!

Relax... He was just being diplomatic, it's not the right time to make enemies with the hearing aid industry...

 

[Keith Handy]

Pretty disappointed with that interview, on both the timescales and the fact the they don't see FX-322 being able to eliminate hearing aids!

It should eventually be able to eliminate or drastically reduce the need for hearing aids, when a better delivery system is devised/formulated.

 

[FGG]

Pretty disappointed with that interview, on both the timescales and the fact the they don't see FX-322 being able to eliminate hearing aids!

He was talking about the cochlear implant population. He said people in the "hearing aid range" could potentially be normal / hearing aid free but CI patients could maybe move to hearing aid range. That's actually amazing.

 

[Zugzug]

I'm betting that the extended audiogram will be the star performer in this round of trials. Tinnitus might be hit and miss, especially if people's tones aren't ultra high pitched.

I completely agree. I think high frequency hearing and tinnitus will be very successful.

Being cautiously pessimistic, I think the gel will run into more problems than we think getting deeper. Multiple doses will show some effect in pushing it deeper, but there will be issues.

If I'm wrong, Breakthrough Therapy status will be achievable and if I'm right, it still may be achievable with the right marketing. Their new hires could help.

Regardless, I think Frequency Therapeutics eventually fixes this problem in the next 5-10 years.

 

[patorjk]

Pretty disappointed with that interview, on both the timescales and the fact the they don't see FX-322 being able to eliminate hearing aids!

I see it as him tempering expectations. It's also inline with the data for far. If Phase 2a has better data, I'm sure they'll adjust their talking points.

Also, behind the scenes they're probably working on ways to make the drug better. They know they can regrow all of the hair cells, the problem seems to be getting the VPA component deeper into the cochlea.

 

[Jrblovsky]

Pretty disappointed with that interview, on both the timescales and the fact the they don't see FX-322 being able to eliminate hearing aids!

Why would one pay thousands for a drug and still be required to pay thousands more for hearing aids? That isn't helpful at all.

 

[Diesel]

I completely agree. I think high frequency hearing and tinnitus will be very successful.

Being cautiously pessimistic, I think the gel will run into more problems than we think getting deeper. Multiple doses will show some effect in pushing it deeper, but there will be issues.

If I'm wrong, Breakthrough Therapy status will be achievable and if I'm right, it still may be achievable with the right marketing. Their new hires could help.

Regardless, I think Frequency Therapeutics eventually fixes this problem in the next 5-10 years.

If Phase 2A + both Phase 1Bs look favorable in multiple primary outcomes, even if multi-dosing is minimal, FX-322 will still exceed Breakthrough Therapy Status requirements.

Once the product is in the market, there will be investment in getting the drug to reach the entire cochlea in an efficient timeframe, no question.

 

[Diesel]

Why would one pay thousands for a drug and still be required to pay thousands more for hearing aids? That isn't helpful at all.

It depends on the price of FX-322... but if you could pay say $2000 for FX-322 and go from heavy-duty $5000 hearing aids to less powerful, easily hidden $2000 hearing aids, I could see the benefit. Not to mention, regaining actual hearing might make living with the less powerful hearing aids more reasonable.

I can't speak for hearing aids, since I don't have them, but I imagine having to go from an entry hearing aid to one of the more powerful ones isn't exactly great.

 

[FGG]

Why would one pay thousands for a drug and still be required to pay thousands more for hearing aids? That isn't helpful at all.

If you listen to the interview, he was talking about people close to the cochlear implant range. Most people aren't in that range and the ones that are would rather get a hearing aid than a cochlear implant. How is that not helpful?

 

[Diesel]

the problem seems to be getting the VPA component deeper into the cochlea.

We assume it is a problem here on this forum. But no mention of it at all from the firm.