Frequency Therapeutics — Hearing Loss Regeneration

[serendipity1996]

Also if you take a look at their website, they emphasise how their small-molecule approach avoids many of the potential pitfalls of traditional gene/cell therapies.

"...reducing complexity by using small molecule therapeutics to temporarily reactivate progenitor cells that are already located at the tissue target site within the body and are pre-programmed to make specific cell types."

• "Avoids the major challenge of delivering and integrating cells into the proper location within an organ
• Activates the body's own progenitor cells at the desired location in targeted tissues"

https://www.frequencytx.com/science/pca-approach/

 

[Diesel]

I think at this point considering the clinical trial data that is being released about FX-322 on actual living human beings, it's probably time we stop looking back and stirring up anxiety about stuff scientists did to mice from up to ten years ago. There is so much whataboutism regarding research involving mice that apparently doesn't directly translate to people.

 

[Sloth]

Thank you all for the informative replies!

Rather than force cells to become something different, we're causing precursor cells to behave in a native manner, mimicking the biology that humans experience during development

So it really just activates the body's own innate ability to regenerate. It's like FX-322 is a surgical tool while competing approaches are more like hammers.

It's also quite funny to me. Scam artists have always sold desperate people stuff that supposedly activates the body's natural healing ability and now we get something like that but for real and scientifically proven.

it's probably time we stop looking back and stirring up anxiety about stuff scientists did to mice from up to ten years ago

I wasn't trying to stir anxiety. I just had 2 competing information and wanted to know which one is correct.

 

[sssing]

A friend of mine said her ENT's theory for tinnitus is the hair cells drop out and become very small crystals which bounce around and cause tinnitus. So this friend doesn't shake her head vigorously. I know it's unbelievable but what do you guys think? I think if there were really hair cell leftovers then it should have been discovered by those researchers who performed autopsies on the inner ear and not have eluded them.

The ENT comes from a very reputable hospital in my country

 

[patorjk]

Probably not based on any news but it's funny how everyone gets worried with a sell off but kind of ignores the jumps.

I'm holding a few shares and I have a feeling things are going to get nuts real soon. When I held EARS, it was mostly on a downward trend. However, starting at about 3 months before the results were due it started climbing, and in the 2 weeks before the results were released it shot up 30%. I still remember wondering if I should sell (all signs pointed to failure, but I wanted it to work so I foolishly held).

With Frequency, there's a lot more excitement and a lot more promise. I'm wondering what it's bump will be. The only thing I could see stopping some kind of rise would be if some bad omens start appearing (ex: insiders dumping mass amounts of stock). My gut is that a lot of people are watching this stock, but are keeping their money elsewhere until the result release date gets closer (maybe like us, they're trying to read the tea leaves).

 

[Diesel]

A friend of mine said her ENT's theory for tinnitus is the hair cells drop out and become very small crystals which bounce around and cause tinnitus. So this friend doesn't shake her head vigorously. I know it's unbelievable but what do you guys think? I think if there were really hair cell leftovers then it should have been discovered by those researchers who performed autopsies on the inner ear and not have eluded them.

The ENT comes from a very reputable hospital in my country

I've got a homeopathic remedy you might be interested in if you think there are crystals bouncing around your cochlea.

 

[xyz]

A friend of mine said her ENT's theory for tinnitus is the hair cells drop out and become very small crystals which bounce around and cause tinnitus. So this friend doesn't shake her head vigorously. I know it's unbelievable but what do you guys think? I think if there were really hair cell leftovers then it should have been discovered by those researchers who performed autopsies on the inner ear and not have eluded them.

The ENT comes from a very reputable hospital in my country

Possible theory. But what is then with the ones who have hearing loss but no tinnitus? Do they have some protective layer in the inner ear we don't have?

 

[FGG]

Possible theory. But what is then with the ones who have hearing loss but no tinnitus? Do they have some protective layer in the inner ear we don't have?

One prominent theory is being discussed on the Will Sedley thread. It has to do with how "predictive" your brain is naturally. Better "predictive" brains are more susceptible to tinnitus.

Dr. Thanos talked about the same thing on his recent podcast too.

