Frequency Therapeutics — Hearing Loss Regeneration

[Ehren M]

Can you imagine improving your score from 28 to 10? At that point it becomes the "meh" tinnitus.

Are there any educated guesses as to whether FX-322 could help relieve the severity of hyperacusis?

I suspect I might have missed relevant posts on this topic... but a quick search didn't turn anything up.

 

[Tezcatlipoca]

That would be a clinically meaningful improvement in terms of TFI. A 10 or less describes people that only hear it in quiet rooms and probably aren't bothered by it daily, maybe even weekly.

At 10 or less we might as well be tinnitus free, I'd be perfectly content with that.

 

[Jcmc]

Are there any educated guesses as to whether FX-322 could help relieve the severity of hyperacusis?

I suspect I might have missed relevant posts on this topic... but a quick search didn't turn anything up.

Maybe. We will know one day.

I think if FX-322 works for tinnitus, it should work for hyperacusis/noxacusis too.

 

[Keith Handy]

Are there any educated guesses as to whether FX-322 could help relieve the severity of hyperacusis?

I suspect I might have missed relevant posts on this topic... but a quick search didn't turn anything up.

I believe @Aaron91 has some thoughts on this that he has been planning to write about in depth.

 

[gregmech26]

Of course many would benefit from FX-322 if they have hearing loss in 8 kHz - 20 kHz!

I have high-frequency tinnitus. If this really works, it would be a game changer.

 

[GlennS]

Yes.

 

[Aaron91]

I believe @Aaron91 has some thoughts on this that he has been planning to write about in depth.

Yes, and I must apologise for not writing this up sooner after having previously stated it would have been done by now. I've had some personal commitments the last couple of weeks and my write ups/time on here got slightly sidetracked by the VPA debate we've just had as I felt that was very current. I'm hoping to get this done now before results come out - I will most likely post it on the hyperacusis category so keep a look out there, but I may also crosspost it here as a comment too.

 

[Keith Handy]

I worry that the TFI scores will fail to adequately address how the characteristics of one's tinnitus may impact the success of FX-322 relieving it, especially via the current and limited delivery method. I suspect those with higher-pitched ringing would get more relief than those with lower tones, and the data won't show that. TFI is just a "how bad is it" index, right? Nothing about high/low, steady/fluctuating, etc.; am I correct?

 

[Aaron91]

I worry that the TFI scores will fail to adequately address how the characteristics of one's tinnitus may impact the success of FX-322 relieving it, especially via the current and limited delivery method. I suspect those with higher-pitched ringing would get more relief than those with lower tones, and the data won't show that. TFI is just a "how bad is it" index, right? Nothing about high/low, steady/fluctuating, etc.; am I correct?

If I'm not mistaken, I think we may get some kind of answer to this through the Quality of Life questionnaire answers. Of course it may be difficult to distinguish whether one's quality of life has improved because of hearing loss or tinnitus improvements, and this is where the full readout at the individual level could be useful.

For example, I would suspect if someone with mild hearing loss has a strong QoL improvement score, especially when paired with a low TFI score, then this will give us a strong indication to how much their suffering has improved given that their primary complaint may have been tinnitus and not hearing loss (this would still be speculation of course). Much to your point, one's suffering with tinnitus is usually the result of not just volume but also other characteristics. I don't think someone would say though that their QoL has improved unless the very thing that bothers them - whether it be volume, pitch or something else - hasn't improved.

Edit: Looking at the TFI index again, I would say it's basically a QoL questionnaire for tinnitus. So I would say even the TFI in isolation would give us a good indication of how the patient is feeling about their tinnitus. And as I said, those feelings will not be determined just by volume, but other characteristics as well.

See a TFI example attached. I'd argue a lot of those questions would see answer improvements as long as the very thing that bothers the patient improves.

 

[Diesel]

I worry that the TFI scores will fail to adequately address how the characteristics of one's tinnitus may impact the success of FX-322 relieving it, especially via the current and limited delivery method. I suspect those with higher-pitched ringing would get more relief than those with lower tones, and the data won't show that. TFI is just a "how bad is it" index, right? Nothing about high/low, steady/fluctuating, etc.; am I correct?

Yeah the TFI doesn't measure the characteristics of tinnitus at all. TFI is very much a quality-of-life questionnaire more than an actual perception measurement. It is a 25-item questionnaire totaling 100 points, and broken into sections to measure how a patient's tinnitus affects their ability to cope, concentrate, sleep, communicate, socialize, etc. It has been validated by research as a consistent tool for monitoring how a patient is living with tinnitus.

I suspect you will be correct that high-frequency tinnitus (8 kHz and above) may see a higher rate of improvement than mid-low frequency tinnitus.

