Frequency Therapeutics — Hearing Loss Regeneration

[Diesel]

Oh hey: I learned something... thanks Wikipedia:

• Phase IIa studies are usually pilot studies designed to demonstrate clinical efficacy or biological activity ('proof of concept' studies);
• Phase IIb studies determine the optimal dose at which the drug shows biological activity with minimal side-effects ('definite dose-finding' studies).

Welp... we definitely just witnessed a "proof of concept" study for hearing loss all right...

 

[MarkRule]

My biggest fear is that we have a drug that works but doesn't come out because participants lied about results. The conspiracy theorist in me thinks that the world's largest hearing aid manufacturer swamped recruitment and messed up results in both Phase 1 and 2 (placebo responders).

 

[Tezcatlipoca]

Assuming FX-322 only shows minor MEASURABLE improvements but is safe, could it hit the market considering there is no existing regenerative drugs?

In my opinion, absolutely. The FDA looks more and more interested in this field. Even a small regeneration would be groundbreaking.

 

[Lucifer]

In my opinion, absolutely. The FDA looks more and more interested in this field. Even a small regeneration would be groundbreaking.

Depends on what the FDA needs from the FX-322 trials to be confident that FX-322 is safe and effective for it to go through to the pivotal phase.

If you think about it, they have technically done a Phase 2a anyways with single dosing of over a 100 patients participating in the four Phase 1b trials.

 

[serendipity1996]

Just came across this if anyone is interested in attending the virtual webinar. More awareness of the pressing need for drug treatments to meet an unmet need. Frequency Therapeutics is listed as one of the supporters, along with a number of other drug companies (e.g., Decibel Therapeutics, Pipeline Therapeutics, Otonomy etc).

HLAA to Hold Patient-Focused Drug Development Webinar and Meeting

HLAA has received permission from the FDA to hold an externally-led Patient Focused Drug Development Meeting on May 25. We will hold a webinar on April 8 with more information on the meeting. All are welcome to attend. This session will be free and open to all.

Patient-Focused Drug Development (PFDD) meetings were first started by the FDA to try and find a better way to hear directly from patients, their caregivers and families. The meetings explore what symptoms matter most to them, the impacts on patients' daily lives, and patients' experiences with currently available treatments. This information helps the FDA both during drug development as well as during review of marketing applications for new drugs

It is exciting that HLAA can lead the charge here with the FDA who will attend and listen. Our hope is that patient engagement through a PFDD will go a long way in shaping future hearing loss treatments and creating a deeper understanding of the impact of hearing loss on individuals, their quality of life and associated comorbidities.​

 

[Ali.sy]

Why are you wasting your time on something that has ended? It's just that FX-322 didn't work, and I'm saying that in a loud voice.

 

[Tezcatlipoca]

Just came across this if anyone is interested in attending the virtual webinar. More awareness of the pressing need for drug treatments to meet an unmet need. Frequency Therapeutics is listed as one of the supporters, along with a number of other drug companies (e.g., Decibel Therapeutics, Pipeline Therapeutics, Otonomy etc).

HLAA to Hold Patient-Focused Drug Development Webinar and Meeting

HLAA has received permission from the FDA to hold an externally-led Patient Focused Drug Development Meeting on May 25. We will hold a webinar on April 8 with more information on the meeting. All are welcome to attend. This session will be free and open to all.

Patient-Focused Drug Development (PFDD) meetings were first started by the FDA to try and find a better way to hear directly from patients, their caregivers and families. The meetings explore what symptoms matter most to them, the impacts on patients' daily lives, and patients' experiences with currently available treatments. This information helps the FDA both during drug development as well as during review of marketing applications for new drugs

It is exciting that HLAA can lead the charge here with the FDA who will attend and listen. Our hope is that patient engagement through a PFDD will go a long way in shaping future hearing loss treatments and creating a deeper understanding of the impact of hearing loss on individuals, their quality of life and associated comorbidities.​

We need to get Frequency Therapeutics to make our case and present the tinnitus resolutions/improvements. This could get us into warp speed for approval.

 

[kiki]

I think in the next Phase 2a they will administer multiple injections at appropriate intervals.

Before that, I think Phase 1b will be done in addition.

