Frequency Therapeutics — Hearing Loss Regeneration

[Aaron91]

I know this is an FX-322 thread but it's worth noting that Otonomy had half their value wiped out today after their meniere's drug failed Phase 3 (again).

Otonomy stock loses half its value after disappointing trial results of vertigo treatment

Biotech is notoriously volatile but I can't help but feel now that not all is well behind the scenes. Otidivex failed phase III 3 years ago and they put it down to a placebo effect from ENTs hyping up patients about getting the drug. Not only has it failed again, but they're also re-running OTO-413 Phase 1 again as well, despite positive results from their initial trial. Looks like any chance of relief in the next 5 years is only going to come from one place, if at all: FX-322.

 

[Nobody19]

That's bad news, but the science behind their Meniere and synapse regeneration drugs is very different.

 

[Aaron91]

That's bad news, but the science behind their Meniere and synapse regeneration drugs is very different.

I'm aware, but that's besides the point.

Otonomy were hoping that their Meniere's drug (Otividex) would make them self-sustaining moving forwards so that they could self-finance the development and clinical trials of their other drugs through Phase 3. That is now no longer viable. They have two years of cashflow left, which should get them through Phase 2 for OTO-413 and OTO-313, but beyond that they will need further investment. I'm now left wondering where that investment is going to come from. The investors who financed Otonomy for Otividex have now had their fingers burnt twice and Otonomy's credibility is damaged.

In other words, pitching for more money in future is gonna be a really hard sell for Otonomy moving forwards. They're really going to have to knock things out the park with their Phase 2 results, otherwise the company will most probably sink before they even get to Phase 3.

 

[weab00]

Biotech is notoriously volatile but I can't help but feel now that not all is well behind the scenes. Otidivex failed phase III 3 years ago and they put it down to a placebo effect from ENTs hyping up patients about getting the drug. Not only has it failed again, but they're also re-running OTO-413 Phase 1 again as well, despite positive results from their initial trial. Looks like any chance of relief in the next 5 years is only going to come from one place, if at all: FX-322.

It sucks but I don't see what this has to do with FX-322, unless you're giving us the warning that most biotechs fail which is already in the back of our minds.

 

[FGG]

I know this is an FX-322 thread but it's worth noting that Otonomy had half their value wiped out today after their meniere's drug failed Phase 3 (again).

Otonomy stock loses half its value after disappointing trial results of vertigo treatment

Biotech is notoriously volatile but I can't help but feel now that not all is well behind the scenes. Otidivex failed phase III 3 years ago and they put it down to a placebo effect from ENTs hyping up patients about getting the drug. Not only has it failed again, but they're also re-running OTO-413 Phase 1 again as well, despite positive results from their initial trial. Looks like any chance of relief in the next 5 years is only going to come from one place, if at all: FX-322.

Intratympanic steroids are so routinely given for Meniere's vertigo attacks (I was offered them by an Otologist who treats a ton of Meniere's for instance when they thought I might have Meniere's) that it's completely unexpected to me this particular drug doesn't work.

If any amount got into the ear, it should work better than placebo/no steroids.

All Otividex is, is a long acting Dexamethasone steroid injection. Like I said, I really wonder if this will change the standard of care using IT steroids for vertigo in general.

 

[Diesel]

Informing little read:

Tinnitus Is Associated With Extended High-frequency Hearing Loss and Hidden High-frequency Damage in Young Patients

 

[Diesel]

Also: Here's the FX-322 article pre-published:

Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study

Attached the PDF. Dig in!

 

[dd314]

Intratympanic steroids are so routinely given for Meniere's vertigo attacks (I was offered them by an Otologist who treats a ton of Meniere's for instance when they thought I might have Meniere's) that it's completely unexpected to me this particular drug doesn't work.

If any amount got into the ear, it should work better than placebo/no steroids.

