Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

Is it possible to receive more than four doses of FX-322 for people in the severe hearing loss range?

If a doctor is willing to do it off label for you, sure.

 

[Diesel]

If the last scenario occurs, that verifies the drug actually works and the dosing/delivery needs adjustment/improvement.

Everything else you have mentioned is a good thought but does not hit the mark. I would imagine the drug will be ripped apart if this occurs. Maybe back to formula.

I hope you're right and they have better than anticipated results.

Unless it totally abates tinnitus the bogus audiology doctors and self help idiots will still claim it doesn't help. Maybe if it shows massive improvements on the TFI but I don't know.

I think you might be disappointed. I expect to see either of the Meh cases. And that will be enough to proceed to product.

 

[FGG]

What are the chances of them switching gears and releasing this primarily as a tinnitus treatment?

Absolutely none imo. They have already shown it improves word scores and clarity regardless of audiogram. That's a way more objective metric than tinnitus indexes.

 

[Gb3]

Is it possible to receive more than four doses of FX-322 for people in the severe hearing loss range?

It all depends what the data tells us.

What if, what if, what if. Why don't we just wait and see.

 

[Orions Pain]

Absolutely none imo. They have already shown it improves word scores and clarity regardless of audiogram. That's a way more objective metric than tinnitus indexes.

I should have clarified. I meant if the FDA doesn't grant approval to release FX-322 as a hearing loss drug for whatever reason, but they do find that participants in the trials all had their tinnitus go away.

We know it works, but I wonder if there are "minimums" they must meet in order to actually release it. Or is it already pretty much locked in if there are no adverse effects?

Let's say that with Phase 2 multiple injections, there are minimal differences between Phase 1 results.

 

[FGG]

I think you might be disappointed. I expect to see either of the Meh cases. And that will be enough to proceed to product.

So you are thinking because of the VPA and timing the injections a week apart you won't see much of anything lower than 8 kHz?

If that ends up the case:

A) I would really wonder why Frequency Therapeutics wouldn't already suspect that since they had pharmacokinetic data from Phase 1.

and

B) I wonder if people might try to get ahold of some VPA and dose themselves concurrent with FX-322. There are already people on this drug for seizures.

 

[FGG]

I should have clarified. I meant if the FDA doesn't grant approval to release FX-322 as a hearing loss drug for whatever reason, but they do find that participants in the trials all had their tinnitus go away.

We know it works, but I wonder if there are "minimums" they must meet in order to actually release it. Or is it already pretty much locked in if there are no adverse effects?

Let's say that with Phase 2 multiple injections, there are minimal differences between Phase 1 results.

I guess they could restart a Phase 2 trial and recruit for tinnitus specifically but that won't be necessary. If it doesn't work for hearing, it's not going to work for tinnitus. Luckily it seems to work for hearing.

 

[Diesel]

So you are thinking because of the VPA and timing the injections a week apart you won't see much of anything lower than 8 kHz?

If that ends up the case:

A) I would really wonder why Frequency Therapeutics wouldn't already suspect that since they had pharmacokinetic data from Phase 1.

and

B) I wonder if people might try to get ahold of some VPA and dose themselves concurrent with FX-322. There are already people on this drug for seizures.

You are correct in my thinking.

I, of course, want to be wrong and it exceeds my expectations. I am also realistic that in its current form, it's market ready. So, maybe compressing the dose schedule to 4 in a week, or doing 8 in 2 weeks resolves the issues, but we won't know that for a while.

It's possible that they did figure out "A" in Phase 1. But I recall in the webcast when asked about multi-dosing, LeBel admitted that they couldn't validate multi-dosing in an animal model; which led me to think they are kind of winging it. Perhaps no clear evidence of what VPA does in this scenario is leaving me with doubts.

For "B" I could see a VPA maker putting it in a gel to be injected intratympanically BEFORE FX-322.

 

[Orions Pain]

What if, what if, what if

It's okay for people to engage in conversation and ask questions! This entire thread is what if's with some facts sprinkled in lol.

 

[FGG]

For "B" I could see a VPA maker putting it in a gel to be injected intratympanically BEFORE FX-322.

Probably not necessary. It's an anti seizure drug (so crosses BBB easily) and a small molecule. It probably crosses the blood cochlear barrier easily enough to be taken systemically.