Phase 1b that aims to improve the efficacy by adjusting the concentration of CHIR99021 and VPA in a single dose.

It is a brush-up to improve the efficacy with a single injection.

I think they aim to improve the efficacy with a single injection.

And then they will repeat the Phase 2a.
They don't waste this first Phase 2a failure.
The aim is to prove that the therapeutic effects are cumulative with each injection without depleting the supporting cells.

It is important not to fail.
But they also have to compete with time.
It is also important not to lose the trust of investors and funders.

From now on, it's a tightrope walk.

I am 58 years old.
Mild deafness and constant severe tinnitus.
For the rest of my life, I want to regain the ability to hear the quiet, beautiful music again without ringing in my ears.

And for people with hearing loss who reach the conversational realm, they will only put a version with an improved delivery method into clinical trials after FX-322 is out on the market.

 

[Diesel]

Why are you wasting your time on something that has ended? It's just that FX-322 didn't work, and I'm saying that in a loud voice.

Can't tell if satire or serious.

 

[Lucifer]

I think in the next Phase 2a they will administer multiple injections at appropriate intervals.

Before that, I think Phase 1b will be done in addition.

Phase 1b that aims to improve the efficacy by adjusting the concentration of CHIR99021 and VPA in a single dose.

It is a brush-up to improve the efficacy with a single injection.

I think they aim to improve the efficacy with a single injection.

And then they will repeat the Phase 2a.
They don't waste this first Phase 2a failure.
The aim is to prove that the therapeutic effects are cumulative with each injection without depleting the supporting cells.

It is important not to fail.
But they also have to compete with time.
It is also important not to lose the trust of investors and funders.

From now on, it's a tightrope walk.

I am 58 years old.
Mild deafness and constant severe tinnitus.
For the rest of my life, I want to regain the ability to hear the quiet, beautiful music again without ringing in my ears.

And for people with hearing loss who reach the conversational realm, they will only put a version with an improved delivery method into clinical trials after FX-322 is out on the market.

I think their next steps is that they should focus on the single dosing of FX-322 as it is shown to be more effective than multi-dosing in weekly succession to make sure it comes out in the market as soon as possible, and then work at refining their delivery method to reach deeper in the round window to help those severe hearing loss sufferers.

 

[Markku]

Just came across this if anyone is interested in attending the virtual webinar. More awareness of the pressing need for drug treatments to meet an unmet need. Frequency Therapeutics is listed as one of the supporters, along with a number of other drug companies (e.g., Decibel Therapeutics, Pipeline Therapeutics, Otonomy etc).

HLAA to Hold Patient-Focused Drug Development Webinar and Meeting

HLAA has received permission from the FDA to hold an externally-led Patient Focused Drug Development Meeting on May 25. We will hold a webinar on April 8 with more information on the meeting. All are welcome to attend. This session will be free and open to all.

Patient-Focused Drug Development (PFDD) meetings were first started by the FDA to try and find a better way to hear directly from patients, their caregivers and families. The meetings explore what symptoms matter most to them, the impacts on patients' daily lives, and patients' experiences with currently available treatments. This information helps the FDA both during drug development as well as during review of marketing applications for new drugs

It is exciting that HLAA can lead the charge here with the FDA who will attend and listen. Our hope is that patient engagement through a PFDD will go a long way in shaping future hearing loss treatments and creating a deeper understanding of the impact of hearing loss on individuals, their quality of life and associated comorbidities.​

Great find! I registered Tinnitus Hub as a partner supporter of this meeting. Even though strictly speaking we're not a hearing loss organization, adding our support is fitting no doubt.

 

[Sunshine007]

I have seen Phase 1b referred to as "cohort expansion" before. My impression is it's a trial to expand Phase 1 over a bigger group of potential patients.

Phase 1/2 is combined safety/efficacy.

But that's the reason I am convinced they will need another Phase 2a regardless of the age-related and severe group results. Because the efficacy data (including Word Scores) are secondary end points in the Phase 1b studies.

But who knows, maybe the FDA allows that data to be used anyway since it's a secondary and not an experimental endpoint.

Based on my understanding, Phase 1 is very low n to show drug does not have major safety issues.

Phase 2 trials are meant to enlarge population and study optimal dose and also fine tune the target population.