All Otividex is, is a long acting Dexamethasone steroid injection. Like I said, I really wonder if this will change the standard of care using IT steroids for vertigo in general.

SPI-1005 seems to work and it's an oral steroid. It's been shown to, among other things, reduce tinnitus and hearing loss for people diagnosed with Meniere's.

 

[Diesel]

Looks like a single injection of CHIR is getting beyond 2 kHz rather quickly in the cochlea, and is indeed traveling in a "wave" as described by Carl LeBel. And, seems to be at pretty high levels over the testing period.

However, VPA appears to be absorbed more quickly before it reaches the same depth in the cochlea. If I am understanding it correctly, the concentrations of both CHIR and VPA need to be consistent at the site of the cochlea for PCA to take place. So, we see why at 8 kHz a single injection showed an improvement on the audiogram in the Phase 1/2.

I'm wondering now, considering the rate of movement and absorption, if the multi-week injections are spaced too far apart. Maybe it should have been like 4 injections in 4 days?

However, it is good to see that the drugs touched as far as 2 kHz in a single injection, so depending on how long even traces stick around in the cochlea over a 7-day timeframe, 4x injections may be effective down to 2 kHz on the audiogram.

 

[Gorbeh3]

Also: Here's the FX-322 article pre-published:

Improved Speech Intelligibility in Subjects With Stable Sensorineural Hearing Loss Following Intratympanic Dosing of FX-322 in a Phase 1b Study

Attached the PDF. Dig in!

 

[GlennS]

It sucks but I don't see what this has to do with FX-322, unless you're giving us the warning that most biotechs fail which is already in the back of our minds.

For me the failure of Lenire (and I do consider it a failure) is reason enough for me to not allow myself to get too obsessed with FX-322.

Don't get me wrong, I am cautiously optimistic, but I'm stopping short of starting the run towards the football that Lucy is holding.

 

[Street Novelist]

You should be working for Frequency Therapeutics, Diesel. I can't begin to describe how valuable your contributions to this thread have been.

 

[UHPTS]

So why couldn't the extended audiogram process be automated? You set the patient up with the headset and the machine, initiate the test, leave for 10 to 15 minutes to do other tasks, and the machine records the patient's responses via a presses of a button or other input device. The machine is programmed to choose tones and levels the same way a live audiologist would, based on responses.

This way everybody could see if they have narrow dips or sharp dropoffs, similar to the ones shown earlier in this thread, which often seem to correspond with tinnitus frequencies, and wouldn't show up on a standard test.

Get a good pair of earphones and listen to this:



You will see where your dips are even without going to audiologist.

 

[Aaron91]

Looks like a single injection of CHIR is getting beyond 2 kHz rather quickly in the cochlea, and is indeed traveling in a "wave" as described by Carl LeBel. And, seems to be at pretty high levels over the testing period.

However, VPA appears to be absorbed more quickly before it reaches the same depth in the cochlea. If I am understanding it correctly, the concentrations of both CHIR and VPA need to be consistent at the site of the cochlea for PCA to take place. So, we see why at 8 kHz a single injection showed an improvement on the audiogram in the Phase 1/2.

Good observation, and I think you are reading correctly, because surely Frequency would have designed the drug with the intention of maintaining whatever the molecule ratio is at time of injection throughout the cochlea. The bottom line is that you can't have PCA with only one of the two molecules, but it would be good if someone more well versed in drug delivery could comment on this. I also wonder then if the CHIR to VPA ratio then would need to be adjusted so that VPA quantities are higher. Given they would have already been aware of this before starting Phase 2, I must also wonder if they've adjusted the ratio as part of experimenting with multiple doses in Phase 2.

Edit: given they are allowed to test multiple doses, would the FDA allow them to adjust the molecule ratio of the drug itself? I have no information on this but I wouldn't be surprised if the FDA didn't allow it. In any case, multiple doses, if effective, should still solve the issue; it may just mean that you have an excess of CHIR that is "wasted". Not that anyone is gonna care if enough of both molecules get to where they need to be.