 

[Jrblovsky]

I guess they could restart a Phase 2 trial and recruit for tinnitus specifically but that won't be necessary. If it doesn't work for hearing, it's not going to work for tinnitus. Luckily it seems to work for hearing.

Restore hearing. Tinnitus goes away. I'm living proof.

When my thresholds recovered the tinnitus went to almost non existent.

Thresholds went to hell and now the tinnitus is horrendous.

Frequency Therapeutics have everything to lose by this taking longer. Drugs are only protected by patent for 20 years if I recall correctly. I'm sure they want to capitalize on FX-322 to drive research for other conditions in the pipeline.

 

[GBB]

It will suck if the tinnitus improvement is major, but multi-dosing doesn't do much for frequencies below 8 kHz so they decide not to go through to Phase 3. What are the chances of them switching gears and releasing this primarily as a tinnitus treatment?

Again probably too early in the game for this sort of speculation. Phase 2 is going to give us good insight imo. I can't help but view this all through a tinnitus lens even though it's primarily for hearing loss.

Even if we have the scenario of 'just' tinnitus improvement, they could easily pivot and move forward.

 

[Lucifer]

It's okay for people to engage in conversation and ask questions! This entire thread is what if's with some facts sprinkled in lol.

There is nothing wrong with asking questions. I know all of us suffer from these hearing conditions such as tinnitus, hyperacusis and hearing loss, and that we just all want FX-322 to work.

My biggest fear is that multi-dosing in its current delivery method won't reach deeper in the round window.

 

[FGG]

Restore hearing. Tinnitus goes away. I'm living proof.

When my thresholds recovered the tinnitus went to almost non existent.

Thresholds went to hell and now the tinnitus is horrendous.

Frequency Therapeutics have everything to lose by this taking longer. Drugs are only protected by patent for 20 years if I recall correctly. I'm sure they want to capitalize on FX-322 to drive research for other conditions in the pipeline.

I wish you could pop up with this anecdote anytime people try to say tinnitus is brain damage/stuck in the brain and fixing the underlying cause won't help...

 

[Matchbox]

If FX-322 works for hearing loss, tinnitus & hyperacusis... This is Nobel Prize or whatever the equivalent is for Applied Sciences.

 

[Keith Handy]

Could they somehow add a test for sound localization to later studies? That seems to be an important aspect of high frequency hearing.

 

[Philip83]

Could they somehow add a test for sound localization to later studies? That seems to be an important aspect of high frequency hearing.

Yes, this is an issue I raised before in this thread. Since they are only dosing and checking one ear in these trials so far, surely the results are affected in a negative way because of this. The outcomes should become even better once they start treating and checking hearing using both ears.

 

[Keith Handy]

Yes, this is an issue I raised before in this thread. Since they are only dosing and checking one ear in these trials so far, surely the results are affected in a negative way because of this. The outcomes should become even better once they start treating and checking hearing using both ears.

Ah, yes, good point about the only-one-ear thing... definitely need both for this. But yeah, EHF is critical for localization, as it's in those frequencies where minute differences in the arrival time of transients can be discerned. Further down in the midrange, only amplitude differences between left and right can be discerned; and in the bass frequencies direction can't really be heard at all, hence the use of single subwoofers rather than pairs.

I assume the "words in noise" test uses monophonic audio, not a binaural recording, so the background noise doesn't resemble how it would all be spatially localized around you in reality with good localization, making it easier to pick out a single voice by focusing on a particular location in the stereo field.

 

[Philip83]

Ah, yes, good point about the only-one-ear thing... definitely need both for this. But yeah, EHF is critical for localization, as it's in those frequencies where minute differences in the arrival time of transients can be discerned. Further down in the midrange, only amplitude differences between left and right can be discerned; and in the bass frequencies direction can't really be heard at all, hence the use of single subwoofers rather than pairs.

I assume the "words in noise" test uses monophonic audio, not a binaural recording, so the background noise doesn't resemble how it would all be spatially localized around you in reality with good localization, making it easier to pick out a single voice by focusing on a particular location in the stereo field.

Agreed. This is actually a big mystery to me how FREQ hasn't been addressing why they are doing their testing on only one ear and how it affects the results. Surely they have taken it into account. It would be an interesting question to ask them once they're (hopefully) back on the Tinnitus Talk Podcast.

 

[Adaś]

I've read that there could be a gene involved in those of us who develop tinnitus.

