Frequency Therapeutics — Hearing Loss Regeneration

[Jurger]

I've been reading the press release again. I did not realise that they also released results from another Phase 1b trial. I thought this was the Phase 1b trial from 2019 but this is a completely new trial that showing meaningful improvements.

"The Company also announced preliminary results today from a recently completed open-label, single-dose study of FX-322 (FX-322-111) designed to evaluate the impact of injection conditions on tolerability. In the multi-center, randomized study, subjects with mild to severe SNHL (n=33) were injected in one ear with FX-322, with the untreated ear as the control. Hearing function was tested over the course of 90 days following dosing.

At day 90 following dosing, thirty-four percent (34%) of subjects achieved a ten percent (10%) or greater absolute improvement in WR scores in the treated ear, which was clinically meaningful and statistically significant compared to the untreated ear (p <0.05). This included a subset of subjects that more than doubled their WR scores. The single dose had a favorable safety profile and was well tolerated. These latest results are supportive of the data reported in the prior single dose Phase 1/2 (FX-322-201) study, recently published in the peer-reviewed journal Otology & Neurotology.

"We now have two independent, single-dose studies showing a hearing signal with FX-322 and with statistically significant improvements in speech intelligibility".​

Which trials are they referring to when they mean FX-322-111 and FX-322-201?

FX-322 in Adults With Age-Related Sensorineural Hearing Loss

FX-322 in Adults With Severe Sensorineural Hearing Loss

The FX-322-111 trial is their latest trial, which they ran parallel to the Phase 2a trial. They didn't have a press release about it until today. The FX-322-201 trial is their first Phase 1/2 trial back in 2019/2020.

The problem with their latest FX-322-111-trial is that there isn't an audiogram improvement, not even in the extended high frequencies. Carl LeBel said this today. The only hearing signal they get is the WR scores, which aren't that great and apparently can't be explained by extended high frequency improvements.

 

[Tezcatlipoca]

So it does work but it's damn near impossible to test on humans, that's just great.

 

[Philip83]

Well, either it does or the Phase 1 super responders were lying since it's beyond what has historically been possible.

I was thinking if the 10 dB improvement at 8 kHz somehow was a fluke, as it was a small sample size of patients, and that word scores somehow potentially are largely uncorrelated with pure-tone scores.

 

[attheedgeofscience]

I don't see where the shift is in the timeline where they started thinking fraud. Unless it was something nefarious like never actually using human cochlea and claiming it was.

I agree: any person in their right mind wouldn't go through all the trouble it takes to set up a biotech just to be a fraud. Fraud in business falls into two main categories:

1. Those intending to be a fraud from the outset (example: Ponzi Scheme, Bernard Madoff).
2. Those who run an honest company, but run into financial problems down the road (example: Lehman Brothers using the "repo 105 transaction" to keep going).

I can only imagine that Frequency Therapeutics is an honest company that has hit a small bump in the road like so many other pharma entities. I would say the stock is now heavily undervalued in light of the findings – the reaction from the market is waaaay too heavy-handed. So much so, that I will seriously consider buying some shares...

 

[Paulmanlike]

I suspect over the coming weeks, there will be more information released on what happened and the future plan for a parallel dosing plan. David Lucchino started off the call today stating, "There are issues with trial design, NOT FX-322."

Now that they've been explicit on the plan for FX-322 to be a "single dose" drug to product, they may start being more forthcoming on data that backs up efficacy/effectiveness/research at a single dose.

They all say that. Auris Medical said the same thing.

 

[Lucifer]

The FX-322-111 trial is their latest trial, which they ran parallel to the Phase 2a trial. They didn't have a press release about it until today. The FX-322-201 trial is their first Phase 1/2 trial back in 2019/2020.

The problem with their latest FX-322-111-trial is that there isn't an audiogram improvement, not even in the extended high frequencies. Carl LeBel said this today. The only hearing signal they get is the WR scores, which aren't that great and apparently can't be explained by extended high frequency improvements.

So how come they improved their word scores but extended high frequency hearing test does not show the improvements?

Just doesn't make sense to me why this happens.

 

[FGG]

Ok, replying now with about 6 pages of comments left to read which is kind of dangerous, but... what would that tell us? We might see things that look like hair cells, but do they work? All this pre-clinical stuff they did counting hair cells in vitro. Was there ever any way of knowing if they were working hair cells?