 

[HootOwl]

A friend of mine said her ENT's theory for tinnitus is the hair cells drop out and become very small crystals which bounce around and cause tinnitus. So this friend doesn't shake her head vigorously. I know it's unbelievable but what do you guys think? I think if there were really hair cell leftovers then it should have been discovered by those researchers who performed autopsies on the inner ear and not have eluded them.

The ENT comes from a very reputable hospital in my country

Not plausible in any biological way I can even remotely conceive.

 

[tommyd87]

Can you point me to where they said it's the same phase 1 dose 4 times. I have not seen that reported anywhere apart from the Pharmocokinetics study they just did with the phase 1 dose in Germany on the cochlear implant patients.

They don't. It's the same dose as in Phase 1/2. The notion it's a higher dose seems to be something that just won't die.

If it is accurate, it actually could have been referring to the fact that there was a low and high dose delivered in the inaugural trial.

 

[Pero1234]

A friend of mine said her ENT's theory for tinnitus is the hair cells drop out and become very small crystals which bounce around and cause tinnitus. So this friend doesn't shake her head vigorously. I know it's unbelievable but what do you guys think? I think if there were really hair cell leftovers then it should have been discovered by those researchers who performed autopsies on the inner ear and not have eluded them.

The ENT comes from a very reputable hospital in my country

Why do ENTs have theories? Aren't they supposed to be knowledgeable of their area of expertise?

"Hi, I am your new teacher Geography... btw, toss out those handbooks. I have a theory that the earth is flat."

 

[xyz]

Why do ENTs have theories? Aren't they supposed to be knowledgeable of their area of expertise?

"Hi, I am your new teacher Geography... btw, toss out those handbooks. I have a theory that the earth is flat."

I think this analogy is a bit misleading. You can't expect ENTs to have answers for something that the current research is also just guessing about.

 

[Jurger]

If it is accurate, it actually could have been referring to the fact that there was a low and high dose delivered in the inaugural trial.

In the Australian Phase 1 trial? Not that I know of. Whatever the case, Phase 1/2, Phase 2a (and most likely onward) have the same dose, albeit multiple times.

 

[tommyd87]

In the Australian Phase 1 trial? Not that I know of. Whatever the case, Phase 1/2, Phase 2a (and most likely onward) have the same dose, albeit multiple times.

https://clinicaltrials.gov/ct2/show/NCT03616223

 

[patorjk]

I didn't realize there was a low dose in the phase I study, this makes Frequency's Phase I results quite a bit more compelling. 15 people were treated with FX-322, but only half of them had the "high" (now regular I suppose) dose.

In their presentation [1] they break it down by Mild and Moderate hearing loss (but don't mention low or high dose), and note that there were 4 individuals who had statistically significant improvements. I'm guessing it's more likely than not that the individuals who had statistically significant improvements had a high dose.

This means that 1 dose leads to statistically significant improvements in hearing in 50% or 57% (it's unclear if there were 7 or 8 high doses) of treated individuals. Given that everyone saw word score improvements, now the additional doses seem even more exciting.

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

 

[tommyd87]

I didn't realize there was a low dose in the phase I study, this makes Frequency's Phase I results quite a bit more compelling. 15 people were treated with FX-322, but only half of them had the "high" (now regular I suppose) dose.

In their presentation [1] they break it down by Mild and Moderate hearing loss (but don't mention low or high dose), and note that there were 4 individuals who had statistically significant improvements. I'm guessing it's more likely than not that the individuals who had statistically significant improvements had a high dose.

This means that 1 dose leads to statistically significant improvements in hearing in 50% or 57% (it's unclear if there were 7 or 8 high doses) of treated individuals. Given that everyone saw word score improvements, now the additional doses seem even more exciting.

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

i have a theory that FX-322 needs to be given in more doses and a higher ml size in order to work way more effectively. I essentially expect that the trials that they do in the future may center around the effects of multiple doses which are of a higher ml size.

 

[d'Wooluf]

a higher ml size in order to work way more effectively

My memory is that this was addressed in their IPO statement. The higher dose made no difference and this was broadly in line with their expectations. Along with that they said that a higher concentration of active ingredients might make a difference. Strangely - from a layperson's perspective - they don't seem to have changed their formulation at all.

