Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

Most interesting take away I got from the Q&A: In the phase I trial, 6 of the patients in the FX-322 group had moderate to moderately severe SNHL, and the other 9 had mild SNHL. The 4 individuals in this group that had significant improvements in their hearing were in the severe SNHL group, and all 6 in the severe SHNL group had improved hearing (it's just that only 4 were statistically significant).

So it sounds like this drug, at least with the phase I dosing and delivery, will benefit people with severe hearing loss. Hopefully the increased dose will change things, and hopefully the delivery mechanisms will improve. It'll also be interesting to see how hearing improves over time since they're measuring the individuals for a longer period of time. Maybe the people with moderate hearing loss will also improve, it'll just take more time for the effects to be noticed. Still, I was glad to hear everyone with severe hearing loss improved. If this drug is effective, it would make the most sense that that group would improve the most.

The word score improvements were all seen in the "moderate to moderately-severe group" compared to the "mild" group. I could be wrong but I don't believe a severe group was tested.

 

[Enclave]

Anyone else listen to webcast and Q and A? Thoughts?

A few "new" points I picked up on:

-- all moderate to moderately severe patients saw a word score increase but 4/6 of them were more robust.

-- theoretically this should help synaptopathy *if* you also have hair cell loss at least because the new hair cells make new connections. This makes me think it works for IHC loss too because isn't that where the synapse loss is in cochlear synaptopathy?

-- they think their method is superior and more like natural regeneration in species that do regenerate because the support cell divides first and isn't just transformed (unlike say Regain, though they didn't mention them by name but they did say "another competitor").

-- I really want to listen again when they repost it but during Q and A someone from Frequency seemed to have responded that they saw changes in their extended measures (ultra high frequency losses and tinnitus) across mild and moderate patients. If I heard that right (and will recheck when posted online), that is *huge* news imo.

-- it seems they didn't do multiple injections pre-clinically in rats but suspects they will get greater improvement w it in humans.

-- zero safety concerns on their end or FDA.

-- the FDA has confirmed that they consider the quality of life implications of this drug to be the same as "life or death" drugs.

Just wanted to add to this list that someone asked a question with regards to "durability" of the improvements seen in treated patients and both Chris Loose and David Lucchino said that are very confident that any improvements gained will last longer than the 7-Month window they're observing patients under, and doubled down by saying the improvements should hold beyond that (unless of course additional insults to hearing are incurred).

 

[Pink Noise]

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

Presentation link.

This filled me with hope - even though I'm having a bad day. My tinnitus is maddening..

 

[FGG]

Just wanted to add to this list that someone asked a question with regards to "durability" of the improvements seen in treated patients and both Chris Loose and David Lucchino said that are very confident that any improvements gained will last longer than the 7-Month window they're observing patients under, and doubled down by saying the improvements should hold beyond that (unless of course additional insults to hearing are incurred).

Thanks for adding that. I also forgot that they mentioned they started seeing hearing changes pretty fast: two weeks after the injection.

 

[FGG]

Well it doesn't look like it's supposed to do anything below 3,000 Hz. Kind of disappointing for me as all my hearing loss is at 3,000 Hz and lower.

If you looked at their recent job postings, it's clear that they are looking to change that. It looks like they are looking to hire in a number of positions (I uploaded example screen shots below) with the second generation of FX-322.

 

[FGG]

Screenshots of job postings:

 

[patorjk]

The word score improvements were all seen in the "moderate to moderately-severe group" compared to the "mild" group. I could be wrong but I don't believe a severe group was tested.

Correct, I say that at the start of my post - "6 of the patients in the FX-322 group had moderate to moderately severe SNHL, and the other 9 had mild SNHL". After that I use the short hand "severe" to refer to the "moderate to moderately severe SNHL" since it's the group with the worst hearing loss and I didn't want to keep typing that long phrase out, though I can see how it may have been confusing.

 

[Lucifer]

@FGG

Would it be possible for Astellas to release the drug first or would Frequency Therapeutics need to release it first before international release by Astellas?

 

[davidmp]

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

Presentation link.

Those slides bring so much hope to me... even if tinnitus is just marginally mentioned.

 

[John Queen]

-- the FDA has confirmed that they consider the quality of life implications of this drug to be the same as "life or death" drugs.

Thank heavens for this. I sent a mail to the FDA last year in which I tried to argue in favor of such a classification, giving examples of how people committed suicide due to conditions that aren't deadly themselves, but significantly alter quality of life.

This is a sign that it might get faster approval even in the US if everything works fine.

 

[WickedCarnival]

Well it doesn't look like it's supposed to do anything below 3,000 Hz. Kind of disappointing for me as all my hearing loss is at 3,000 Hz and lower.