Phase 3 is the pivotal trial where you show with statistical significance what the drug does vs placebo

I don't think the primary or secondary labels matters as long as it is properly randomized and endpoints are defined upfront.

Essentially the only thing the Phase 2 has done is confirmed the single dose regimen. The remaining Phase 1Bs could help fix the target population. The biggest remaining question might be what the placebo effect will be and how to power the pivotal study.

Given there are no safety issues, it's plausible that FX-322 might still go to Phase 3 after the remaining readouts. I don't think the regulators will have a problem but whether Frequency Therapeutics will be willing with the data is the issue.

 

[Lucifer]

Based on my understanding, Phase 1 is very low n to show drug does not have major safety issues.

Phase 2 trials are meant to enlarge population and study optimal dose and also fine tune the target population.

Phase 3 is the pivotal trial where you show with statistical significance what the drug does vs placebo

I don't think the primary or secondary labels matters as long as it is properly randomized and endpoints are defined upfront.

Essentially the only thing the Phase 2 has done is confirmed the single dose regimen. The remaining Phase 1Bs could help fix the target population. The biggest remaining question might be what the placebo effect will be and how to power the pivotal study.

Given there are no safety issues, it's plausible that FX-322 might still go to Phase 3 after the remaining readouts. I don't think the regulators will have a problem but whether Frequency Therapeutics will be willing with the data is the issue.

You have been one of the only few to have said that FX-322 could possibly go to Phase 3/pivotal phase without a repeat of the Phase 2b. I agree with you that it has been proven safe. They had over 100-200 patients to prove that it was safe, and even with four doses of FX-322 there were no safety issues.

The only issue is the efficacy which was a problem with the Phase 2a but the two previous Phase 1b trials had positive outcomes in the improvement in word scores. Even if the Phase 2a failed, would the FDA accept the previous two Phase 1b trials as enough evidence to proceed to a Phase 3/pivotal phase? Especially if the age-related and severe hearing loss trial results coming out later in the year have positive outcomes in word score improvements, showing that FX-322 works as a single dose? This is why I believe they won't need to repeat the Phase 2a but many of the users here think they will need to.

 

[Sunshine007]

Even if the Phase 2a failed, would the FDA accept the previous two Phase 1b trials as enough evidence to proceed to a Phase 3/pivotal phase? Especially if the age-related and severe hearing loss trial results coming out later in the year have positive outcomes in word score improvements, showing that FX-322 works as a single dose? This is why I believe they won't need to repeat the Phase 2a but many of the users here think they will need to.

I think it really comes down to the upcoming readouts. If the readouts are similar to the Phase 1, it is quite possible in my opinion. Whether they will is of course the million dollar question It is is a different population age wise and hearing loss wise.

If the readouts are good, they will have safety data from n=~200 and efficacy data from n=~100 for the pivotal trial dose.

 

[Philip83]

They also told me they called the clinic and told them the tinnitus was basically gone and they said "thanks".

Shouldn't they have been doing a post-dose TFI test for the 90 day read-out?

 

[Lucifer]

I think it really comes down to the upcoming readouts. If the readouts are similar to the Phase 1, it is quite possible in my opinion. Whether they will is of course the million dollar question It is is a different population age wise and hearing loss wise.

If the readouts are good, they will have safety data from n=~200 and efficacy data from n=~100 for the pivotal trial dose.

I wonder if that's why they decided to add those extra Phase 1b trials when the Phase 2a results were going to south to have something for the FDA to convince them on allowing FX-322 to go through to the pivotal phase. I wouldn't be surprised.

 

[Paulmanlike]

I don't know if anybody feels the same, but I think FX-322 is the end of the line. The evidence against this not working is substantial.

I've lost all hope in FX-322 and I get the impression many people were depending on this and they don't want to let it go.

I think the next thing we have to hope for is that Otonomy will succeed.

It just doesn't work.

I acknowledge the trial was flawed but even with those flaws the results just show next to nothing in terms of efficacy.

It's just the way it is.

Change my mind. I wish you could.

 

[Keith Handy]

Great find! I registered Tinnitus Hub as a partner supporter of this meeting. Even though strictly speaking we're not a hearing loss organization, adding our support is fitting no doubt.

