Frequency Therapeutics — Hearing Loss Regeneration

[RingingBrother]

From what I understood of the animal models, it was inner hair cells.

Both FX-322 and FX-345?

 

[RingingBrother]

From what I understood of the animal models, it was inner hair cells.

We all know this is going to fail, why do we get our hopes up every time?

I think they haven't released anything for FX-345 yet. I'm not sure.

 

[Nick47]

I think they haven't released anything for FX-345 yet. I'm not sure.

@RingingBrother, again it's only my understanding and correct me if I'm wrong, but both target inner hair cells. The difference between them is FX-345 penetrates deeper into the cochlear, in theory targeting lower frequencies.

 

[Chad Lawton]

@RingingBrother, again it's only my understanding and correct me if I'm wrong, but both target inner hair cells. The difference between them is FX-345 penetrates deeper into the cochlear, in theory targeting lower frequencies.

Carl LeBel said on the HLAA Q&A earlier this year that their compounds activate both inner and outer hair cells. I speculate that it has more to do with the cochlear anatomy than the compound only targeting 1 type of hair cell. If you look at their treated mouse cochlea image which is currently slide 48 on their investor deck you can see there was robust inner hair cell response at the highest frequencies but little outer hair cell growth but as you get deeper into the cochlea, you can see more outer hair cells responded.

 

[CRGC]

Frequency Therapeutics to Participate in September Investor and Medical Conferences

• American Academy of Otolaryngology – Head and Neck Surgery (AAO-HNSF) 2022 Annual Meeting and OTO Experience: "Presentation on results of four single-dose trials of FX-322, showing improved speech perception" by Kevin Franck, Ph.D., SVP Marketing and New Product Planning, Tuesday, September 13, 2022, 5 p.m. EST

Source: BusinessWire

Wondering if there will be any new information on FX-322, or just a rehash of their past positive results.

 

[Street Novelist]

I wish they would tell us when the FX-345 trial will begin.

 

[Keith Handy]

Wondering if there will be any new information on FX-322, or just a rehash of their past positive results.

99% sure there will be no new info. It doesn't happen at these events. When they have something to announce, they make their own announcements. They should be doing safety trials for the newer FX-345 soon, though, so keep an eye out for that.

 

[Padraigh Griffin]

I wish they would tell us when the FX-345 trial will begin.

Had it not started yet? Ah well. That is the game changer. I really don't know why they keep flogging a dead horse with FX-322 but hey that's just my opinion. Getting down to c. 4,000 Hz is what we need.

 

[Nobody19]

I wish they would tell us when the FX-345 trial will begin.

Why don't you look on their website?

 

[vttbx]

Carl LeBel said on the HLAA Q&A earlier this year that their compounds activate both inner and outer hair cells. I speculate that it has more to do with the cochlear anatomy than the compound only targeting 1 type of hair cell. If you look at their treated mouse cochlea image which is currently slide 48 on their investor deck you can see there was robust inner hair cell response at the highest frequencies but little outer hair cell growth but as you get deeper into the cochlea, you can see more outer hair cells responded.

Is there anything preventing FX-345 from affecting frequencies up to 20 kHz? Or are the higher frequencies more difficult to treat?

 

[Gb3]

Is there anything preventing FX-345 from affecting frequencies up to 20 kHz? Or are the higher frequencies more difficult to treat?

Do you think you are a dog?

 

[Cernuto]

Is there anything preventing FX-345 from affecting frequencies up to 20 kHz? Or are the higher frequencies more difficult to treat?

My understanding is the highest frequencies are treated first due to the nature of the way the drug travels through the cochlea.

 

[Nick47]

Is there anything preventing FX-345 from affecting frequencies up to 20 kHz? Or are the higher frequencies more difficult to treat?

The lower frequencies are harder to reach as they are further in the cochlear. It sounds like a change to the delivery agents rather than the FX-322 formula will be used for FX-345. Either way be realistic, I'm not impressed with Frequency Therapeutics so far as a company.

