Frequency Therapeutics — Hearing Loss Regeneration

[Lucifer]

FX-322 and PIPE-505 have a similar timeline so they may come out at the same time. You have FX-322 that can regrow IHCs, OHCs and synapses where there are lost hair cells, then you have PIPE-505 which can grow synapses and minimal OHC regrowth.

That's the trifecta.

I just hope the next set of trials, the follow-up appointments are up to Day 90 compared to up to Day 210 for FX-322 Phase 2a trial.

 

[Street Novelist]

I can't even imagine if FX-322 doesn't work. Because if it doesn't work, then their dream of curing MS using the same strategy is probably a failure as well. It feels like if this drug fails, the entire company fails.

 

[Diesel]

I can't even imagine if FX-322 doesn't work. Because if it doesn't work, then their dream of curing MS using the same strategy is probably a failure as well. It feels like if this drug fails, the entire company fails.

I actually think if they thought the drug was a failure after Phase 2a, the messaging would have immediately started focusing on the MS drug in the pipeline. There are other examples where as soon as a drug trial fails, the company quickly moves on (OTIVIDEX) to what's next in the pipeline. But, instead they're still pushing FX-322.

 

[FGG]

I can't even imagine if FX-322 doesn't work. Because if it doesn't work, then their dream of curing MS using the same strategy is probably a failure as well. It feels like if this drug fails, the entire company fails.

Pipeline Therapeutics has a similar MS drug (two different drugs actually) so there are multiple companies interested in the approach generally.

 

[Street Novelist]

I actually think if they thought the drug was a failure after Phase 2a, the messaging would have immediately started focusing on the MS drug in the pipeline. There are other examples where as soon as a drug trial fails, the company quickly moves on (OTIVIDEX) to what's next in the pipeline. But, instead they're still pushing FX-322.

But the mechanism behind both hair cell regeneration and curing MS is the same, right? Activation of progenitor cells.

 

[Diesel]

But the mechanism behind both hair cell regeneration and curing MS is the same, right? Activation of progenitor cells.

Yes. They are activating progenitors. However, in MS, the progenitors are supposed to activate and do not, or too slowly, if I understand the distinction correctly. In normal conditions, the adult progenitors are functioning as expected. In the ear, they only activated once and effectively went dormant.

Disclaimer: My knowledge of the effects of demyelination in MS, and how remyelination in healthy people works is limited.

 

[Lucifer]

I'd also like to add that the PIPE-505 trial lasts for 8 months with follow-up appointments up to Day 90, so hopefully future FX-322 trials last up to 8 months or less if the follow-up appointments are up to Day 90.

 

[GlennS]

The rats had improved ABRs and when sacrificed they had some OHC and IHC regrowth.

What's an ABR? Might want to lay off on too many acronyms for the mere mortals here.

 

[FGG]

What's an ABR? Might want to lay off on too many acronyms for the mere mortals here.

Auditory Brainstem Response. It's how they test babies' hearing too. It gives you a general idea.

 

[Trevor_phillips]

Just recently found out about the results from FX-322's Phase 2a clinical trial. I'm quite disheartened but I can't say I'm surprised as I previously had serious doubt and critical view of the FX-322 model.

If we all just disconnect from our bias and look at it from an engineering and mechanical point of view, regenerating cochlear hair cells alone is not the answer. You also need to have functional neuronal connections. Analogous to this is, you can't just reattach an arm and expect full recovery. Many times the nerves don't reattach. Similarly, you can't just expect renewed cochlear hair cells will reattach neuronally either.

As for our ears, I don't believe that simply regenerating cochlear hair cells is the solution but it is a significant discovery. The issue is if those hair cells can correctly reattach back to the central nervous system, to the auditory nerve. If not, then the regenerated cochlear hair cells are defective structures.

As some have previously pointed out that the "founder" of Frequency Therapeutics (serious conflict of interest here) says the regenerated hair cells do reattach back but their animals study data did not show this. The study mentioned neuronal growth but did not show if it actually connected back to the main nerve. If it did, then I'm sure they would have shown it in their research paper because this is as significant as regenerating cochlear hair cells.

The hair cell regeneration from their animal studies is strong (although I think independent scientific verification will nail this debate). But, I think the next key development is making further research into correct cochlear hair cell reconnections and I hope Frequency Therapeutics can survive financially to do further research.