In order for the drug to restore lower frequencies, it has to be able to reach further towards the cochlea apex. See my earlier post regarding Otomagnetics delivery system. Theoretically, that system will allow the molecules to go further into the cochlea via continuous magnetic force rather than "splooging" a bolus of the drug into the round window with a needle and hoping it will somehow travel where it needs to go (gravity, movement, etc)

 

[MRItechssuck]

I didn't recall seeing in your video when this magnetic field technology may be in use?

 

[MRItechssuck]

Thank heavens for this. I sent a mail to the FDA last year in which I tried to argue in favor of such a classification, giving examples of how people committed suicide due to conditions that aren't deadly themselves, but significantly alter quality of life.

This is a sign that it might get faster approval even in the US if everything works fine.

Maybe the new "right-to-try" legislation will help in this regard... I mentioned this to one of Dr. Shore's minions.

 

[Momme]

In order for the drug to restore lower frequencies, it has to be able to reach further towards the cochlea apex. See my earlier post regarding Otomagnetics delivery system. Theoretically, that system will allow the molecules to go further into the cochlea via continuous magnetic force rather than "splooging" a bolus of the drug into the round window with a needle and hoping it will somehow travel where it needs to go (gravity, movement, etc)

Can someone explain this "for dummies" with Hz, frequencies and tinnitus?

 

[Chriscom]

Thanks to all who followed this presentation summarized it and discussed its implications. Appreciate it.

 

[FGG]

Can someone else listen to the Q and A at around 5:21 and confirm for me what I think I'm hearing? It suggests to me that they saw "trends" in what they have now included as their secondary endpoints (including tinnitus) across mild and moderate hearing loss subjects.

Was it inadvertently revealed while answering another question that Frequency Therapeutics definitely saw tinnitus improvements in phase 1. It sounds that way to me (and makes sense, why else would would they have tacked that as a measure in phase 2 without patient testimonials suggesting an improvement?) and i listened to it 3 times now.

 

[Chriscom]

-- the FDA has confirmed that they consider the quality of life implications of this drug to be the same as "life or death" drugs

FWIW the exact quote from the stream is,

"I think what they've clearly said was that, though this isn't a life-threatening disease, it's a life-altering disease, and they take this just as seriously."

 

[Chriscom]

Can someone else listen to the Q and A at around 5:21 and confirm for me what I think I'm hearing? It suggests to me that they saw "trends" in what they have now included as their secondary endpoints (including tinnitus) across mild and moderate hearing loss subjects.

Was it inadvertently revealed while answering another question that Frequency Therapeutics definitely saw tinnitus improvements in phase 1. It sounds that way to me (and makes sense, why else would would they have tacked that as a measure in phase 2 without patient testimonials suggesting an improvement?) and i listened to it 3 times now.

I don't think so, though I'm planning to give the whole thing another listen.

The speaker was talking about areas where improvements have already been measured, already discussed above. He's saying going forward, in addition to continuing those measurements, they're going to add: "ultra-high frequencies, quality of life, and tinnitus, and other endpoints that we think can give us a fuller picture of what this medication can potentially do."

That being said, I don't think they would test just for the sheer joy of it.

 

[tarmaced]

Thanks for staying on top of this guys and digesting the information by discussing it back and forth. It's super appreciated.

 

[ChrisBoyMonkey]

Anyone else listen to webcast and Q and A? Thoughts?

A few "new" points I picked up on:

-- all moderate to moderately severe patients saw a word score increase but 4/6 of them were more robust.

-- theoretically this should help synaptopathy *if* you also have hair cell loss at least because the new hair cells make new connections. This makes me think it works for IHC loss too because isn't that where the synapse loss is in cochlear synaptopathy?

-- they think their method is superior and more like natural regeneration in species that do regenerate because the support cell divides first and isn't just transformed (unlike say Regain, though they didn't mention them by name but they did say "another competitor").

-- I really want to listen again when they repost it but during Q and A someone from Frequency seemed to have responded that they saw changes in their extended measures (ultra high frequency losses and tinnitus) across mild and moderate patients. If I heard that right (and will recheck when posted online), that is *huge* news imo.

-- it seems they didn't do multiple injections pre-clinically in rats but suspects they will get greater improvement w it in humans.

-- zero safety concerns on their end or FDA.

-- the FDA has confirmed that they consider the quality of life implications of this drug to be the same as "life or death" drugs.

This is great news. I really hope we can learn more about the effects on tinnitus soon.

 

[brokensoul]

It's so incredibly odd that they did not take extended audiograms in the first trial.

Given the delivery challenge, they must have known that the small molecules had the highest chance to affect the higher frequencies of the cochlea. Don't tell me this is something they overlooked. If they did, it's kind of a major facepalm imo. Brilliant scientists, my hat's off for what they are doing. It's amazing next level science. Somehow however they did basic audiograms. It does not make any sense.