 

[FGG]

SPI-1005 seems to work and it's an oral steroid. It's been shown to, among other things, reduce tinnitus and hearing loss for people diagnosed with Meniere's.

It's not an oral steroid but I agree that it seems to work for aural symptoms of Meniere's.

 

[Keith Handy]

Get a good pair of earphones and listen to this:

You will see where your dips are even without going to audiologist.

1. The audiogram is not to "see for yourself" what you can hear, it's to have hard medical evidence on record.

2. Audiograms need to be done at specific dB levels to measure at what level you can no longer hear, and consumer electronics are not calibrated for this.

3. On hearing a pitch sweep, your brain will often deceive you by filling in short gaps.

 

[Keith Handy]

However, it is good to see that the drugs touched as far as 2 kHz in a single injection, so depending on how long even traces stick around in the cochlea over a 7-day timeframe, 4x injections may be effective down to 2 kHz on the audiogram.

That would be a beautiful thing.

 

[patorjk]

Looks like a single injection of CHIR is getting beyond 2 kHz rather quickly in the cochlea, and is indeed traveling in a "wave" as described by Carl LeBel. And, seems to be at pretty high levels over the testing period.

However, VPA appears to be absorbed more quickly before it reaches the same depth in the cochlea. If I am understanding it correctly, the concentrations of both CHIR and VPA need to be consistent at the site of the cochlea for PCA to take place. So, we see why at 8 kHz a single injection showed an improvement on the audiogram in the Phase 1/2.

I'm wondering now, considering the rate of movement and absorption, if the multi-week injections are spaced too far apart. Maybe it should have been like 4 injections in 4 days?

However, it is good to see that the drugs touched as far as 2 kHz in a single injection, so depending on how long even traces stick around in the cochlea over a 7-day timeframe, 4x injections may be effective down to 2 kHz on the audiogram.

Are VPA and CHIR the two drugs that make up FX-322? I thought I remember Carl LeBel saying that each worked on its own, but that they had a synergistic effect and worked much better together (though I could be misremembering things).

Are you saying both drugs are needed for hair cell regeneration to take place?

 

[Diesel]

Are VPA and CHIR the two drugs that make up FX-322? I thought I remember Carl LeBel saying that each worked on its own, but that they had a synergistic effect and worked much better together (though I could be misremembering things).

Are you saying both drugs are needed for hair cell regeneration to take place?

FX-322 is made up of two small molecules. They are VPA and CHIR. They both need to be at certain concentrations to be effective in activating progenitors.

 

[FGG]

Good observation, and I think you are reading correctly, because surely Frequency would have designed the drug with the intention of maintaining whatever the molecule ratio is at time of injection throughout the cochlea. The bottom line is that you can't have PCA with only one of the two molecules, but it would be good if someone more well versed in drug delivery could comment on this. I also wonder then if the CHIR to VPA ratio then would need to be adjusted so that VPA quantities are higher. Given they would have already been aware of this before starting Phase 2, I must also wonder if they've adjusted the ratio as part of experimenting with multiple doses in Phase 2.

Edit: given they are allowed to test multiple doses, would the FDA allow them to adjust the molecule ratio of the drug itself? I have no information on this but I wouldn't be surprised if the FDA didn't allow it. In any case, multiple doses, if effective, should still solve the issue; it may just mean that you have an excess of CHIR that is "wasted". Not that anyone is gonna care if enough of both molecules get to where they need to be.

Totally a hypothetical, but since VPA is already an approved drug in an injectable form (like Dexamethasone is), couldn't you just chase FX-322 with more VPA (off label) if needed in the interim between a new formulation?

 

[Diesel]

Looks like a single injection of CHIR is getting beyond 2 kHz rather quickly in the cochlea, and is indeed traveling in a "wave" as described by Carl LeBel. And, seems to be at pretty high levels over the testing period.