Can you provide some references in this subject? I always wondered why the heck so many of my colleagues that abused their ears the same or even worse do not suffer from tinnitus, but I do.

 

[Keith Handy]

Agreed. This is actually a big mystery to me how FREQ hasn't been addressing why they are doing their testing on only one ear and how it affects the results. Surely they have taken it into account. It would be an interesting question to ask them once they're (hopefully) back on the Tinnitus Talk Podcast.

I wonder how would an audiologist or ENT objectively test this though? Just have the patient close their eyes and point to wherever the administrator of the test is rubbing their fingers together as they move them around? Or have the patient identify the locations of sounds in pre-made binaural recordings?

These are the only things I can think of and they both sound kind of clumsy.

 

[Jrblovsky]

I wish you could pop up with this anecdote anytime people try to say tinnitus is brain damage/stuck in the brain and fixing the underlying cause won't help...

The people who think that way are absolute imbeciles. I think of everything as a mechanical issue. Look at a car. If you have a bad sensor it goes into closed loop and bypasses the malfunctioning components. It also kicks on that annoying check engine light. Until it's fixed the light is on.

I think the repair of the cochlea will fix the problem.

To piggyback off my earlier statement, I wonder where these people get any of their information.

Before the tinnitus started everything worked correctly. Either noise or drugs for most of us damaged something. When we think deep into that, what could it be? We know it's nothing in the middle or outer ear, so it has to be either the cochlea or the auditory nerve itself. The auditory nerve itself is rarely damaged from what I have read and researched. This is why cochlear implants are able to provide stimulation directly to the brain with electrical impulses. The overall thinking here is typical of any person who goes to college or medical school. Only what the professors and texts say is right, wrong. This is why you see so many professors and educators angry that 25-year-old entrepreneurs are making $150k a year and defying the status quo.

My overall point in this rant is that these morons who are dead set on permanent brain damage can't pull their heads out of their rears and actually think. There is no doubt in my mind that repairing auditory stimulation will end tinnitus. Fix the hearing loss, problem goes away.

The last thing that really is bothersome about what you mentioned is the same people preach about the brain and plasticity but then make their statements. Absolutely appalling. Idiots!

 

[Diesel]

Agreed. This is actually a big mystery to me how FREQ hasn't been addressing why they are doing their testing on only one ear and how it affects the results. Surely they have taken it into account. It would be an interesting question to ask them once they're (hopefully) back on the Tinnitus Talk Podcast.

I believe the one ear test is for a few reasons:
1. Safety - A reaction in 1 ear is obviously safer than having both be affected
2. Control - They're able to confirm that only the treated ear shows improvement

The results definitely will be impacted for some measures, but it remains to be seen how that will be taken into consideration. For example, TFI and QoL studies in the Phase 2A would likely show a more significant improvement if both ears were treated. Some might argue WIN score may look more significant. I know for example a TFI improvement of 14-points is considered clinically meaningful, so I don't know if a score of 7-points for one ear treated can still apply?

They've mentioned a couple of times that they're treating the "worse ear" with FX-322, and have an additional set of filtering criteria that they have not yet disclosed for the Phase 2A participants. These additional filters may be in place to help make the one-ear treatment improvement lead to more significant improvement for some measures.

 

[Keith Handy]

I believe the one ear test is for a few reasons:
1. Safety - A reaction in 1 ear is obviously safer than having both be affected
2. Control - They're able to confirm that only the treated ear shows improvement

If safety scores really well in current trials, I wonder if they're considering bilateral testing in the future.

 

[Jrblovsky]

Can you provide some references in this subject? I always wondered why the heck so many of my colleagues that abused their ears the same or even worse do not suffer from tinnitus, but I do.

I don't agree with this either. Basically everyone has had their ears ring at some point in there life. Whether it be loud music, gunshots, explosions, construction noise, etc.

It does seem however that some people have weak ears that are subject to damage while others have ears made of cast iron.

I think of it this way from my own experience. I was exposed to maximum of 15 gunshots, I however believe it may have only been 10. Regardless there are men and women in the Armed Forces and Law Enforcement I know personally that have been exposed to way more impulse noise from shootings and tours of duty. This occurred where shit hit the fan and they did not have time to use hearing protection as they would have been fatally injured by a gunman/enemy soldiers. Some of them have tinnitus but most do not. Even the ones that do, have it to an extremely mild degree and are not bothered by it.