Did they expect it to work better and consider only up to 8kHz relevant for hearing?

 

[brokensoul]

Do we have a best guess idea why only 4 people saw 10dB improvement at 8kHz?

This is hard to evaluate. Did their study include the actual audiograms of the trial participants? My question is basically did the other participants have a hearing threshold shift at 8kHz or did they happen to have excellent hearing already at that frequency? If they also have a threshold shift it remains a big question why there was a small, but statistically significant improvement for those 4 and not for the others.

I know it's probably been discussed already. I don't recall exactly what people thought of this.

I wonder if it has anything to do with the actual damage at that frequency. FX-322 maybe only works if there is space to regrow the hair cell in that region and doesn't work if there is still a dysfunctional hair cell occupying that space? I mean, FX-322 doesn't clean up "broken" hair cells, does it? I can see it functioning if the cochlear epithelium is clean, but not sure what it does when there is still some dysfunctional hair cell / stereocilia left.

 

[RB2014]

It's so incredibly odd that they did not take extended audiograms in the first trial.

Given the delivery challenge, they must have known that the small molecules had the highest chance to affect the higher frequencies of the cochlea. Don't tell me this is something they overlooked. If they did, it's kind of a major facepalm imo. Brilliant scientists, my hat's off for what they are doing. It's amazing next level science. Somehow however they did basic audiograms. It does not make any sense.

Did they expect it to work better and consider only up to 8kHz relevant for hearing?

Agreed, it looks like there were probably some gains in the higher frequencies. The only thing that I can think of is that they thought it would work better than it did... 10 dB at 8 kHz... and didn't think to test the higher frequencies. Also, most places can only test up to 8 kHz. 8 kHz is also considered high on the frequency scale for hearing. I'm not sure if a 10 dB gain at 16 kHz is considered clinically meaningful either. Just some reasons for why they excluded anything higher than 8 kHz.

I do agree that it is an oversight though. The only logical conclusion is that the higher word scores were from improvements in 8 kHz and above. This might have caught them off guard as well.

Hopefully with increased dosages they are able to penetrate deeper into the cochlea and get more gains across a wider range of frequencies. Looking at the picture of the cochlea though I'm not sure how the solution is going to get too deep inside.

 

[FGG]

It's so incredibly odd that they did not take extended audiograms in the first trial.

Given the delivery challenge, they must have known that the small molecules had the highest chance to affect the higher frequencies of the cochlea. Don't tell me this is something they overlooked. If they did, it's kind of a major facepalm imo. Brilliant scientists, my hat's off for what they are doing. It's amazing next level science. Somehow however they did basic audiograms. It does not make any sense.

Did they expect it to work better and consider only up to 8kHz relevant for hearing?

I think it's because traditionally for safety studies audiograms are only measured up to 8000 Hz and phase 1 was ultimately a safety study. Plus, so few people have repeat extended audiograms as a baseline to screen for the initial study. It may have made recruitment harder if they wanted to focus more on that as a primary end starting with phase 1 (vs tacking it on now as an experimental arm).

I think it's also possible even they were surprised by how much word score improvement there was with minimal standard audiogram changes at the small phase 1 safety trial dose.

They alluded to this in their presentation (with a pictorial representation of speech across the frequencies): above 8000 Hz is useful in speech clarity, even if below 8000 Hz is more useful. I think their results made them go back and look at this.

There are many reasons this information can be useful in this arm: if say you get a 20-30 db change at 4000 Hz, but a 60 dB change at 14000 Hz, that also says a lot about what concentration is needed to make what impact.

 

[ChrisBoyMonkey]

Can someone else listen to the Q and A at around 5:21 and confirm for me what I think I'm hearing? It suggests to me that they saw "trends" in what they have now included as their secondary endpoints (including tinnitus) across mild and moderate hearing loss subjects.

Was it inadvertently revealed while answering another question that Frequency Therapeutics definitely saw tinnitus improvements in phase 1. It sounds that way to me (and makes sense, why else would would they have tacked that as a measure in phase 2 without patient testimonials suggesting an improvement?) and i listened to it 3 times now.

I listened to it and someone asks if they saw any improvements in secondary measures (tinnitus is one of them). What they said is they saw "trends".

It's so incredibly odd that they did not take extended audiograms in the first trial.

Given the delivery challenge, they must have known that the small molecules had the highest chance to affect the higher frequencies of the cochlea. Don't tell me this is something they overlooked. If they did, it's kind of a major facepalm imo. Brilliant scientists, my hat's off for what they are doing. It's amazing next level science. Somehow however they did basic audiograms. It does not make any sense.

Did they expect it to work better and consider only up to 8kHz relevant for hearing?

