Frequency Therapeutics — Hearing Loss Regeneration

[Tezcatlipoca]

Depends on your definition of the future. There's almost a 100% chance that something will help in the next 10-20 years. How soon they improve delivery will be a major factor in determining this.

There's a lot of work going on in the field and more and more heads are turning this way, I'd say 10 years max.

 

[kiki]

Depends on your definition of the future. There's almost a 100% chance that something will help in the next 10-20 years. How soon they improve delivery will be a major factor in determining this.

Oh, even 10 years is too far away and hopeless. I may not be alive 20 years from now. At least 5 years.

Is there any possibility of improving the delivery method that can improve the audiogram even a little?

Since it has reached the cochlea, is there any possibility of improvement not only by delivery but also by increasing the concentration?

 

[r34d1ng]

The drug failed. Everyone agrees.

IMHO, Phase 2a failed, not the drug. It's too soon to say that.

 

[Bambam0]

This reads like massive denial...

I just like the stock.

 

[Keith Handy]

"Frequency Therapeutics throws a left punch, but misses! Otonomy counters with an upper-cut!"

Otonomy Initiates Phase 2 Clinical Trial of OTO-313 in Tinnitus

Has to be unilateral??

 

[grate_biff]

multiple injections aren't mucking up people's middle ear passage.

(The qoute came off a bit wrong as he meant a delivery that would NOT do this.)

I wonder if they did a conductive HT in that regard? I remember when my ears where clogged after an ear infection. I could hardly hear on that ear at all, but the conductive test showed that my audiogram was as before. (Still no good, but not worse.) I think this "clogging" can last for a long time too.

Also in regards to the "not walk on the newly seeded lawn" problem: FX-322 has two molecules, right? One to divide the progenitor cells and one to make em a new hair cell? Maybe, just maybe, having them working as a compound is doing exactly that? Walking on the lawn, I mean. Maybe it would be better to let the first molecule do its job first, wait a while and then do the second one?

Also, is it absolutely impossible to reach the round window with a needle? Or the oval window for that matter (probably easier accessible)? It would be a much more intricate procedure, I understand, but if it is possible, they should at least try it on a living human being. In utero or in vivo (what ever you call it). Give the needle a good squeeze as well to give it some current .

I just had my TT muscle severed and they had to bend the whole eardrum to the side. That would give you better access, right?

Get the drug in there without relying on diffusion, permeability which I really think is what the word says: It's a bit diffuse how much will get through. But also not clogging up the ear would be great.

The whole procedure need to be more clinical and direct if possible.

Also, as said here, it takes about 12 days for a new HC to grow, but how long does it take for it to connect to the hearing nerve via new synapses connecting and also for the brain to "get" the input getting back?

I'm hoping the 210 day readout for at least the EHF audiograms to show us something more than at 90. I'm hoping both us and Frequency Therapeutics will be surprised.

It's been said here, and I agree: Even though audiograms are not flawless, an out dated tool and can be a bit subjective, WR score are much more so imo. I have done it and one can always guess and sometimes you will be right and sometimes not, even depending on how much you are able to concentrate on that particular testing day.

These were my thoughts. I'm still in shock. So many years of hope and emotional and (economic) involvement just shattered. I still have hope for Frequency Therapeutics though. I think delivery is key.

 

[Lucifer]

@FGG, from the trials so far can we tell if FX-322 regrows IHCs or OHCs? If they continue with the single dosing of FX-322 would it have regrown both IHCs and OHCs but the multiple dosing of FX-322 in quick succession killed the regrowing process?

 

[Jack Straw]

The rational move is to cut losses immediately and wait for good news to justify re-investing. And if it keeps bleeding down after you sell, you can decide whether you want to buy back in at a lower price.

By the time you hear good news it's too late to buy. Pharma investing is all about believing in the company/drug before the results come out. It's the only way to make money on investment in pharma.

 

[FGG]

Oh, even 10 years is too far away and hopeless. I may not be alive 20 years from now. At least 5 years.

Is there any possibility of improving the delivery method that can improve the audiogram even a little?

Since it has reached the cochlea, is there any possibility of improvement not only by delivery but also by increasing the concentration?

I think he was just trying to be extra conservative to meet a 100% likelihood. I would be really surprised personally if it took 10-20 years as a researcher in the field told me that she feels confident they will solve the "flat epithelia" problem and be able to transform fibroblasts to support cells and then ultimately hair cells within 15 years. That problem is many magnitudes harder than starting from support cells.

Phase 2a puts Frequency Therapeutics behind at least 18 month to 2 years imo. Which isn't great news of course. I don't see them not restarting Phase 2. It's actually possible other companies (eg. Otonomy with Oto-6xx) may even get close to them time frame wise to market if that's the case. They aren't even the only two contenders. Other companies have hair cell regeneration drugs already in pre-clinical: Akouous and Decibel.

