Frequency Therapeutics — Hearing Loss Regeneration

[Tezcatlipoca]

This rating was before the bad news came out.

Are you sure? The title of the article says "stick" and it was posted at 2:25 PM.

 

[Lucifer]

Are you sure? The title of the article says "stick" and it was posted at 2:25 PM.

Ok then I may be wrong. It said 8:05am but I think it is because of NZT and EST so I think you're correct.

 

[Lucifer]

I think Phase 2a is a wash except perhaps at the individual level. I don't think time will change that.

My eye is on the single dose severe hearing loss group at this point.

I'm not sure if you responded to my last statement.

When they say diminishing returns, does that mean that multiple doses of FX-322 cause the improvement in hearing to be lower than in Phase 1b?

 

[Street Novelist]

So, they currently have a severe hearing loss trial underway. When are those results supposed to be released?

Can anyone answer this?

 

[Keith Handy]

Apparently testing 16 kHz to 20 kHz is so hard to calibrate that it's generally considered unreliable. A lot of places that do EHF have 16 kHz as the cut off.

I'm going to fire off a guess as to the reason for the difficulty in calibrating for EHF. The higher a tone is, the more it runs into interference patterns from its own reflections off surfaces, and this would include all the surfaces of the outer ear - not just the canal, but the thing people normally refer to as "the ear" sticking out the side of your head. If the source of an EHF tone moves the slightest bit in relation to your ear, even using a headset, the reinforcing and cancellation from reflections will totally throw its apparent amplitude off. I've noticed this when positioning earbuds near my ears to hear the highest frequencies; aiming it straight down the canal does not give the clearest signal like you would expect it to.

 

[FGG]

and about if anyone would ever want me.

Please don't pile this on top of your fears, even though I get it. It's a worry a lot of us have. But you have such a great heart. I'd buy expensive stock options that say you can find a partner at some point even through all of these trials.

 

[Tezcatlipoca]

Ok then I may be wrong. It said 8:05am but I think it is because of NZT and EST so I think you're correct.

Thank God. Also Riley placed it at $35 this morning.

https://www.streetinsider.com/dr/news.php?id=18169286

And it still has either a buy or a strong buy rating.

 

[Ed209]

If you watch the video, it is not actually teaching people 'how to fake it.' It discusses how difficult it would be to actually fake a test if you read the description and also the comments posted by the guy, e.g "I think you grossly misunderstood the point of the video. It shows how futile it is to even attempt to Fake a hearing loss. Watch it again with the correct lens."

You've just validated the point I was trying to make. I didn't watch the video as it's content is of no interest to me. I was focusing on the discussions around it and the intent to post that video. People were saying at the time that the tests couldn't be faked, and now there's been a complete 180 on it because of the new results. There seems to be a bias in the direction of whatever outcome puts a positive spin on the situation. That's all I was trying to say.

I understand how emotionally charged this thread is and what was at stake.

 

[r34d1ng]

Isn't that great news? FREQ will still be getting investors and they can continue to develop FX-322.

As I stated in my previous message, this rating was prior to the PR release with Phase 2a results, so now it is pretty much useless. Oppenheimer, however, did issue a post-PR rating setting a price target of $20. Stock is at $8 or so, so I guess these guys still have some confidence in FX-322.

 

[Cernuto]

Also, take into consideration the placebo effect is a real thing. People may react one way before placebo, then differently after placebo due to the nature of their expectations and perceptions. We can speculate why, but it is what it is.

Maybe a better designed study could factor out more of the placebo influence?

Personally, I would still like to try the drug. I think a lot of us here would. We should be able to if it's proven safe and so far it is.

 

[AtlasFainted]

@FGG

I think I remember talking to you several months ago about how it would take a year of trials to approve a reformulation of an FDA approved drug.

The context being that the delivery vehicle to treat the entire cochlea exists (I think pipeline is using it?), but this technology is not used for the current iteration of FX-322.

The results of this latest study are disappointing to be sure. However, considering that they are moving forward with single dosing, maybe the overall timeline to get a shot that treats the entire cochlea hasn't been affected?

This whole study was always a little suspect to me. "1 shot only reaches UH frequencies, let's inject them 3 more times and see what happens!"... too many variables at play there. They didn't know what to expect & neither did we. Then you have the other issues with the trial that are currently being discussed on this thread.