They mentioned they will be doing ultra high frequencies next as they know those are the areas the drug reaches the most.

 

[FGG]

I listened to it and someone asks if they saw any improvements in secondary measures (tinnitus is one of them). What they said is they saw "trends".

So how do you interpret that? They also said they saw "trends" in those measures with both mild and moderate to moderately severe groups.

Since they also said neither they nor the FDA was concerned with any side effects, trends surely means positive trends, right?

 

[brokensoul]

Another thing I'm thinking is that Frequency Therapeutics is working on hair cell regeneration and this is only one element of the hearing regeneration puzzle. Even if they can solve the delivery challenge, and I think they will since other companies can already do it, we are still left wondering about synapse regeneration and auditory nerve repair.

Are we assuming downstream reparation after hair cell regeneration? I know Stanford said the nerve 'magically' reconnects so that's great, presuming the nerve is still functional enough to do so (there could be an issue perhaps). Are we also assuming or hoping that the synapses will regrow as well? Has Frequency Therapeutics stated anything in that regard?

We also have PIPE working on synapse regeneration, in case not all required synapses regrow, but this is a different company. So I suspect that after FX-322 we may still have to wait for PIPE to come through with a working solution to fix the complete auditory system (excluding the brain) and find some synergy between both solutions.

It's a pity we don't have a large concern working on all the elements of the puzzle.

Even if FX-322 works well they are going to move on to other diseases. I understand though, their company is PCA technology and they will expand that into all possible treatments and synapse regeneration is not done through PCA.

Anyhow, first thing first, let's see if their already promising results improve in their second trial, otherwise we're probably still in it for the long haul.

 

[FGG]

Do we have a best guess idea why only 4 people saw 10dB improvement at 8kHz?

This is hard to evaluate. Did their study include the actual audiograms of the trial participants? My question is basically did the other participants have a hearing threshold shift at 8kHz or did they happen to have excellent hearing already at that frequency? If they also have a threshold shift it remains a big question why there was a small, but statistically significant improvement for those 4 and not for the others.

I know it's probably been discussed already. I don't recall exactly what people thought of this.

I wonder if it has anything to do with the actual damage at that frequency. FX-322 maybe only works if there is space to regrow the hair cell in that region and doesn't work if there is still a dysfunctional hair cell occupying that space? I mean, FX-322 doesn't clean up "broken" hair cells, does it? I can see it functioning if the cochlear epithelium is clean, but not sure what it does when there is still some dysfunctional hair cell / stereocilia left.

We don't know what their audiograms looked like. It's possible only 4 people had damage there.

It's also probable imo that since it was a smaller dose used for phase 1, it just didn't travel very far distal to the round window and it "barely" made it to 8000 Hz in a few individuals. There are small individual differences in middle ear size and in round window diffusion, too.

I think the "space" theory would be more likely if they had seen improvements at 6000 Hz for some and 8000 Hz for others etc...

 

[brokensoul]

I think it's because traditionally for safety studies audiograms are only measured up to 8000 Hz and phase 1 was ultimately a safety study. Plus, so few people have repeat extended audiograms as a baseline to screen for the initial study. It may have made recruitment harder if they wanted to focus more on that as a primary end starting with phase 1 (vs tacking it on now as an experimental arm).

I think it's also possible even they were surprised by how much word score improvement there was with minimal standard audiogram changes at the small phase 1 safety trial dose.

They alluded to this in their presentation (with a pictorial representation of speech across the frequencies): above 8000 Hz is useful in speech clarity, even if below 8000 Hz is more useful. I think their results made them go back and look at this.

There are many reasons this information can be useful in this arm: if say you get a 20-30 db change at 4000 Hz, but a 60 dB change at 14000 Hz, that also says a lot about what concentration is needed to make what impact.

Ah, I can see what you're saying. Makes more sense to me now. Thanks for your feedback! You're right the objective was only to check safety and asking for extended audiogram history may have complicated that, since it seems it's not common at all.

FWIW, I've told all audiologists I've met that they should always take extended audiograms. It makes no sense to check less than half the spectrum. They seem mostly stuck though in their erroneous way of thinking that >8kHz is not required. Old ways die hard, but I hope I got through to some of them. I finally found a great audiologist in a university hospital though that checked mine up to 16kHz. She said it's usually only done for cancer patients, but since I insisted, she did so for me.

 

[Chriscom]

I listened to it and someone asks if they saw any improvements in secondary measures (tinnitus is one of them). What they said is they saw "trends".

They mentioned they will be doing ultra high frequencies next as they know those are the areas the drug reaches the most.

The key word "trends" is something @FGG was referencing and that I didn't catch, FYI, so I'll have to go back for that. I mean it makes sense since they're testing for it, while it's clear they're talking only cautiously at this point about tinnitus.