 

[Jurger]

i have a theory that FX-322 needs to be given in more doses and a higher ml size in order to work way more effectively. I essentially expect that the trials that they do in the future may center around the effects of multiple doses which are of a higher ml size.

I don't think they're going to mess with quantity. Besides, the round window membrane can only 'absorb' so much with each injection. The cochlea itself is about as large as the top of a finger.

What they probably will try to do is see what kind of benefit people with more severe and profound hearing loss can have. Perhaps with more than 4 injections. Or ENTs can just decide themselves that a certain patient might benefit from more than 4 injections. We know from the treatment of sudden hearing loss that ENTs sometimes go beyond 4 injections of dexamethasone to treat it if they're still seeing improvement, so it's not unheard of. Of course you'll have to account for the risk of leaving a hole in the eardrum, which would then need to be repaired with a separate procedure.

 

[sssing]

https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372587

Think I had never seen the Australian trial webpage... just sharing, fyi

'All participants will be injected once with an identical volume (0.2 mL)
into the middle ear. This injection will be performed by a specialist and qualified cochlear implant surgeon. The participants will differ in obtaining Placebo (12-24 hours prior to implantation) or FX-322 (18mg)...'

 

[Diesel]

I don't think they're going to mess with quantity. Besides, the round window membrane can only 'absorb' so much with each injection. The cochlea itself is about as large as the top of a finger.

What they probably will try to do is see what kind of benefit people with more severe and profound hearing loss can have. Perhaps with more than 4 injections. Or ENTs can just decide themselves that a certain patient might benefit from more than 4 injections. We know from the treatment of sudden hearing loss that ENTs sometimes go beyond 4 injections of dexamethasone to treat it if they're still seeing improvement, so it's not unheard of. Of course you'll have to account for the risk of leaving a hole in the eardrum, which would then need to be repaired with a separate procedure.

Carl LeBel mentioned in the Goldman Fireside chat that they are trying to answer the following hypothesis in the Phase 2A with the 2x and 4x dose cohorts. By delivering more doses, do one or more of the following happen:

- Improvements in the same hearing range among more participants ie: greater response. (same as the Phase 1/2, 8kHz+)
- Improvements into the lower frequency ranges (Below 8kHz)
- A combination of both

I am not a scientist. If the perilymph in the cochlea has some diffusion capability; after multiple doses in a weekly interval, I don't see how FX-322 wouldn't have penetrated more deeply. It seems to stay concentrated at effective levels for about 2 weeks-or-so based on the immediate improvements in the Phase 1/2.

 

[Jurger]

Carl LeBel mentioned in the Goldman Fireside chat that they are trying to answer the following hypothesis in the Phase 2A with the 2x and 4x dose cohorts. By delivering more doses, do one or more of the following happen:

- Improvements in the same hearing range among more participants ie: greater response. (same as the Phase 1/2, 8kHz+)
- Improvements into the lower frequency ranges (Below 8kHz)
- A combination of both

I am not a scientist. If the perilymph in the cochlea has some diffusion capability; after multiple doses in a weekly interval, I don't see how FX-322 wouldn't have penetrated more deeply. It seems to stay concentrated at effective levels for about 2 weeks-or-so based on the immediate improvements in the Phase 1/2.

If the drug never reaches the apex, more injections will probably not help. If the drug does get to the apex but in such an amount that it's not effective, more injections might do the trick to get a response.

From the literature I've seen the apex is notoriously hard to reach, but I pray to God I'm wrong.

 

[ThomasRobert]

If the drug never reaches the apex, more injections will probably not help. If the drug does get to the apex but in such an amount that it's not effective, more injections might do the trick to get a response.

From the literature I've seen the apex is notoriously hard to reach, but I pray to God I'm wrong.

Can we do this after the injection?

 

[AtlasFainted]

If the drug never reaches the apex, more injections will probably not help. If the drug does get to the apex but in such an amount that it's not effective, more injections might do the trick to get a response.

From the literature I've seen the apex is notoriously hard to reach, but I pray to God I'm wrong.