The delivery vehicle is key, and always has been in my opinion. Get single dosing approved, then reformulate with a vehicle that fully serves its purpose.

Thoughts?

 

[wwtsai]

Can anyone answer this?

The trial is slated to end June 2021 with results out Q3 2021.

FX-322 in Adults With Severe Sensorineural Hearing Loss

 

[Zugzug]

Perhaps a case of getting too greedy too soon. I think we know this was driven with the intention of reaching the lower frequencies and to determine whether there's some kind of relationship between penetration and damage/regeneration. They clearly went way, way too far. A better approach would have been to have spaced out the injections differently within each group. For example, 8 severe patients get them once a week, another 8 severe patients get them bi-weekly, and another 8 patients get them once a month. Same then for each other category. It would complicate and delay the readout, but at least then you'd have some insight into what the ideal time lag between each dose should be. This may of course present its own set of challenges by making it difficult to determine any statistically significant differences.

Perhaps they were better off running an expanded Phase 1 trial where they test the various time lags between dose to inform the time-gap for Phase 2. Ball = dropped.

Something else that doesn't make any sense to me is why 7 days? It's such a nice, round easy-to-explain time frame, but what they are really doing is balancing two difficult science problems.

Too short of injection intervals: Risk adverse effects (including lawn effect).

Too long: No chance of penetrating deeper and the drug is restricted to EHF only.

So why 7 days? It just happens to be 1 week? Why isn't it 12.4 days? If we consider too short being a Type I error and too long being a Type II error, why wouldn't they lean on the side of reducing Type I errors?

I say all of this now. In the present time, I didn't see the lawn effect and saw deeper penetrance. It does seem odd, though, that they didn't fully commit to the EHF strategy. Who cares if it's a weird time frame? This is science.

 

[Tezcatlipoca]

As I stated in my previous message, this rating was prior to the PR release with Phase 2a results, so now it is pretty much useless. Oppenheimer, however, did issue a post-PR rating setting a price target of $20. Stock is at $8 or so, so I guess these guys still have some confidence in FX-322.

Thanks for the clarification. Riley did put FREQ at $35 this morning though.

 

[FGG]

@FGG

I think I remember talking to you several months ago about how it would take a year of trials to approve a reformulation of an FDA approved drug.

The context being that the delivery vehicle to treat the entire cochlea exists (I think pipeline is using it?), but this technology is not used for the current iteration of FX-322.

The results of this latest study are disappointing to be sure. However, considering that they are moving forward with single dosing, maybe the overall timeline to get a shot that treats the entire cochlea hasn't been affected?

This whole study was always a little suspect to me. "1 shot only reaches UH frequencies, let's inject them 3 more times and see what happens!"... too many variables at play there. They didn't know what to expect & neither did we. Then you have the other issues with the trial that are currently being discussed on this thread.

The delivery vehicle is key, and always has been in my opinion. Get single dosing approved, then reformulate with a vehicle that fully serves its purpose.

Thoughts?

My thoughts on this depend partially on what happens in the severe trial arm.

But even looking at the pharmacokinetics, it looks like the drug combo really only gets to around 6 kHz at best so they would have to reformulate at some point no matter what (whether the drug delivery is meh or abysmal).

 

[Ilias T]

@FGG

I think I remember talking to you several months ago about how it would take a year of trials to approve a reformulation of an FDA approved drug.

The context being that the delivery vehicle to treat the entire cochlea exists (I think pipeline is using it?), but this technology is not used for the current iteration of FX-322.

The results of this latest study are disappointing to be sure. However, considering that they are moving forward with single dosing, maybe the overall timeline to get a shot that treats the entire cochlea hasn't been affected?

This whole study was always a little suspect to me. "1 shot only reaches UH frequencies, let's inject them 3 more times and see what happens!"... too many variables at play there. They didn't know what to expect & neither did we. Then you have the other issues with the trial that are currently being discussed on this thread.

The delivery vehicle is key, and always has been in my opinion. Get single dosing approved, then reformulate with a vehicle that fully serves its purpose.

Thoughts?

You are very realistic with this post. We need to remember that failures happen.

If people faked their results, they will probably consider the most "realistic" outcomes, and move on.

They might change delivery, the drug itself, their trials, their group, we just don't know the future.

Now that the shares are so low, I might buy like 10 or 15 shares just for fun. I didn't invest earlier. Even if they go - 100%, it's just about 100€. I won't be too shocked lol.