From a statistical significance standpoint, it might be that high-frequency tinnitus, which seems pretty common and most bothersome from anecdotes on this forum, may result in a dramatic drop in TFI from a baseline score. I also have theorized that simply increasing the signal from damaged hair cells anywhere in the cochlea may help to reduce the perception of tinnitus if it is lower in the frequency range. So, that may also help reduce the TFI score moderately.

I definitely do not expect to see some ground-breaking p-value even when the final data is released. But I would expect them to highlight patients that saw dramatic drops in their TFI, indicating that it helped people the most where the tinnitus and repaired damage had a high correlation.

Of note, Clinical Significant TFI score drop is 14 points with bi-lateral tinnitus. For one treated ear, they may assume a 7 point drop is considered significant.

Also, this is how a clinician is normally trained to translate the TFI score into understanding the severity of a patient's tinnitus:

• Mean score of 14 (range 0-17) not a problem.
• Mean score of 21 (range 18-31) small problem.
• Mean score of42 (range 32-53) moderate problem.
• Mean score of 65 (range 54-72) big problem.
• Mean score of 78 (range 73-100) very big problem.

 

[Zugzug]

Yeah the TFI doesn't measure the characteristics of tinnitus at all. TFI is very much a quality-of-life questionnaire more than an actual perception measurement. It is a 25-item questionnaire totaling 100 points, and broken into sections to measure how a patient's tinnitus affects their ability to cope, concentrate, sleep, communicate, socialize, etc. It has been validated by research as a consistent tool for monitoring how a patient is living with tinnitus.

I suspect you will be correct that high-frequency tinnitus (8 kHz and above) may see a higher rate of improvement than mid-low frequency tinnitus.

From a statistical significance standpoint, it might be that high-frequency tinnitus, which seems pretty common and most bothersome from anecdotes on this forum, may result in a dramatic drop in TFI from a baseline score. I also have theorized that simply increasing the signal from damaged hair cells anywhere in the cochlea may help to reduce the perception of tinnitus if it is lower in the frequency range. So, that may also help reduce the TFI score moderately.

I definitely do not expect to see some ground-breaking p-value even when the final data is released. But I would expect them to highlight patients that saw dramatic drops in their TFI, indicating that it helped people the most where the tinnitus and repaired damage had a high correlation.

Of note, Clinical Significant TFI score drop is 14 points with bi-lateral tinnitus. For one treated ear, they may assume a 7 point drop is considered significant.

Also, this is how a clinician is normally trained to translate the TFI score into understanding the severity of a patient's tinnitus:

• Mean score of 14 (range 0-17) not a problem.
• Mean score of 21 (range 18-31) small problem.
• Mean score of42 (range 32-53) moderate problem.
• Mean score of 65 (range 54-72) big problem.
• Mean score of 78 (range 73-100) very big problem.

This has me thinking. I've read the same thing from the American Academy of Audiology. It's interesting that they don't define clinically meaningful change by percentage improvement, but rather absolute score change of 13 or more.

Under this current guideline, there will be a hardcore floor effect. Someone with a baseline TFI of <13 is ineligible no matter what. Even people >=13, is it really reasonable to expect someone to go from 14 to 1 or 25 to 12?

I also have a preemptive fear regarding the Phase 2a results. Tinnitus can be prone to the placebo effect. Depending on when the data is collected, I wonder if we will see both the placebo and treated groups see TFI improvements. The TFI is such a crude test for measuring tinnitus. What if everyone sleeps better knowing they are in a clinical trial for hearing improvement? What if someone in the placebo group happens to have a few good tinnitus days and thinks they are in the treated group?

Seems difficult. I know personally, my tinnitus varies based on sleep, diet, stress, etc. It's going to be hard to use such a crude test to really make sense out of this.

On the clinical trials page, it says they are measuring things by "screening to day 210." Does anyone know how often they are screening?

One last remark: Even if they did obtain tons of data and re-evaluation of TFI frequently, isn't there a ton of variability in the baseline TFI (i.e. whether they were having good or bad day stretches)?

 

[FGG]

I worry that the TFI scores will fail to adequately address how the characteristics of one's tinnitus may impact the success of FX-322 relieving it, especially via the current and limited delivery method. I suspect those with higher-pitched ringing would get more relief than those with lower tones, and the data won't show that. TFI is just a "how bad is it" index, right? Nothing about high/low, steady/fluctuating, etc.; am I correct?

It would help so much if they tone matched and matched to audiogram findings but maybe that's asking too much for the extended arm.

 

[Zugzug]

Are we rallying?!

 

[Diesel]

This has me thinking. I've read the same thing from the American Academy of Audiology. It's interesting that they don't define clinically meaningful change by percentage improvement, but rather absolute score change of 13 or more.

Under this current guideline, there will be a hardcore floor effect. Someone with a baseline TFI of <13 is ineligible no matter what. Even people >=13, is it really reasonable to expect someone to go from 14 to 1 or 25 to 12?