Additionally, of course, there are opinions out there that says hearing loss isn't all that related to damaged ear structures but is related to our CNS rewiring and the loss of ability to process auditory signals. That is a possibility for a subset of hearing issues but FX-323 model is not targeting that so having doubts in this train of thought leads to nowhere.

Anyway, I hope you're all doing well or as well as we can be with tinnitus.

This is the reason why I think it is better to get FX-322 first (assuming it comes to the market) and afterwards a synaptogenesis drug (OTO-413 or PIPE 505), because if the hair cells aren't able to form proper synaptic connections to the SGN, then a synaptogenesis drug will be needed. I remember that I read an article mentioning that the "fresh" hair cells often lose their synaptic connection or even they do not connect at all, leading to an dysfynctional hair cell.

I have higher hope for a synaptogenesis drug than for FX-322, to be honest. It's simpler to regrow synapses than hair cells. I think PIPE-505 and OTO-413 are more promising even if they're a few years behind FX-322.

 

[Lucifer]

This is the reason why I think it is better to get FX-322 first (assuming it comes to the market) and afterwards a synaptogenesis drug (OTO-413 or PIPE 505), because if the hair cells aren't able to form proper synaptic connections to the SGN, then a synaptogenesis drug will be needed. I remember that I read an article mentioning that the "fresh" hair cells often lose their synaptic connection or even they do not connect at all, leading to an dysfynctional hair cell.

I have higher hope for a synaptogenesis drug than for FX-322, to be honest. It's simpler to regrow synapses than hair cells. I think PIPE-505 and OTO-413 are more promising even if they're a few years behind FX-322.

PIPE-505 should only be a year behind FX-322 if it does go to Phase 2a. If FX-322 needs to repeat Phase 2, then they should come out at the same time.

 

[Chad Lawton]

Phase II results, with almost 100 participants, were devastating. FX-322 showed no signal at all, with no difference between drug and placebo. FX-322 simply worked no better than sugar water.

What people are failing to consider is that this drug application method is pretty unique in that the drug is delivered directly to the area that it works on. The majority of other drugs are metabolized somewhere else in the body and then circulate through the blood to reach their target. Not hard to see how injecting placebo or multiple drug doses into the ear every week can jack up the chemistry of the healing process and make it appear as if the drug doesn't work.

 

[Diesel]

I was just thinking about the FX-322 restoring IHC theory (only or in the first pass).

The audiogram is capable of measuring OHC performance/health, but generally not IHC; and there is a stronger association between IHC performance and various word score tests.

In the Phase 1/2 data, it was observed that 4 participants saw an improvement at 8 kHz. Also, Frequency Therapeutics, through the perilymph study showed in their models that the two drugs that make up FX-322 get maybe as deep as where "6 kHz" would be in the cochlea.

Since there isn't a good measure of OHC growth down to 6 kHz, and only a few examples at 8 kHz; I wonder if applying the "IHC only/first" theory down to that relative frequency (6 kHz) explains the dramatic increase in word scores? If one considers the audiogram "banana" or the speech example in prior Frequency Therapeutics presentations, there are a number of consonants that exist in the English language at and above 6 kHz.

 

[FGG]

I was just thinking about the FX-322 restoring IHC theory (only or in the first pass).

The audiogram is capable of measuring OHC performance/health, but generally not IHC; and there is a stronger association between IHC performance and various word score tests.

In the Phase 1/2 data, it was observed that 4 participants saw an improvement at 8 kHz. Also, Frequency Therapeutics, through the perilymph study showed in their models that the two drugs that make up FX-322 get maybe as deep as where "6 kHz" would be in the cochlea.

Since there isn't a good measure of OHC growth down to 6 kHz, and only a few examples at 8 kHz; I wonder if applying the "IHC only/first" theory down to that relative frequency (6 kHz) explains the dramatic increase in word scores? If one considers the audiogram "banana" or the speech example in prior Frequency Therapeutics presentations, there are a number of consonants that exist in the English language at and above 6 kHz.

I had this thought, too. Where the IHC loss was focused would be extremely relevant as far as getting mild or dramatic word score gains (and tinnitus effects as well). It's so complicated when diagnostics are so limiting.

 

[RB2014]

What people are failing to consider is that this drug application method is pretty unique in that the drug is delivered directly to the area that it works on. The majority of other drugs are metabolized somewhere else in the body and then circulate through the blood to reach their target. Not hard to see how injecting placebo or multiple drug doses into the ear every week can jack up the chemistry of the healing process and make it appear as if the drug doesn't work.