 

[FGG]

I'm not sure if you responded to my last statement.

When they say diminishing returns, does that mean that multiple doses of FX-322 cause the improvement in hearing to be lower than in Phase 1b?

They meant multiple doses (either placebo or drug), the more IT injections in rapid succession, the worse.

 

[Lucifer]

The trial is slated to end June 2021 with results out Q3 2021.

FX-322 in Adults With Severe Sensorineural Hearing Loss

It looks like they are still recruiting for severe hearing loss. I wonder if the delay of recruiting is because they are finding it very hard to find severe hearing loss patients.

 

[throwaway]

Shouldn't they already have some of the results back from Phase 2B & 2C? Why did they sell their shares if the results were good?

 

[Aaron91]

I'm going to fire off a guess as to the reason for the difficulty in calibrating for EHF. The higher a tone is, the more it runs into interference patterns from its own reflections off surfaces, and this would include all the surfaces of the outer ear - not just the canal, but the thing people normally refer to as "the ear" sticking out the side of your head. If the source of an EHF tone moves the slightest bit in relation to your ear, even using a headset, the reinforcing and cancellation from reflections will totally throw its apparent amplitude off. I've noticed this when positioning earbuds near my ears to hear the highest frequencies; aiming it straight down the canal does not give the clearest signal like you would expect it to.

This is an excellent point. I have some experience in audio engineering from my musician days and this makes a lot of sense. It also makes me realise that the audiogram is actually very prone to user error in general, so a WR and WIN score would be much more appropriate. It's evident diagnostics are behind the curve.

Something else that doesn't make any sense to me is why 7 days? It's such a nice, round easy-to-explain time frame, but what they are really doing is balancing two difficult science problems.

Too short of injection intervals: Risk adverse effects (including lawn effect).

Too long: No chance of penetrating deeper and the drug is restricted to EHF only.

So why 7 days? It just happens to be 1 week? Why isn't it 12.4 days? If we consider too short being a Type I error and too long being a Type II error, why wouldn't they lean on the side of reducing Type I errors?

I say all of this now. In the present time, I didn't see the lawn effect and saw deeper penetrance. It does seem odd, though, that they didn't fully commit to the EHF strategy. Who cares if it's a weird time frame? This is science.

It feels very convenient, doesn't it? A quick Google search tells me that it takes a few days for the ear drum to close up after an ITT injection, so perhaps they were coming at it not so much from a "what's the least amount of time we can leave the cochlea alone" point of view as opposed to "how soon can we deliver this again to get it deeper" point of view.

The thing is, 7 days is still a very convenient number. It's one week, after all. Why not 10 days? Why not 20 days? I hate to say it, but it almost sounds as if this was a decision made by a manager and not a scientist.

 

[Street Novelist]

The trial is slated to end June 2021 with results out Q3 2021.

FX-322 in Adults With Severe Sensorineural Hearing Loss

Thanks for responding... It says on the website June. Hopefully they release the results then.

 

[Lucifer]

They meant multiple doses (either placebo or drug), the more IT injections in rapid succession, the worse.

Oh fuck, so multiple FX-322 doses in weekly succession was worse and showed no improvement compared to only one dose of FX-322 in Phase 1b.

I really hope the Phase 1b results were legit then. It doesn't explain the positive Phase 2a anecdote, how they improved after apparently getting 2 doses of FX-322.

Fuck my life, God is out to punish me for my sins. I hope severe hearing loss category show improvements then or we will be waiting a long time. If it helps mild-moderate hearing loss sufferers in the age-related hearing loss as well, then FDA should allow them to go to the pivotal phase.

 

[FGG]

Oh fuck, so multiple FX-322 doses in weekly succession was worse and showed no improvement compared to only one dose of FX-322 in Phase 1b.

I really hope the Phase 1b results were legit then. It doesn't explain the positive Phase 2a anecdote, how they improved after apparently getting 2 doses of FX-322.

Fuck my life, God is out to punish me for my sins. I hope severe hearing loss category show improvements then or we will be waiting a long time. If it helps mild-moderate hearing loss sufferers in the age-related hearing loss as well, then FDA should allow them to go to the pivotal phase.

Worse in aggregate. It doesn't necessarily mean the anecdote isn't true (but the individual data will be more illuminating).