Here's my theory on increased word scores in Phase 1B. Go ahead and laugh if you feel like it. Hair cells were created but they were not working. These structures attracted synaptic growth in the general vicinity which then connected to some of the remaining 'real' hair cells. So synaptopathy improvement basically.

I would think that they would already know from histology pre-clinically if it did that. Unless it only works in vivo in humans that way.

 

[Jurger]

So how come they improved their word scores but extended high frequency hearing test does not show the improvements?

Just doesn't make sense to me why this happens.

That's the question. But is's obviously not good news since the German and Australian study confirmed delivery of the drug to the cochlea.

 

[MrCrybaby]

I think the biggest takeaway for me is that we need a better was of measuring auditory signal. Audiogram is flawed... word recognition is flawed... We need a better way to design these studies.

IMHO there is so much high quality science behind FX-322 that even if it's not the answer we were hoping for it is likely a piece of the puzzle.

 

[Lucifer]

I realise both clinical trials for the severe category and age-related hearing loss have the same study start date of September 17th 2020, estimated primary completed date of March 2021 and estimated study completion date of June 2021.

I'm worried about the severe category not being positive as they had no problem releasing the results for the age-related hearing results. I really hope the severe category release positive results and the participants had substantial improvements.

 

[Jcmc]

They need to focus on how to deliver the drugs to the complete cochlea (INSIDE).

I understand reaching the inside of the cochlea without causing damage is very hard but they should find a way, if they want success with these drugs.

 

[tomytl]

Being a "top notch hair cell regeneration scientist" would imply he knows how to regenerate hair cells, no? So what is his solution to there not being a viable treatment for it yet?

He is doing research on how to regenerate hair cells. Of course he doesn't have the holy grail in his hand, but I guess he might understand more than most others what is going on. I don't want to undisclose his name because I didn't ask his permission for that. Here some outtakes of our conversation about the current state of hair cell regeneration:

- Research in hair cell regeneration is an unstoppable trend
- Hair cell regeneration will be the holy grail which would take longer due to its complexity
- I cannot say how good FX-322 will be, but it's a step in the right direction
- We are working diligently on hair cell regeneration. I am confident this can be done, I cannot give a firm timeline
- We have many leads, which if developed successfully, each could lead to robust regeneration

 

[Zugzug]

Hi all, long time follower of this thread, but I am nowhere near as intelligent as many of you so prefer to just read and learn from afar! However I'm just wondering if someone can confirm if my understanding of the results is correct? Because the placebo group showed an increase in WR and the test group also showed an increase, they basically cancel each other out? It's not that the test group showed no increase?

So if the placebo group had actually been a 'proper' placebo, showing no increase, would the FX-322 group have shown a statistically significant increase?

Hope that makes sense. From a tired mum of a newborn who was up all night feeling sorry for myself over the results.

More or less, but it's not totally clear, as this question isn't totally binary, but a sliding scale. For example, placebos can improve some, but if they do, the FX-322 groups have to crush them. Likewise, the placebos can see approximately zero changes and the FX-322 groups only have to improve a little bit.

The overall feeling is a bit of both. Like the FX-322 group underperformed themselves, but could have pulled out a victory if the placebos didn't perform so well.

 

[Diesel]

I realise both clinical trials for the severe category and age-related hearing loss have the same study start date of September 17th 2020, estimated primary completed date of March 2021 and estimated study completion date of June 2021.

I'm worried about the severe category not being positive as they had no problem releasing the results for the age-related hearing results. I really hope the severe category release positive results and the participants had substantial improvements.

They haven't released the results for the age-related trial. They're expected in Q2. The Age-Related Trial is FX-322-112.

What they previewed today was an open-label safety study, FX-322-111.

 

[Aaron91]

I realise both clinical trials for the severe category and age-related hearing loss have the same study start date of September 17th 2020, estimated primary completed date of March 2021 and estimated study completion date of June 2021.

I'm worried about the severe category not being positive as they had no problem releasing the results for the age-related hearing results. I really hope the severe category release positive results and the participants had substantial improvements.

I think you're confused. The study they released today wasn't the age-related study - those results are pending, as are those for the severe SNHL. The results from the Phase 1 study mentioned today was an off-label Phase 1 study in addition to their two other Phase 1 studies this year. By the end of this year, they will have completed four Phase 1 studies since the company was founded in addition to one Phase 2 study. Which brings me to my next point.