 

[Guywithapug]

 

[Lucifer]

(The qoute came off a bit wrong as he meant a delivery that would NOT do this.)

I wonder if they did a conductive HT in that regard? I remember when my ears where clogged after an ear infection. I could hardly hear on that ear at all, but the conductive test showed that my audiogram was as before. (Still no good, but not worse.) I think this "clogging" can last for a long time too.

Also in regards to the "not walk on the newly seeded lawn" problem: FX-322 has two molecules, right? One to divide the progenitor cells and one to make em a new hair cell? Maybe, just maybe, having them working as a compound is doing exactly that? Walking on the lawn, I mean. Maybe it would be better to let the first molecule do its job first, wait a while and then do the second one?

Also, is it absolutely impossible to reach the round window with a needle? Or the oval window for that matter (probably easier accessible)? It would be a much more intricate procedure, I understand, but if it is possible, they should at least try it on a living human being. In utero or in vivo (what ever you call it). Give the needle a good squeeze as well to give it some current .

I just had my TT muscle severed and they had to bend the whole eardrum to the side. That would give you better access, right?

Get the drug in there without relying on diffusion, permeability which I really think is what the word says: It's a bit diffuse how much will get through. But also not clogging up the ear would be great.

The whole procedure need to be more clinical and direct if possible.

Also, as said here, it takes about 12 days for a new HC to grow, but how long does it take for it to connect to the hearing nerve via new synapses connecting and also for the brain to "get" the input getting back?

I'm hoping the 210 day readout for at least the EHF audiograms to show us something more than at 90. I'm hoping both us and Frequency Therapeutics will be surprised.

It's been said here, and I agree: Even though audiograms are not flawless, an out dated tool and can be a bit subjective, WR score are much more so imo. I have done it and one can always guess and sometimes you will be right and sometimes not, even depending on how much you are able to concentrate on that particular testing day.

These were my thoughts. I'm still in shock. So many years of hope and emotional and (economic) involvement just shattered. I still have hope for Frequency Therapeutics though. I think delivery is key.

Same man, I would never have thought that multiple doses of FX-322 weekly would be so bad, it should have been the opposite.

If they were to redo it again do you think monthly doses of FX-322 will be a better option or would that be too soon as well?

 

[Sunshine007]

They were saying everyone increased their word scores significantly, including placebo so there was an increased effect in all groups but no difference from placebo (which doesn't differentiate the drug from placebo in the trial in that case). Their claim is that they found "inconsistencies" that point to it being related to people artificially depressing their word score to meet trial requirements.

Actually, around the 17-minute mark in their call they say the increases they saw was less than what they observed "Changes in the WRS are lower than in the past single studies".

My understanding is they are essentially saying curves don't separate at all and are sloping upwards but the the slope is lower than (the FX-322 arm) in the previous single studies.

Clearly the fact the drug did nothing seems to be the crucial factor here. This suggests either the effect observed earlier was a fluke or the multiple injections killed the effect.

 

[GlennS]

"Frequency Therapeutics throws a left punch, but misses! Otonomy counters with an upper-cut!"

Otonomy Initiates Phase 2 Clinical Trial of OTO-313 in Tinnitus

 

[GlennS]

Phase 2a failed, not the drug. It's too soon to say that.

How often do Phase 2s fail with drug testing and it still get released in the end?

 

[Tezcatlipoca]

How often do Phase 2s fail with drug testing and it still get released in the end?

Sorry for the wall of text, but I think we all need to read this.

In practice, clinical testing progression and design has become increasingly flexible as the science of clinical trials has evolved. Phase 1 might be combined with Phase 2 if the drug is expected to have toxicity unacceptable for healthy volunteers. If the product's mechanism of action and safety profile are well characterized, phase 2 testing may be shortened or skipped altogether. When there is sufficient evidence that a change in a biomarker reliably predicts a clinical benefit, the biomarker can serve as a surrogate measure for that clinical benefit in a trial, and the effect of the product on the surrogate measure can be a basis for product approval. Surrogate measures are often biomarkers that help diagnose or monitor a disease, such as blood pressure to predict stroke risk or the amount of human immunodeficiency virus in the blood to predict the development of acquired immunodeficiency syndrome. The nature of definitive trials also varies. Larger and longer trials may be needed if, for example, the condition to be treated is chronic or if the event the drug is intended to prevent occurs infrequently. Smaller or shorter trials may be needed where, for example, the drug produces a dramatic improvement in patients, or is intended for short-term conditions like many infections. Other factors, such as whether the condition is widespread or rare, whether it is life-threatening, and whether there are other effective treatments for the condition are also important in determining what kind of clinical testing is appropriate. Where a drug or biologic is intended to treat a serious condition for which there are limited available alternative therapies, FDA has implemented four separate expedited development and review programs. For example, when there is evidence that a biomarker is "reasonably likely to predict" clinical benefit, that biomarker can be a basis for approval under FDA's accelerated approval authority. In these situations, sponsors have been required to conduct post-market confirmatory studies to further define the clinical benefit of the drug.