 

[Diesel]

Let's set expectations for FX-322 gaining Breakthrough Therapy Designation in 2021:

FX-322 was given the Fast Track Status by the FDA in 2019. Indicating that the FDA acknowledges that FX-322 addresses 1 or more of the following:

1. Showing superior effectiveness, effect on serious outcomes or improved effect on serious outcomes
2. Avoiding serious side effects of an available therapy
3. Improving the diagnosis of a serious condition where early diagnosis results in an improved outcome
4. Decreasing a clinical significant toxicity of an available therapy that is common and causes discontinuation of treatment
5. Ability to address emerging or anticipated public health need

I suspect the FDA believes FX-322 applies to 1, 3, and 5 as it relates to SNHL.

The Breakthrough Therapy Designation is typically given in addition to the Fast Track Status.

It's likely after the Phase 2A and both Phase 1B trials end, Frequency Therapeutics will meet with the FDA to request the Breakthrough Therapy Designation be given to FX-322. To gain Breakthrough Therapy Designation, FX-322 must demonstrate substantial improvement over available therapy on 1 or more clinically significant endpoints. (There are not other therapies, so it just needs to demonstrate a substantial improvement).

The Primary End Points that are likely to be considered from the Phase 2A + Phase 1Bs are as follows:

1. Speech Intelligibility (Words in Quiet)
   
2. Speech Intelligibility (Words in Noise)
   
3. Standard Pure Tone Audiometry

All Experimental End Points (EHF Audiogram, Tinnitus, QoL, etc) cannot be considered for Breakthrough Therapy Designation.

I think the Breakthrough Therapy Designation is going to be highly likely by end of 2021. Here's why:

1. Speech Intelligibility (Words in Quiet) - Already shows substantial improvement.
   
   The Phase 1/2 results already showed clinically significant improvements in word score. As long as the 72 patients that receive FX-322 show similar gains at a minimum, this SINGLE endpoint will satisfy the Breakthrough Therapy Designation requirements (remember, 1 or more clinically significant endpoint).
   
   
2. Speech Intelligibility (Words in Noise) - Likely to show substantial improvement with more patients.
   
   The higher dose Phase 2A participants and potentially Age-Related Phase 1B may produce enough collective improvements to push this endpoint into clinical significance. The Phase 1/2 produced a mixed bag. The group-level improvement wasn't significant, but the SNR data was significant. I suspect more patients will be enough to demonstrate clinical improvements.
   
   
3. Standard Pure Tone Audiometry - Has potential to meet this.
   
   The Phase 1/2 data was not significant. And likely, the single-dose patients from the Phase 2A + both Phase 1Bs won't be significant either. However, if multiple doses show larger dB improvements at 8 kHz and/or consistent improvements at lower frequencies, the outcomes may look statistically significant and/or clinically meaningful. A greater population of patients may be enough for this as well.

So, I think by end of Q3/2021. FX-322 will satisfy Breakthrough Therapy Designation requirements by demonstrating substantial improvement at least 2/3 of its primary endpoints.

 

[Philip83]

I wonder how would an audiologist or ENT objectively test this though? Just have the patient close their eyes and point to wherever the administrator of the test is rubbing their fingers together as they move them around? Or have the patient identify the locations of sounds in pre-made binaural recordings?

These are the only things I can think of and they both sound kind of clumsy.

I meant more that they would treat both ears in the trial and then do the WIN tests with headphones playing things in both ears. But, like Diesel mentioned, I understand that there were reasons why only one ear was tested.

Maybe Phase 3 will see both ears be included.

 

[Diesel]

I meant more that they would treat both ears in the trial and then do the WIN tests with headphones playing things in both ears. But, like Diesel mentioned, I understand that there were reasons why only one ear was tested.

Maybe Phase 3 will see both ears be included.

I could see it happening in a Phase 3. By the end of this year, they'll have enough single-ear data to validate against a control.

I believe Carl LeBel mentioned that they had considered treating both ears. It would certainly be useful to collect two-ear data in a 500+ participant Phase 2B/3.