I think gently nudging the language from "hearing loss" to "hearing disorders" would be a good start.

 

[kiki]

I think their next steps is that they should focus on the single dosing of FX-322 as it is shown to be more effective than multi-dosing in weekly succession to make sure it comes out in the market as soon as possible, and then work at refining their delivery method to reach deeper in the round window to help those severe hearing loss sufferers.

I hope the future you are thinking of will come true.

It is currently the most ideal.
My own thoughts are a little more pessimistic, but I'm still hopeful.

"0 → 1" is the most difficult.
I hope this drug will be on the market as soon as possible.

I think that the hurdles for the next "10", "20", "40", "80" ... will be lower after becoming "1".

 

[ColinUK]

Shouldn't they have been doing a post-dose TFI test for the 90 day read-out?

I just don't get this either. I mean with such a disastrous trial you would think that they would want to salvage anything that was positive, so the only conclusion you can come to is there is nothing. I mean in the webcast they said that they didn't expect anything positive with the tinnitus readout.

Here based on the anecdotal evidence, one person's tinnitus was basically cured and one person did nothing, so even if we believe them it still doesn't help come to any conclusion.

I would really like to see some information if only to confirm these accounts. I would really hope people wouldn't lie about stuff like this, but when people claim their tinnitus is cured, how do you not hang onto that glimmer of hope.

It's terrible and almost cruel really that people have been waiting for 4 years and all anyone wants is some information, they did this trial and supposedly got the information so just release it to put people out of their misery.

I really wanted this to work. I really believed in the team behind it, but some transparency and honesty would be appreciated, it's not just a business making money but a business offering hope.

But as others have said, I think the reality of the situation is that it just doesn't work and I need to let go of the hope and just move on. I would just like to have some facts to help this as it's tough to let go.

 

[Diesel]

I think gently nudging the language from "hearing loss" to "hearing disorders" would be a good start.

I second this. "Hearing loss" doesn't align with the life-long effects that it has. Disorder is a good start, but why not just go all the way to "Disease"... since it fits the classical definition. If suddenly research said that "30+ Million Americans suffer from Mild-Severe Hearing Disease." It sounds like it should be taken more seriously.

Secondly, a lot of the common symptoms need a second name that makes it sound more devastating. Like "tinnitus" for example, that gets the light, friendly "ringing in the ears" description every time it's mentioned by the press. Which, in my opinion, again totally minimizes the effect/experience of the disorder. Almost makes it sound cute. Why not give tinnitus a second name that makes it more recognizable. For example, Screaming Ear Disease, or Osbourne's Disease (after Ozzy, who is the first musician that I knew had it before I got it).

 

[d'Wooluf]

I don't know if anybody feels the same, but I think FX-322 is the end of the line.

I think it's probably the end of the line for FX-322 (a sliver of hope remaining) but not necessarily the end for Frequency Therapeutics. They are well-resourced. I just wish they'd get over themselves, tone down the self-promotion and put science above making themselves even richer than they already are.

Change my mind. I wish you could.

Wouldn't it be a pleasant surprise if it came through though.

 

[Pete88]

I don't know if anybody feels the same, but I think FX-322 is the end of the line. The evidence against this not working is substantial.

I've lost all hope in FX-322 and I get the impression many people were depending on this and they don't want to let it go.

I think the next thing we have to hope for is that Otonomy will succeed.

It just doesn't work.

I acknowledge the trial was flawed but even with those flaws the results just show next to nothing in terms of efficacy.

It's just the way it is.

Change my mind. I wish you could.

Success is NOT a straight line. Several tests and experiments showed that one dose works to a certain degree.

One test showed that multiple doses doesn't work. Ok cool, 1 dose it is. To write it off because an ambitious experiment didn't result in overall success is pessimistic. If the results for more 1 dose experiments also fails, then sure, maybe then we can start seeing it as a fail.

This is the first hiccup so far in their pursuit for hearing loss regeneration. They can't get honeruns every time they push the limits.

 

[Zugzug]

I want to say something about the curiosity with TFI from Phase 2:

Other than possibly some emotional reassurance that the drug will eventually help, the data is unreliable. Frequency Therapeutics had a business decision to make and I think they chose right, although I would have preferred to give better examples of "unconscious bias" rather than making it seem passively aggressively like people were bending the rules to get in.