Source:
https://www.fda.gov/media/102332/download (page 3-4)​

 

[FGG]

@FGG, from the trials so far can we tell if FX-322 regrows IHCs or OHCs? If they continue with the single dosing of FX-322 would it have regrown both IHCs and OHCs but the multiple dosing of FX-322 in quick succession killed the regrowing process?

No we can't. The only thing that I can conclude is that one group had "inconsistencies" (aka lying): Phase 1 participants, Phase 2a participants (this is what Frequency Therapeutics says) or the company themselves.

There is some test/retest variation on Word scores but doubling is not within that variation (concentrating harder or not), especially not with multiple participants.

So, the drug has a hearing effect if you believe both Frequency Therapeutics and the Phase 1 participants. The drug "doesn't do anything" if you think one of those two groups is lying.

As to the "what" hearing improvement may have happened, the IHCs is my own personal theory because nothing else makes sense to me. You can't use trial data to prove or disprove it, unfortunately, because none of the testing directly measures it (and audiograms measure OHCs).

But if this is a true hearing effect (and the Phase 2a are where the true "inconsistencies" happened), then Frequency Therapeutics themselves has to figure out what exactly happened before they continue and this will require a lot of detailed individual data (among other things) we would not have access to imo. This is why even if the severe group has great data (I think it has the best chance of that), I think it's very highly likely they would still have to repeat Phase 2.

 

[Lucifer]

Actually, around the 17-minute mark in their call they say the increases they saw was less than what they observed "Changes in the WRS are lower than in the past single studies".

My understanding is they are essentially saying curves don't separate at all and are sloping upwards but the the slope is lower than (the FX-322 arm) in the previous single studies.

Clearly the fact the drug did nothing seems to be the crucial factor here. This suggests either the effect observed earlier was a fluke or the multiple injections killed the effect.

I'm going with the multiple injections killed the effect. They have done two Phase 1b trials that showed improvement in word scores with one dose of FX-322. Will McLean stated that it takes 12 days to regrow hair cells so maybe monthly doses will be a better solution.

 

[FGG]

How often do Phase 2s fail with drug testing and it still get released in the end?

Not sure, but it definitely happens. Even just off the top of my head, Durrect's Posimer (long acting local anesthetic) failed a Phase 3, did a post-mortem on the trial to figure out what went wrong and eventually got approved a few months ago.

It depends entirely on what went wrong.

 

[FGG]

Actually, around the 17-minute mark in their call they say the increases they saw was less than what they observed "Changes in the WRS are lower than in the past single studies".

My understanding is they are essentially saying curves don't separate at all and are sloping upwards but the the slope is lower than (the FX-322 arm) in the previous single studies.

Clearly the fact the drug did nothing seems to be the crucial factor here. This suggests either the effect observed earlier was a fluke or the multiple injections killed the effect.

They said both that they think they inconsistencies were in all groups, placebo and all drug cohorts and also that the effect of multiple injections worsened outcomes.

Aka perfect storm.

 

[Zugzug]

Why hold off the pivotal phase if the mild-moderate severe candidates show meaningful improvements in word scores?

Small sample sizes. Phase 1b trials are considered exploratory. Let's say the older patient trial was pretty successful in WR only. Then we will have Phase 1/2 and Trial 112 supporting WR improvement, but Phase 2a showing big WR improvement in the placebo. Questions will then come about whether the Phase 1 trials were just lucky.

I think best case scenario is that Trial 112 and 113 are successful, they make good arguments about why WR failed in Phase 2a, and we are feeling solid about a drug repeating Phase 2 for word scores only. PTA is still a total disaster. Much of the point of these new trials is to help save face and provide people with a continued belief in the overall science.

 

[RichieTheKid]

Agree, if the age-related hearing loss trial shows meaningful improvements but the severe hearing loss trial show little or no improvements the FDA should allow FX-322 to continue with the pivotal phase early next year as they could market it for mild-moderately severe hearing loss patients with the potential of decreasing tinnitus or getting rid of it completely.

Why hold off the pivotal phase if the mild-moderate severe candidates show meaningful improvements in word scores?

This is what I'm saying. We can't expect a miracle drug at this point in science and development.

 

[Ed209]

There's a lot of work going on in the field and more and more heads are turning this way, I'd say 10 years max.