They should have foreseen this if they thought it was going to be an issue. They only came up with the idea of multiple injections based on the poor results of Phase 1. They developed an entire clinical trial around more is probably better... We can try to explain away the results of the trial after the fact, but they had a long time in planning to come up with this trial and they have much more data than we do to make these decisions.

At the end of the day the results are still discouraging.

 

[UHPTS]

They should have foreseen this if they thought it was going to be an issue. They only came up with the idea of multiple injections based on the poor results of Phase 1.

Could you please elaborate on the first sentence? It makes no sense to me.

How would they have known this was going to be an issue? What idea should they have come up with instead? Poor results of Phase 1?

You try, you fail or succeed. There is no success without fail and each fail pushes you up a bit. At least that is what my crystal ball tells me. Mine is cheap, it doesn't really see the future. If you got better one, please ask it what steps Frequency Therapeutics should take next. Huge thanks in advance!

The reason why Frequency Therapeutics did Phase 2a the way they did was simply because they were very confident about the effects of FX-322. It didn't work out the way they wanted. Lesson learned for them is to make a smaller study with the same parameters prior to a large study.

Results of other phases are phenomenal! You don't fake improvement in hearing loss. They are on the good track. Some hiccups will happen. Don't trash them for one fail.

 

[Tezcatlipoca]

Poor results of Phase 1?

Exactly. Every trial but Phase 2a was great.

 

[roy1159]

I was just thinking about the FX-322 restoring IHC theory (only or in the first pass).

The audiogram is capable of measuring OHC performance/health, but generally not IHC; and there is a stronger association between IHC performance and various word score tests.

In the Phase 1/2 data, it was observed that 4 participants saw an improvement at 8 kHz. Also, Frequency Therapeutics, through the perilymph study showed in their models that the two drugs that make up FX-322 get maybe as deep as where "6 kHz" would be in the cochlea.

Since there isn't a good measure of OHC growth down to 6 kHz, and only a few examples at 8 kHz; I wonder if applying the "IHC only/first" theory down to that relative frequency (6 kHz) explains the dramatic increase in word scores? If one considers the audiogram "banana" or the speech example in prior Frequency Therapeutics presentations, there are a number of consonants that exist in the English language at and above 6 kHz.

Consonants are actually the more significant part regarding speech comprehension problems in HFHL and speech comprehension in general. Speech audiogram can measure some function of IHC. Restoring frequencies around 6 kHz should be a top priority or else the drug doesn't treat true hearing loss - inability to comprehend speech.

 

[RB2014]

Could you please elaborate on the first sentence? It makes no sense to me.

How would they have known this was going to be an issue? What idea should they have come up with instead? Poor results of Phase 1?

You try, you fail or succeed. There is no success without fail and each fail pushes you up a bit. At least that is what my crystal ball tells me. Mine is cheap, it doesn't really see the future. If you got better one, please ask it what steps Frequency Therapeutics should take next. Huge thanks in advance!

The reason why Frequency Therapeutics did Phase 2a the way they did was simply because they were very confident about the effects of FX-322. It didn't work out the way they wanted. Lesson learned for them is to make a smaller study with the same parameters prior to a large study.

Results of other phases are phenomenal! You don't fake improvement in hearing loss. They are on the good track. Some hiccups will happen. Don't trash them for one fail.

My first sentence was poorly worded. Agreed. Everyone, including Frequency Therapeutics, were hoping for better results from the initial Phase. A 20 to 30 dB improvement, across all frequencies, would have been a nice start. Completely restoring hearing and getting rid of tinnitus would have been a win. Instead we got 10 dB at 8 kHz and improved word scores. It was because of these poor results that they decided to try the multiple injections. They were looking for better results with multiple injections as you mentioned because they did see some potential in FX-322. The fact that we have done something is a great achievement. I agree there, and we can look it that way as well, but the Phase 1b results are barely clinically meaningful.

They need to either look at their delivery method and/or try to figure out why the results have fallen short of the initial expectations after doing all of the preliminary research they did.

Going back to single injections and keeping everything the same is not going to go well for them or their investors. I personally hope that they can repeat the results they achieved in Phase 1b, and market it and sell it, and stay viable as a company, but the endgame is to cure hearing loss and tinnitus.