 

[Gorbeh3]

I just want to throw this out there. I had probed into the Phase 2 clinical trials and the following came up:

- "The trial was looking specifically for people who had significant dips at 4 kHz to 8 kHz on their audiogram. They did not say if a specific baseline was required for frequencies below that".

- "The trial is specifically looking for people who can pinpoint the event in which their hearing loss occurred (and I suppose it is thus heavily implied only people with NIHL are eligible for this phase).

You will only be eligible for this trial if you can say something like, "That gunshot two years ago is the event in which I experienced hearing loss" or "After I went to that really loud concert is when it became apparent I had hearing loss."

If you cannot pinpoint an event responsible for your hearing loss, you will not be eligible for the trial."​

I don't know if it means anything significant but I just wanted to post it.

 

[Ed209]

This is an excellent point. I have some experience in audio engineering from my musician days and this makes a lot of sense. It also makes me realise that the audiogram is actually very prone to user error in general, so a WR and WIN score would be much more appropriate. Its evident diagnostics are behind the curve.

Audiograms have approximately a 10 dB HL margin of error. There can be user error involved, but a good audiologist would spot this as they are supposed to repeat the same frequencies a few times in a random order to verify the accuracy of the measurements. At the end, they often give a credibility/accuracy score, such as what you see here:

 

[FGG]

I just want to throw this out there. I had probed into the Phase 2 clinical trials and the following came up:

- "The trial was looking specifically for people who had significant dips at 4 kHz to 8 kHz on their audiogram. They did not say if a specific baseline was required for frequencies below that".

- "The trial is specifically looking for people who can pinpoint the event in which their hearing loss occurred (and I suppose it is thus heavily implied only people with NIHL are eligible for this phase).

You will only be eligible for this trial if you can say something like, "That gunshot two years ago is the event in which I experienced hearing loss" or "After I went to that really loud concert is when it became apparent I had hearing loss."

If you cannot pinpoint an event responsible for your hearing loss, you will not be eligible for the trial."​

I don't know if it means anything significant but I just wanted to post it.

Yep. I was asked if mine was sudden. But it could have been any sudden loss (viral for instance). My interviewer wasn't sure if my particular ototoxicity excluded me so she had to go down the hall and ask but it didn't matter anyway as my audiogram did exclude me. It doesn't necessarily mean noise induced but they clearly wanted to separate age-related or similar slow declines.

 

[AtlasFainted]

My thoughts on this depend partially on what happens in the severe trial arm.

But even looking at the pharmacokinetics, it looks like the drug combo really only gets to around 6 kHz at best so they would have to reformulate at some point no matter what (whether the drug delivery is meh or abysmal).

Yeah this is what I mean. We should be focusing on initial approval regardless of whether the current combo reaches all the frequencies we want.

They will end up reformulating either way because the technology exists and multiple shots per ear is damn inconvenient for everyone. At that point we'll see the inner ear distribution we're looking for.

 

[Tezcatlipoca]

Yeah this is what I mean. We should be focusing on initial approval regardless of whether the current combo reaches all the frequencies we want.

They will end up reformulating either way because the technology exists and multiple shots per ear is damn inconvenient for everyone. At that point we'll see the inner ear distribution we're looking for.

Exactly, the anecdotes during the first Tinnitus Talk Podcast interview gave us hope for tinnitus; now we have a couple of anecdotes in this second trial.

 

[Zugzug]

Exactly, the anecdotes during the first Tinnitus Talk Podcast interview gave us hope for tinnitus; now we have a couple of anecdotes in this second trial.

I've flipped, in the sense that I have more faith in OTO-313 and SPI-1005 than I do FX-322 for more immediate relief of tinnitus.

I still intend on being a bear for those drugs. I need to study them.

 

[lymebite]

I realize that faking the word recognition test is the issue here, not the pure tone audiometry, but I wonder why FREQ did not use an OAE test (in addition to the other tests). As I understand it, OAEs are used for infants who cannot communicate, and with adults for legal situations when it is important to know that the person is not faking a hearing loss (for example with a disability claim).

Easy to Google about OAEs, here is one site with a good overview:

"Many audiology clinics have added OAE to the standard battery of tests that they perform on every ear/hearing patient. Since patient participation is not needed, the results are completely objective."

"If the audiogram indicates a hearing loss, but the OAE and the pure tone audiogram do not agree, the patient may be malingering (faking a hearing loss)."

http://blog.e3diagnostics.com/oae-testing-and-the-standard-audiological-test-battery