Once you choose the path of "our science works, but Phase 2 needs more work and direction," you can't come back later and be like "oh boy, look at those awesome TFI results!" It would come off unscientific and unprofessional -- like they had excuses for why PTA and word scores (of all important tests for hearing) weren't stratified, but somehow there was no unconscious bias aspect to tinnitus.

They tanked Phase 2 to save face. It's smart, given the circumstances. It's not sexy to say this, but people need to lose the all or nothing attitude. Hearing regeneration will eventually work, which is better than it eventually not working. Unfortunately, we have to come to terms with the delay in the timeline.

 

[Diesel]

Success is NOT a straight line. Several tests and experiments showed that one dose works to a certain degree.

One test showed that multiple doses doesn't work. Ok cool, 1 dose it is. To write it off because an ambitious experiment didn't result in overall success is pessimistic. If the results for more 1 dose experiments also fails, then sure, maybe then we can start seeing it as a fail.

This is the first hiccup so far in their pursuit for hearing loss regeneration. They can't get honeruns every time they push the limits.

I know I'm rationalizing by writing this, but the "textbook" definition of the "2A" in "Phase 2A" signifies that the study is a proof of concept for multi-dosing. Turns out the weekly does concept wasn't proven. Unfortunately for Frequency Therapeutics, they did a terrible job of properly communicating that the Phase 2A was an experiment. Instead they focused on communicating that expectations of getting the drug deeper, creating stronger responses at the EHF range, or getting more participants to respond.

 

[grate_biff]

Secondly, a lot of the common symptoms need a second name that makes it sound more devastating. Like "tinnitus" for example, that gets the light, friendly "ringing in the ears" description every time it's mentioned by the press. Which, in my opinion, again totally minimizes the effect/experience of the disorder. Almost makes it sound cute. Why not give tinnitus a second name that makes it more recognizable. For example, Screaming Ear Disease, or Osbourne's Disease (after Ozzy, who is the first musician that I knew had it before I got it).

How about "Icantbelieveithasntkilledme-tus"?

 

[Chad Lawton]

Assuming FX-322 only shows minor MEASURABLE improvements but is safe, could it hit the market considering there is no existing regenerative drugs?

Yes. It only needs to provide a clinically significant improvement for it to be viable which is a pretty low bar. Here is their presentation from October:



Those with severe hearing loss in the single dose trial had a doubling in word recognition scores which is life changing for those people. I think the stock price is an absolute steal right now and everyone is overreacting. I've bought about $10,000 worth in the last couple days and plan to buy more tomorrow if it stays in the mid 8 range considering they have little debt and over $6 a share in cash on hand.

 

[Zugzug]

Another thing I want to address from a mathematical point of view is the following idea: (Using fake numbers) - Does four successful Phase 1b trials with n=25 each equate or override one unsuccessful Phase 2 with n=100?

No. There are many reasons for this, but here's a simple reason. In Phase 1 trials, the primary thing being tested is safety. This means the recruiting approach is to choose smaller sample sizes with the understanding that the absolute worst thing here is safety violations. Efficacy could be a pleasant accident, but it's not the main benchmark.

Trial design and statistical inferences planned in advance are also more experimental. Don't believe me? Here's a quote from the published Phase 1/2 paper:

A sample size of approximately 24 subjects was considered adequate for an initial assessment of safety and tolerability and was not based on formal statistical considerations. Prespecified statistical analyses were exclusively descriptive and included 95% confidence intervals (CIs) as appropriate. Audiometric analyses were considered exploratory and conducted without multiplicity adjustments.
​

What they are basically saying is "we're not trying to prove anything about efficacy." The problem is, to do science properly, this trial can't be used as an efficacy proof just because they like the results. Why? If the results were bad, they would say "Oh, well we were focused on safety." They will use the same excuse if the remaining Phase 1b trials fail.

On the other hand, a Phase 2 efficacy study -- even if it's a Phase 2a so slightly more experimental -- is largely putting yourself out there on display. If they results are a boom, you get to celebrate. If they are not, you have to save face.