 

[John Joseph]

My understanding is the highest frequencies are treated first due to the nature of the way the drug travels through the cochlea.

In theory, yes. In pure terms of physical proximity, that's the case. But there might be some other factor at play.

The crux of this question is very interesting to me and I hope they're trying to figure out why the outer hair cell improvement is lagging behind the inner, especially in the upper register.

 

[SmallRonnie]

My understanding is the highest frequencies are treated first due to the nature of the way the drug travels through the cochlea.

I believe most people with tinnitus have high frequency hearing loss too. Makes sense if it's the easiest to damage then it should be the easiest to heal too.

 

[EkkoMusic]

if it's the easiest to damage then it should be the easiest to heal.

Can you explain? From what I understand:

1. Certain hair cells are not intrinsically stronger than other hair cells.
2. In cases of SSNHL recovery with steroids, antivirals, etc., high frequency hearing function is less likely to be restored than lower frequency hearing function.

Please correct me if we have data that says otherwise!

 

[SmallRonnie]

Can you explain? From what I understand:

1. Certain hair cells are not intrinsically stronger than other hair cells.
2. In cases of SSNHL recovery with steroids, antivirals, etc., high frequency hearing function is less likely to be restored than lower frequency hearing function.

Please correct me if we have data that says otherwise!

I'm just going off the anatomy of the cochlea. The higher frequency parts are on the outside and get hit first so I would assume that's why they usually get damaged more. Like how when you're bowling and the front pins are always more likely to get knocked down. Not very scientific but seems logical and most people with tinnitus do just have higher frequency hearing loss. I'm not a doctor lol.

I'm not sure about how those steroids work but FX-322 does work better for higher frequency hearing loss and FX-345 is then better for more lower frequencies too. I just assumed it's because the drug needs to physically hit those areas and they are the closest to the delivery point.

Maybe the steroids are more systemic? The steroids are always given IT? I don't know how they work at all.

 

[vttbx]

Do you think you are a dog?

Only in years.

 

[John Joseph]

I'm just going off the anatomy of the cochlea. The higher frequency parts are on the outside and get hit first so I would assume that's why they usually get damaged more. Like how when you're bowling and the front pins are always more likely to get knocked down. Not very scientific but seems logical and most people with tinnitus do just have higher frequency hearing loss. I'm not a doctor lol.

I'm not sure about how those steroids work but FX-322 does work better for higher frequency hearing loss and FX-345 is then better for more lower frequencies too. I just assumed it's because the drug needs to physically hit those areas and they are the closest to the delivery point.

Maybe the steroids are more systemic? The steroids are always given IT? I don't know how they work at all.

Well, FX-322 only really touches the higher frequencies, so yes, that's where it works best, because that's the only place it could work.

The only audiogram improvements in any of the trials were seen in a few patients at 8 kHz. I don't believe any of the extended high frequency audio testing showed any notable improvements. So, this, along with the image of the mouse cochlea basically showing the same results (outer hair cell regrowth improving the further down the cochlea you go), seems to suggest there is something getting in the way of robust regeneration at the very high frequencies.

I'm sure they're interested in why and I hope they crack it.

 

[Nick47]

The only audiogram improvements in any of the trials were seen in a few patients at 8 kHz.

They had audiogram improvements?

 

[VTae]

It only restores hair cells. The hair cells that it restores have fresh cochlear synapses but it doesn't re-connect old synapses to old hair cells. At least they haven't provided any evidence of this in their preclinical research.

Can someone elaborate on that? If only hair cells are restored, but the synapses aren't connected to the nerves/brain, then how is that helpful? Won't these hair cells be dead weight?

 

[Hottopic29]

Can someone elaborate on that? If only hair cells are restored, but the synapses aren't connected to the nerves/brain, then how is that helpful? Won't these hair cells be dead weight?

There are other drugs in the works to repair synapses so maybe both will be needed.