I believe @HootOwl mentioned a couple of other drugs that are in trials hit the full frequency range.

So it is possible, but the timeline & FDA current regs mean that the current formulation has to stay the same until Frequency does another special FDA trial to prove a new formulation reaches the low frequencies better. This trial would take a year or so.

As @Diesel said, hopefully more doses will prove to reach the lower frequencies better before that happens.

 

[FGG]

I believe @HootOwl mentioned a couple of other drugs that are in trials hit the full frequency range.

So it is possible, but the timeline & FDA current regs mean that the current formulation has to stay the same until Frequency does another special FDA trial to prove a new formulation reaches the low frequencies better. This trial would take a year or so.

As @Diesel said, hopefully more doses will prove to reach the lower frequencies better before that happens.

Both @HootOwl and I have corresponded with Pipeline and they said their drug and formulation reaches all the way to the apex. So, obviously it's doable.

There is an abbreviated FDA process for reformulations that wouldn't require an entire separate lengthy trial.

 

[Pink Noise]

Happy page 300.

 

[Diesel]

I believe @HootOwl mentioned a couple of other drugs that are in trials hit the full frequency range.

So it is possible, but the timeline & FDA current regs mean that the current formulation has to stay the same until Frequency does another special FDA trial to prove a new formulation reaches the low frequencies better. This trial would take a year or so.

As @Diesel said, hopefully more doses will prove to reach the lower frequencies better before that happens.

Problem solved... Cochlear Pump...

https://www.biorxiv.org/content/10.1101/838508v1.full.pdf

 

[Lucifer]

Can we do this after the injection?

View attachment 39537

If this is what it takes for FX-322's current method to reach the apex then I'm down with that lol.

 

[tommyd87]

Carl LeBel mentioned in the Goldman Fireside chat that they are trying to answer the following hypothesis in the Phase 2A with the 2x and 4x dose cohorts. By delivering more doses, do one or more of the following happen:

- Improvements in the same hearing range among more participants ie: greater response. (same as the Phase 1/2, 8kHz+)
- Improvements into the lower frequency ranges (Below 8kHz)
- A combination of both

I am not a scientist. If the perilymph in the cochlea has some diffusion capability; after multiple doses in a weekly interval, I don't see how FX-322 wouldn't have penetrated more deeply. It seems to stay concentrated at effective levels for about 2 weeks-or-so based on the immediate improvements in the Phase 1/2.

There are three things that might happen from what I can observe.

First, FX-322 makes it in all areas of the cells correctly and offers a helpful response.

Second, if it is initially concentrating in the higher frequencies and it shows effect to the areas of the cochlear which influence these to a greater extent from the first dosing or round of dosing and there is minimal effect to the lower frequencies from this course then I'd assume it could be possible that they should try to repeat the treatment.

It is possible that the amount of gel used may work fantastically for the upper range in the beginning but stops there because it is hitting that area first, and then does not progress further than it can treat. The second dose might then treat the other areas not reached in the first treatment because it can miss these, and then go straight to the treatable areas that were not affected in the initial dose.

Third, there's totally no benefit which would be unlikely.

It is incredibly obvious from the stuff shown to date that the two issues are FX-322's effect and also success of delivery. It somewhat seems that there is evidence of both and thus this is a major step for success.

 

[tommyd87]

I believe @HootOwl mentioned a couple of other drugs that are in trials hit the full frequency range.

So it is possible, but the timeline & FDA current regs mean that the current formulation has to stay the same until Frequency does another special FDA trial to prove a new formulation reaches the low frequencies better. This trial would take a year or so.

As @Diesel said, hopefully more doses will prove to reach the lower frequencies better before that happens.

I reckon that they will work with this although they then will need to trial the new dose design (either size or number of the doses) for safety again first. From what was seen in the initial phase, it is pretty unlikely to be rejected based on safety stuff.

 

[FGG]

Problem solved... Cochlear Pump...

https://www.biorxiv.org/content/10.1101/838508v1.full.pdf

There are actually a number of possible ways:

This, delivered surgically through Canalostomy, ultrasound microbubbles, Otomagnetics, reformulation, etc.