However, VPA appears to be absorbed more quickly before it reaches the same depth in the cochlea. If I am understanding it correctly, the concentrations of both CHIR and VPA need to be consistent at the site of the cochlea for PCA to take place. So, we see why at 8 kHz a single injection showed an improvement on the audiogram in the Phase 1/2.

I'm wondering now, considering the rate of movement and absorption, if the multi-week injections are spaced too far apart. Maybe it should have been like 4 injections in 4 days?

However, it is good to see that the drugs touched as far as 2 kHz in a single injection, so depending on how long even traces stick around in the cochlea over a 7-day timeframe, 4x injections may be effective down to 2 kHz on the audiogram.

I hope to see that patients have super hearing at in the Extended High Frequency range. The concentration up there is really high for all 3 hours needed to meet predicted effectiveness.

 

[Aaron91]

Are VPA and CHIR the two drugs that make up FX-322? I thought I remember Carl LeBel saying that each worked on its own, but that they had a synergistic effect and worked much better together (though I could be misremembering things).

Are you saying both drugs are needed for hair cell regeneration to take place?

It would appear that you need both. Here's what Carl said:

"I didn't appreciate this, but FX-322 is really comprised of two molecules, and these two molecules are going after two of these pathways that control the progenitor cells in the cochlea. One can't – we believe – one can't just use one drug to treat, we believe it has to be more than one drug. "

 

[Diesel]

Totally a hypothetical, but since VPA is already an approved drug in an injectable form (like Dexamethasone is), couldn't you just chase FX-322 with more VPA (off label) if needed in the interim between a new formulation?

Good theory. I wouldn't trust an ENT to do it.

 

[Diesel]

Looking at this SNR comparison (for the WIN test) between FX-322 and Placebo, I am also hopeful that a larger sample set from the Phase 2A should show clear improvements in hearing in noise.

It's clear that the SNR differences were statistically significant (p=0.012), but the sample set was too small to show overall WIN improvements (p=.211).

 

[dd314]

It's not an oral steroid but I agree that it seems to work for aural symptoms of Meniere's.

Whoops, I meant orally administered. It's also being tested to suppress the cytokine storm in severe COVID-19 cases, so it looks like inflammation is the name of the game with Meniere's, but I guess that was known already.

 

[Keith Handy]

Totally a hypothetical, but since VPA is already an approved drug in an injectable form (like Dexamethasone is), couldn't you just chase FX-322 with more VPA (off label) if needed in the interim between a new formulation?

I do like how we're all brainstorming ideas for getting the drug deeper in. We should compile them and send them to their researchers. They'd probably politely tell us why none of our ideas would work.

 

[Diesel]

FUN FACT:

In the research paper, it is noted that 2/4 patients that received FX-322 saw a meaningful improvement in SNR hearing with a -3.1dB SNR decrease at 50% correct.

OTO-413 showed nearly the same level of SNR improvement, -3 dB at 50% correct.

So... we may not even need OTO-413 if FX-322 shows similar results at a larger scale in WIN/SNR improvements.

 

[Guywithapug]

I do like how we're all brainstorming ideas for getting the drug deeper in. We should compile them and send them to their researchers. They'd probably politely tell us why none of our ideas would work.

Maybe inject the drug, put patient on a rotisserie, rotate for 45 minutes until done.

 

[scotty03874]

Looking at this SNR comparison (for the WIN test) between FX-322 and Placebo, I am also hopeful that a larger sample set from the Phase 2A should show clear improvements in hearing in noise.

It's clear that the SNR differences were statistically significant (p=0.012), but the sample set was too small to show overall WIN improvements (p=.211).

Just released today 10 minutes ago:

Frequency Therapeutics Announces Publication of Phase 1/2 Data Showing Hearing Improvements in Acquired Sensorineural Hearing Loss Patients Receiving FX-322

 

[Gb3]

Stock just shot up after hours.