 

[Jrblovsky]

Let's set expectations for FX-322 gaining Breakthrough Therapy Designation in 2021:

FX-322 was given the Fast Track Status by the FDA in 2019. Indicating that the FDA acknowledges that FX-322 addresses 1 or more of the following:

1. Showing superior effectiveness, effect on serious outcomes or improved effect on serious outcomes
2. Avoiding serious side effects of an available therapy
3. Improving the diagnosis of a serious condition where early diagnosis results in an improved outcome
4. Decreasing a clinical significant toxicity of an available therapy that is common and causes discontinuation of treatment
5. Ability to address emerging or anticipated public health need

I suspect the FDA believes FX-322 applies to 1, 3, and 5 as it relates to SNHL.

The Breakthrough Therapy Designation is typically given in addition to the Fast Track Status.

It's likely after the Phase 2A and both Phase 1B trials end, Frequency Therapeutics will meet with the FDA to request the Breakthrough Therapy Designation be given to FX-322. To gain Breakthrough Therapy Designation, FX-322 must demonstrate substantial improvement over available therapy on 1 or more clinically significant endpoints. (There are not other therapies, so it just needs to demonstrate a substantial improvement).

The Primary End Points that are likely to be considered from the Phase 2A + Phase 1Bs are as follows:

1. Speech Intelligibility (Words in Quiet)
   
2. Speech Intelligibility (Words in Noise)
   
3. Standard Pure Tone Audiometry

All Experimental End Points (EHF Audiogram, Tinnitus, QoL, etc) cannot be considered for Breakthrough Therapy Designation.

I think the Breakthrough Therapy Designation is going to be highly likely by end of 2021. Here's why:

1. Speech Intelligibility (Words in Quiet) - Already shows substantial improvement.
   
   The Phase 1/2 results already showed clinically significant improvements in word score. As long as the 72 patients that receive FX-322 show similar gains at a minimum, this SINGLE endpoint will satisfy the Breakthrough Therapy Designation requirements (remember, 1 or more clinically significant endpoint).
   
   
2. Speech Intelligibility (Words in Noise) - Likely to show substantial improvement with more patients.
   
   The higher dose Phase 2A participants and potentially Age-Related Phase 1B may produce enough collective improvements to push this endpoint into clinical significance. The Phase 1/2 produced a mixed bag. The group-level improvement wasn't significant, but the SNR data was significant. I suspect more patients will be enough to demonstrate clinical improvements.
   
   
3. Standard Pure Tone Audiometry - Has potential to meet this.
   
   The Phase 1/2 data was not significant. And likely, the single-dose patients from the Phase 2A + both Phase 1Bs won't be significant either. However, if multiple doses show larger dB improvements at 8 kHz and/or consistent improvements at lower frequencies, the outcomes may look statistically significant and/or clinically meaningful. A greater population of patients may be enough for this as well.

So, I think by end of Q3/2021. FX-322 will satisfy Breakthrough Therapy Designation requirements by demonstrating substantial improvement at least 2/3 of its primary endpoints.

If FX-322 hits any of those scenarios you posted previously, besides the final one, I think you are going to be disappointed.

The FDA isn't going to give FX-322 Breakthrough Therapy Designation unless it works beyond a reasonable doubt. The physicians who make these approvals are not going to be nearly as enthusiastic as anyone on this board.

Unless everyone in the trial shows their tinnitus gets quieter by a measured variable or they have hearing threshold improvements to a large degree, it's not happening.

I'm very optimistic but also very realistic.

 

[Diesel]

If FX-322 hits any of those scenarios you posted previously, besides the final one, I think you are going to be disappointed.

The FDA isn't going to give FX-322 Breakthrough Therapy Designation unless it works beyond a reasonable doubt. The physicians who make these approvals are not going to be nearly as enthusiastic as anyone on this board.

Unless everyone in the trial shows their tinnitus gets quieter by a measured variable or they have hearing threshold improvements to a large degree, it's not happening.

I'm very optimistic but also very realistic.

The fact of the matter is:

"Working beyond a reasonable doubt" is displayed by statistical significant and clinically meaningful improvements in the data when reviewed by the FDA.

Even the "Meh" scenarios that I outlined might just push Primary Outcome #2 into significance.

Also, the Review Team at the FDA isn't all physicians. It consists of medical physicians, statisticians, chemists, biologists, toxicology specialists, and pharmacists. So it will be given a broad view by a number of different backgrounds.

Tinnitus won't be factored for Breakthrough Therapy Designation at all. It's an experimental outcome.