I'm beginning to conclude that the only way Frequency Therapeutics can save their skin here is through a good readout in their severe SNHL Phase 1 study. As others have said, it would seem to me that that is the least likely group to suffer from some kind of performance bias because they're pretty deaf as it is anyway. The question I have is: would the FDA grant approval for a combined Phase 2/3 study on the grounds of having demonstrated safety across 200+ patients in previous trials, despite having seen efficacy at only Phase 1 level?

 

[Spiral]

So when is the next trial?

 

[Lucifer]

They haven't released the results for the age-related trial. They're expected in Q2. The Age-Related Trial is FX-322-112.

What they previewed today was an open-label safety study, FX-322-111.

Can you link the clinical trial to FX-322-111 on the ClinicalTrials.gov website? I'm not sure which one it is?

 

[FGG]

I was thinking if the 10 dB improvement at 8 kHz somehow was a fluke, as it was a small sample size of patients, and that word scores somehow potentially are largely uncorrelated with pure-tone scores.

That's why I brought up IHCs maybe being preferentially treated. Because unless the Phase 1 super responders were lying (though they didn't need to for Phase 1 entry unlike any liars in Phase 2a), the drug did *something* dramatic and unprecedented in multiple subjects with word scores that had never been done before.

If there is no audiogram changes that "something" could be preferentially treating IHCs first (important for speech but not measured on audiogram like OHCs). Pre clinically both were generated but maybe in vivo you'd have to treat IHCs first, wait (way longer than a week), then retreat.

It's definitely not the idea that maybe IT injections in general treat hearing loss because IT steroids would always work for hearing loss if that were the case and not just acutely.

 

[Diesel]

The question I have is: would the FDA grant approval for a combined Phase 2/3 study on the grounds of having demonstrated safety across 200+ patients in previous trials, despite having seen efficacy at only Phase 1 level?

I suspect, after reviewing my homework on the FDA Fast Track status, that they MAY have already received preliminary approval from the FDA prior to the press release today, OR the FDA recommended that they reclassify the trial strategy to a single dose so that it fits within the FDA review process.

Otherwise, they would be doing it on the whim without any notification from the FDA... which would indeed be a second-degree fuckup for today.

 

[Lucifer]

I think you're confused. The study they released today wasn't the age-related study - those results are pending, as are those for the severe SNHL. The results from the Phase 1 study mentioned today was an off-label Phase 1 study in addition to their two other Phase 1 studies this year. By the end of this year, they will have completed four Phase 1 studies since the company was founded in addition to one Phase 2 study. Which brings me to my next point.

I'm beginning to conclude that the only way Frequency Therapeutics can save their skin here is through a good readout in their severe SNHL Phase 1 study. As others have said, it would seem to me that that is the least likely group to suffer from some kind of performance bias because they're pretty deaf as it is anyway. The question I have is: would the FDA grant approval for a combined Phase 2/3 study on the grounds of having demonstrated safety across 200+ patients in previous trials, despite having seen efficacy at only Phase 1 level?

What are four Phase 1b trials you are talking about? The only three I know are off-label safety, age-related and severe.

 

[Street Novelist]

Why not inject back-to-back dosages to push the first injection further into the cochlea?

 

[Tezcatlipoca]

I suspect, after reviewing my homework on the FDA Fast Track status, that they MAY have already received preliminary approval from the FDA prior to the press release today, OR the FDA recommended that they reclassify the trial strategy to a single dose so that it fits within the FDA review process.

Otherwise, they would be doing it on the whim without any notification from the FDA... which would indeed be a second-degree fuckup for today.

Aren't they already in close communication with the FDA? They have never fucked up paperwork or due diligence. My bet is that since the bar is so low on Hearing Science, the FDA already gave them the OK for the Phase 3 trial.

 

[Nobody19]

Can you link the clinical trial to FX-322-111 on the ClinicalTrials.gov website? I'm not sure which one it is?

I think it's this one:

FX-322 in Adults With Age-Related Sensorineural Hearing Loss

Edit: it's not.

 

[Diesel]

That's why I brought up IHCs maybe being preferentially treated. Because unless the Phase 1 super responders were lying (though they didn't need to for Phase 1 entry unlike any liars in Phase 2a), the drug did *something* dramatic and unprecedented in multiple subjects with word scores that had never been done before.