There are also technical reasons why a bunch of Phase 1 studies don't equate to a Phase 2. For example, four Phase 1 studies introduce four sets of recruiting standards, and therefore, four sets of fixed effects.

If they somehow get this to pivotal on the backs of a bunch of successful Phase 1 studies (probability is so low that it shouldn't invoke any emotional investment), it will have everything to do with a current lack of other drugs. It has nothing to do with finagling the science in a convenient way.

 

[Aaron91]

I want to say something about the curiosity with TFI from Phase 2:

Other than possibly some emotional reassurance that the drug will eventually help, the data is unreliable. Frequency Therapeutics had a business decision to make and I think they chose right, although I would have preferred to give better examples of "unconscious bias" rather than making it seem passively aggressively like people were bending the rules to get in.

Once you choose the path of "our science works, but Phase 2 needs more work and direction," you can't come back later and be like "oh boy, look at those awesome TFI results!" It would come off unscientific and unprofessional -- like they had excuses for why PTA and word scores (of all important tests for hearing) weren't stratified, but somehow there was no unconscious bias aspect to tinnitus.

They tanked Phase 2 to save face. It's smart, given the circumstances. It's not sexy to say this, but people need to lose the all or nothing attitude. Hearing regeneration will eventually work, which is better than it eventually not working. Unfortunately, we have to come to terms with the delay in the timeline.

I agree they can't have it both ways, but that doesn't mean there isn't a scenario where they can't. TFI was experimental and not a criterion (to my understanding), so if Frequency Therapeutics are saying the unconscious bias is about WR scores and audiograms because they specifically communicated that with regards to those tests, there is a world where they can come back and say "hey, look at these improved TFI scores - we never communicated anything about some kind of minimum suffering here to get into the trial". That's assuming of course we even get a positive readout for TFI, which seems highly unlikely, even in the face of the patient I've spoken to who said their tinnitus is practically gone.

I don't want to sound like I'm clutching at straws here because I also believe we are going to see another Phase 2 trial, nor do I think a positive 210-readout for tinnitus is going to get us to Phase 3. The only world in which we get to Phase 3 is if the Phase 1b trials knock the results out the park and Frequency Therapeutics pitch a pivotal trial to the FDA on the grounds of recruiting severe and age-related patients only. They will have demonstrated safety in over 200 patients by then. The question is whether Frequency Therapeutics want to gamble with a new trial design at pivotal. The problem is, if they fail Phase 2 again with a new trial design, FX-322 is finished anyway. The whole situation is terrible because most companies only have one get-out-of-jail free card in this process and they've already used theirs up before we even get to Phase 2. Otonomy got to Phase 3 with Otividex with no issues, only to then fail twice in a row. Frequency Therapeutics can't afford that now.

 

[Diesel]

They tanked Phase 2 to save face. It's smart, given the circumstances. It's not sexy to say this, but people need to lose the all or nothing attitude. Hearing regeneration will eventually work, which is better than it eventually not working. Unfortunately, we have to come to terms with the delay in the timeline.

Well put. From a business standpoint, it makes sense to scrap Phase 2A and move on with a clearer/simpler path to an FDA-Approved product in the short-term.

Right now, they're working purely on initial investment and cash, no real revenue stream. And now, a stock price that is half of its IPO value. So, they need to be extremely smart with how to allocate limited resources, and show continuous iterative successes that de-risk the development of FX-322.

A single dose drug route eliminates the need to again retry 1 or more multi-dose trials, which would further push out any potential pivotal trial, and continue to muddy the likelihood of FDA-Approval. Imagine if they re-did another Phase 2A, but with 4x monthly doses, and that didn't work? Would there be any trust that the drug worked? Would any investors be willing to come back to the table for a third Phase 2A? Or to pick up all the sunk-costs to THEN go to a single-dose route? Would there be money left in the tank to get the delivery method trials updated?

Simplifying to a single dose enables them to identify a specific population of patients where the drug is most consistently effective. Some consensus here is that the severe trial may be the most reliable beachhead for a first-generation product. If approved for these smaller, specific populations, they can then begin to generate cashflow to fund more multi-dose trials, upgrades to delivery methods, and other reformulations. Plus, the stockholders will certainly like a company with a product-driven revenue.