 

[VTae]

There are other drugs in the works to repair synapses so maybe both will be needed.

Yes but regardless, if there was any improvement in their trial (the 10% they claim), then somehow it worked. But that sounds physically impossible. How could it have helped if there are no synaptic connections? Is the data just wrong? What really is going on here? This sounds so sketchy.

 

[SmallRonnie]

Yes but regardless, if there was any improvement in their trial (the 10% they claim), then somehow it worked. But that sounds physically impossible. How could it have helped if there are no synaptic connections? Is the data just wrong? What really is going on here? This sounds so sketchy.

I thought I read somewhere that new synapses will grow if the hair cells are regenerated but can't remember where.

Cochlear implants improve hearing so why wouldn't regenerating hair cells work.

 

[VTae]

I thought I read somewhere that new synapses will grow if the hair cells are regenerated but can't remember where.

Cochlear implants send electric signals directly to the nerves underneath, though, no? So they don't need these nerves to reconnect, they could just brute-force a current strong enough to get there.

Regardless, I have no idea what I'm talking about, I'm just trying to understand. So, I'd appreciate if someone could find that citation.

 

[Chad Lawton]

Can someone elaborate on that? If only hair cells are restored, but the synapses aren't connected to the nerves/brain, then how is that helpful? Won't these hair cells be dead weight?

The new hair cells that are created using FX-322 do form synaptic connections. The original damaged hair cells that are still in place and have lost their synaptic connection before FX-322 administration will not form synaptic connections after FX-322 administration.

 

[Chad Lawton]

Is there anything preventing FX-345 from affecting frequencies up to 20 kHz? Or are the higher frequencies more difficult to treat?

No, higher frequencies are easier to treat than lower frequencies based on their proximity to the round window membrane. The biggest risk I see with FX-345 is that it may be too high of a concentration at the highest frequencies and may be too potent because their preclinical data shows that the highest frequencies may reach 100x the target concentration level during administration. We will have to see though, maybe it will be a non issue.

 

[John Joseph]

They had audiogram improvements?

Yes, according to these slides (page 17 and 36), there were 4 (out of 13) subjects that saw 10-15 dB improvements at 8 kHz.

https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1

It also looks like they only tested up to 8 kHz in the trial(s) that the stat comes from, so there might have been some extended high frequency improvement as well, but it's impossible to say without the data.

I'm pretty sure the trials since then have included extended high frequency testing, but they were poorly designed with populations that weren't really responding to begin with, so with the right trial set up, improvement in that range is still a possibility I suppose.

I think they're on the right path as far as a real breakthrough with this technology. Where they're at on that path, it's hard to say. It could be a while for a really refined, successful treatment. Or we might be surprised with expectation beating results from a reformulated trial for FX-322 and beyond with FX-345 results coming out next year.

 

[John Joseph]

No, higher frequencies are easier to treat than lower frequencies based on their proximity to the round window membrane. The biggest risk I see with FX-345 is that it may be too high of a concentration at the highest frequencies and may be too potent because their preclinical data shows that the highest frequencies may reach 100x the target concentration level during administration. We will have to see though, maybe it will be a non issue.

Huh, never thought of that aspect. Interesting speculation for sure.

 

[VTae]

The new hair cells that are created using FX-322 do form synaptic connections. The original damaged hair cells that are still in place and have lost their synaptic connection before FX-322 administration will not form synaptic connections after FX-322 administration.

Thanks for the clarification. Do we know how these synaptic connections form? And does that mean that, after therapy, the patient will end up with a bunch of damaged dead-weight hair cells grouped together with these brand new hair cells, competing for space?

Hair cells are "carried" by progenitor cells, right? So, my understanding now is that this is what takes place:

(Progenitor Cell with Damaged Hair Cell) + FX-322 = (Progenitor Cell with Damaged Hair Cell) + (Progenitor Cell with Healthy Hair Cell)

Is that picture correct?