If there is no audiogram changes that "something" could be preferentially treating IHCs first (important for speech but not measured on audiogram like OHCs). Pre clinically both were generated but maybe in vivo you'd have to treat IHCs first, wait (way longer than a week), then retreat.

It's definitely not the idea that maybe IT injections in general treat hearing loss because IT steroids would always work for hearing loss if that were the case and not just acutely.

Yeah I was trying to find some research showing if there is an "order of operations" for growth of inner and outer hair cells in utero for humans. It appears that the whole development of the cochlea takes about 6 weeks. And, the inner hair cells are the more "primitive" hearing function shared with lower mammals & vertebrates.

So, perhaps the order in utero is IHC develops, synapses to SG, the OHC develops, synapses to IHC/SG

If that is the case, then you might be right, the IHC needs to be functioning and providing a "GO" signal for the outer hair cell progenitors to kick on and do their work.

 

[Diesel]

I think it's this one:

FX-322 in Adults With Age-Related Sensorineural Hearing Loss

No, that is FX-322-112.

 

[wwtsai]

I suspect, after reviewing my homework on the FDA Fast Track status, that they MAY have already received preliminary approval from the FDA prior to the press release today, OR the FDA recommended that they reclassify the trial strategy to a single dose so that it fits within the FDA review process.

Otherwise, they would be doing it on the whim without any notification from the FDA... which would indeed be a second-degree fuckup for today.

Would be great either way... as bad as the news was today, I still want the goop in my ears ASAP.

 

[FGG]

Yeah I was trying to find some research showing if there is an "order of operations" for growth of inner and outer hair cells in utero for humans. It appears that the whole development of the cochlea takes about 6 weeks. And, the inner hair cells are the more "primitive" hearing function shared with lower mammals & vertebrates.

So, perhaps the order in utero is IHC develops, synapses to SG, the OHC develops, synapses to IHC/SG

If that is the case, then you might be right, the IHC needs to be functioning and providing a "GO" signal for the outer hair cell progenitors to kick on and do their work.

Yes, I was reading about this a lot today. Embryologically, you grow IHCs first and signals from them seem necessary for OHC growth. I'm so glad you found this, too.

If this is the case, it would be seen here, too (that is if people were honest about word scores for Phase 2a).

The severe group stands the most chance of replicating this. Especially if they were single dose.

 

[Aaron91]

I suspect, after reviewing my homework on the FDA Fast Track status, that they MAY have already received preliminary approval from the FDA prior to the press release today, OR the FDA recommended that they reclassify the trial strategy to a single dose so that it fits within the FDA review process.

Otherwise, they would be doing it on the whim without any notification from the FDA... which would indeed be a second-degree fuckup for today.

I hope you're right! Any way we can reconcile this with what Carl said today in a soundbite:

"It's fair to say we have more Phase 2 work to do. Some of these things we uncovered out of the four-injection study, we really want to home in on as we begin to think about what a pivotal trial design will look like in the future"​

I don't know if I should read this as them doing another Phase 2 trial prior to a Phase 3 trial, or them doing a Phase 2 trial as part of a pivotal Phase 2/Phase 3 trial?

 

[Lucifer]

No, that is FX-322-112.

View attachment 44218

Thank you for this but I can't seem to find the FX-322-111 study on the ClinicalTrials.gov website.

 

[Aaron91]

Yeah I was trying to find some research showing if there is an "order of operations" for growth of inner and outer hair cells in utero for humans. It appears that the whole development of the cochlea takes about 6 weeks. And, the inner hair cells are the more "primitive" hearing function shared with lower mammals & vertebrates.

So, perhaps the order in utero is IHC develops, synapses to SG, the OHC develops, synapses to IHC/SG

If that is the case, then you might be right, the IHC needs to be functioning and providing a "GO" signal for the outer hair cell progenitors to kick on and do their work.

Yes, I was reading about this a lot today. Embryologically, you grow IHCs first and signals from them seem necessary for OHC growth. I'm so glad you found this, too.

If this is the case, it would be seen here, too (that is if people were honest about word scores for Phase 2a).

The severe group stands the most chance of replicating this. Especially if they were single dose.

Can we get some sources please, guys? For my own sanity/self-preservation I need to go down this rabbithole myself.