I've just gotta point out that we used to joke about the 10-year figure because people have been saying that for decades. I hope you're right, but the years fly by, and nothing ever seems to change. What we need is significantly more money going into research and for tinnitus and other ear-related conditions to be taken seriously. At present, this is still not the case, although it is improving.

@Markku said this in 2013 which he may find interesting:

Note to self: Remember to be disappointed if within 7 years time there aren't more effective treatments for tinnitus.

Well, I think we can safely say that there's a shit ton of disappointment on this board.

 

[TrevorSanders]

IMHO, Phase 2a failed, not the drug. It's too soon to say that.

Most things point in the direction that the drug failed though. Having no scientifically significant improvements on the audiogram in any groups does not look well for the drug's efficacy.

 

[FGG]

Small sample sizes. Phase 1b trials are considered exploratory. Let's say the older patient trial was pretty successful in WR only. Then we will have Phase 1/2 and Trial 112 supporting WR improvement, but Phase 2a showing big WR improvement in the placebo. Questions will then come about whether the Phase 1 trials were just lucky.

I think best case scenario is that Trial 112 and 113 are successful, they make good arguments about why WR failed in Phase 2a, and we are feeling solid about a drug repeating Phase 2 for word scores only. PTA is still a total disaster. Much of the point of these new trials is to help save face and provide people with a continued belief in the overall science.

That's beyond "lucky" statistically. I would say there is something shady going on if those effects turn out to be only ever seen in Phase 1.

 

[Tezcatlipoca]

I would say there is something shady going on if those effects turn out to be only ever seen in Phase 1.

Shady? As in FREQ lying? I don't think that's the case.

 

[Lucifer]

No we can't. The only thing that I can conclude is that one group had "inconsistencies" (aka lying): Phase 1 participants, Phase 2a participants (this is what Frequency Therapeutics says) or the company themselves.

There is some test/retest variation on Word scores but doubling is not within that variation (concentrating harder or not), especially not with multiple participants.

So, the drug has a hearing effect if you believe both Frequency Therapeutics and the Phase 1 participants. The drug "doesn't do anything" if you think one of those two groups is lying.

As to the "what" hearing improvement may have happened, the IHCs is my own personal theory because nothing else makes sense to me. You can't use trial data to prove or disprove it, unfortunately, because none of the testing directly measures it (and audiograms measure OHCs).

But if this is a true hearing effect (and the Phase 2a are where the true "inconsistencies" happened), then Frequency Therapeutics themselves has to figure out what exactly happened before they continue and this will require a lot of detailed individual data (among other things) we would not have access to imo. This is why even if the severe group has great data (I think it has the best chance of that), I think it's very highly likely they would still have to repeat Phase 2.

Well let's hope the severe hearing loss trial pulls through. How did the word scores double in Phase 1b; it doesn't make sense how this happened.

I had a look at both trials and 24 patients will receive FX-322 and 6 patients will receive placebo for both trials.

Is 6 patients who will be receiving placebo be enough to determine if FX-322 works or not, if it does show word score improvements with a single dose of FX-322?

 

[Cernuto]

They provided pictures that show clear and compelling indications of new hair cells being generated. Granted, it was a test environment. Still, it's hard to wrap my head around why it 'failed'. It could be some minor detail with their delivery or formulation that needs to be tweaked?

 

[Lucifer]

Small sample sizes. Phase 1b trials are considered exploratory. Let's say the older patient trial was pretty successful in WR only. Then we will have Phase 1/2 and Trial 112 supporting WR improvement, but Phase 2a showing big WR improvement in the placebo. Questions will then come about whether the Phase 1 trials were just lucky.

I think best case scenario is that Trial 112 and 113 are successful, they make good arguments about why WR failed in Phase 2a, and we are feeling solid about a drug repeating Phase 2 for word scores only. PTA is still a total disaster. Much of the point of these new trials is to help save face and provide people with a continued belief in the overall science.

Even with the small sample size it doesn't explain how some patients basically doubled their word scores. If the age-related hearing loss and severe hearing loss trials show meaningful improvements then we will know that FX-322 works and the problem with Phase 2a was the multiple dosing.

 

[Lucifer]

This is what I'm saying. We can't expect a miracle drug at this point in science and development.

It doesn't need to be perfect but if it helps most mild-moderate severe hearing loss patients I think it should still go through to the pivotal phase. We just need the age-related hearing loss trials to show meaningful word score improvements which could convince the FDA to proceed through to the pivotal phase early next year for mild-moderately severe hearing loss candidates.

 

[FGG]

Shady? As in FREQ lying? I don't think that's the case.

Or the Phase 1 group for a reason I can't figure out. But that's not my first thought either.