 

[OptimusPrimed]

Has anyone entertained the idea that perhaps the hair cells were restored but not functional because of previous cochlear synaptopathy? As @Lucifer alluded, it could have to be a two-step process to restore fully functional hearing.

Also as for the delivery only reaching 6 kHz, perhaps therapeutic delivery of sound waves that span from 20 kHz to the lower kHz might force the medication to undulate through the perilymphatic fluid?

Absolutely a great talk on this subject here:

 

[Lucifer]

Has anyone entertained the idea that perhaps the hair cells were restored but not functional because of previous cochlear synaptopathy? As @Lucifer alluded, it could have to be a two-step process to restore fully functional hearing.

Also as for the delivery only reaching 6 kHz, perhaps therapeutic delivery of sound waves that span from 20 kHz to the lower kHz might force the medication to undulate through the perilymphatic fluid?

Absolutely a great talk on this subject here:

That could be the reason why the improvements weren't so great with FX-322 by itself. I'm hoping if PIPE-505 shows proof of synapses regrowing then in the future you could take both FX-322 and PIPE-505 to restore IHCs, OHCs and synapses.

At the end of June we will find out the results of PIPE-505. I'm glad there are many companies working on hearing restoration but too bad I got this way too early.

 

[Tezcatlipoca]

That could be the reason why the improvements weren't so great with FX-322 by itself. I'm hoping if PIPE-505 shows proof of synapses regrowing then in the future you could take both FX-322 and PIPE-505 to restore IHCs, OHCs and synapses.

At the end of June we will find out the results of PIPE-505. I'm glad there are many companies working on hearing restoration but too bad I got this way too early.

5-10 more years and we would just take Ebselen for spikes and protection while PIPE-505/FX-322 regrow hair cells and synapses.

 

[Lucifer]

5-10 more years and we would just take Ebselen for spikes and protection while PIPE-505/FX-322 regrow hair cells and synapses.

Yea, we might not even need Ebselen if FX-322 and PIPE-505 solve our problems.

 

[Jcmc]

Yea, we might not even need Ebselen if FX-322 and PIPE-505 solve our problems.

FX-322 just failed. Or am I missing something?

 

[Diesel]

Has anyone entertained the idea that perhaps the hair cells were restored but not functional because of previous cochlear synaptopathy? As @Lucifer alluded, it could have to be a two-step process to restore fully functional hearing

Interesting thought.

They've claimed that intact hair cells with damaged synapses will not regenerate with FX-322, and will remain in an "unsynapsed" state. This is where the belief that OTO-413 / PIPE-505 may be beneficial.

Where damaged human hair cells are regrown in vitro, they've observed the cells creating a long nerve ending, which implies that it should reattach. I believe they did reattach in mice. This scenario assumes that the cell is damaged and not synapses to the nerve.

Another scenario might be where a hair cell is damaged and is still synapsed. In this case, perhaps FX-322 causes the cell to regenerate and the cell a "reuses" the existing synaptic connection. This actually seems likely.

If what Otonomy and Pipeline Therapeutics claim, that synapses are damaged much more quickly/easily than the hair cells themselves, then either of their synaptogenesis drugs may show significant improvements.

 

[Zugzug]

Yea, we might not even need Ebselen if FX-322 and PIPE-505 solve our problems.

Honestly, I want at least one of them to solve a problem. That is my dream.

 

[Guywithapug]

Researchers discover elusive cell type in fish sensory organs

Here's an interesting read regarding sensory hair cell regeneration.

 

[Tezcatlipoca]

FX-322 just failed. Or am I missing something?

It failed a trial.

 

[FGG]

Researchers discover elusive cell type in fish sensory organs

Here's an interesting read regarding sensory hair cell regeneration.

Interesting, but not related to hair cell regeneration. They studied a cell type called an ionocyte, which is a specialized support cell that Zebrafish have in their lateral line. This newly discovered cell type is unique in that in can change the fluid composition depending on the environment (i.e. salt or fresh water) and it can do so in the adult fish with different cell signaling. The researchers are hoping they can switch on similar genes to help cochlear fluid disorders (e.g., Meniere's).

 

[Lucifer]

FX-322 just failed. Or am I missing something?

Weekly dosing of FX-322 failed but single dosage only had positive outcomes in the Phase 1b trials.