I also have a preemptive fear regarding the Phase 2a results. Tinnitus can be prone to the placebo effect. Depending on when the data is collected, I wonder if we will see both the placebo and treated groups see TFI improvements. The TFI is such a crude test for measuring tinnitus. What if everyone sleeps better knowing they are in a clinical trial for hearing improvement? What if someone in the placebo group happens to have a few good tinnitus days and thinks they are in the treated group?

Seems difficult. I know personally, my tinnitus varies based on sleep, diet, stress, etc. It's going to be hard to use such a crude test to really make sense out of this.

On the clinical trials page, it says they are measuring things by "screening to day 210." Does anyone know how often they are screening?

One last remark: Even if they did obtain tons of data and re-evaluation of TFI frequently, isn't there a ton of variability in the baseline TFI (i.e. whether they were having good or bad day stretches)?

All good questions, and I have some thoughts. First, I agree the TFI is sort of crude. Just like all the other hearing tests, as we have learned. So, not much of a surprise there.

There absolutely is a serious floor effect with the TFI... but I suspect that recruiting a homogenous moderate hearing loss group that probably has notably terrible tinnitus should yield favorable changes in the TFI score. This may have been one of the "additional filter criteria" they looked for, everyone had to have bothersome tinnitus levels as a baseline.

We have to keep in mind that the TFI is measured over the course of 6 months. Starting at baseline. I would expect to see the placebo-effect not be consistent over the course of a 6-month period. For those treated with FX-322, we might see it decrease by a certain amount, and stay/stabilize at that new lower average level. That would show significance. A placebo case may drop initially, but then return to baseline or vary a lot because other factors are contributing to the tinnitus that is not FX-322 (obviously because they got placebo). This would also add to stat significance. Multi-dosing may also lend to stronger stabilization at that lower TFI level, which would add to a binary statistical calculation.

It appears they are doing the same set of tests at every visit. The mention "partial" scores for Tinnitus and QOL because they're treating a single ear and not both. And, it has been implied that some of these changes are much more gradual as hearing improves.

 

[Keith Handy]

Don't get me wrong, if TFI improvements are "iffy" due to participants coming in with a wide range of tinnitus symptoms, but extended audiograms show a really good improvement, I will still believe in the treatment. It's a question of to what degree others, who make important decisions, will be convinced.

 

[Diesel]

It would help so much if they tone matched and matched to audiogram findings but maybe that's asking to much for the extended arm.

I was thinking about this. I wonder if any non-Frequency Therapeutics sponsored research may eventually take place with FX-322 where more detailed analysis of tinnitus / hyperacusis take place. For example, what's stopping a university from acquiring FX-322 from Frequency Therapeutics and doing a really detailed assessment of the drug's effect on specific tinnitus measures?

 

[AfroSnowman]

I also have a preemptive fear regarding the Phase 2a results. Tinnitus can be prone to the placebo effect.

I agree, but you would think if something worked for real, the kind of worked that we all are looking for where you couldn't hear it any more or it was suddenly actually maskable it would be pretty unambiguous right?

 

[Zugzug]

All good questions, and I have some thoughts. First, I agree the TFI is sort of crude. Just like all the other hearing tests, as we have learned. So, not much of a surprise there.

There absolutely is a serious floor effect with the TFI... but I suspect that recruiting a homogenous moderate hearing loss group that probably has notably terrible tinnitus should yield favorable changes in the TFI score. This may have been one of the "additional filter criteria" they looked for, everyone had to have bothersome tinnitus levels as a baseline.

We have to keep in mind that the TFI is measured over the course of 6 months. Starting at baseline. I would expect to see the placebo-effect not be consistent over the course of a 6-month period. For those treated with FX-322, we might see it decrease by a certain amount, and stay/stabilize at that new lower average level. That would show significance. A placebo case may drop initially, but then return to baseline or vary a lot because other factors are contributing to the tinnitus that is not FX-322 (obviously because they got placebo). This would also add to stat significance. Multi-dosing may also lend to stronger stabilization at that lower TFI level, which would add to a binary statistical calculation.

It appears they are doing the same set of tests at every visit. The mention "partial" scores for Tinnitus and QOL because they're treating a single ear and not both. And, it has been implied that some of these changes are much more gradual as hearing improves.

To maybe make my original point more clear, I think I was more concerned about 90 day readouts. You're right that 6 months is a lot more time for things to stabilize.

Regarding "additional filters," it sounds nice, but is it hard to achieve in practice? So far, it looks like we know that their additional filters are based on the responders in Phase 1/2. If their filter also includes people with bad tinnitus, I would imagine recruiting would be hard.

This forum is a very biased set of data, with people with reactive brains. Plenty of people have hearing loss without highly debilitating tinnitus. I don't think tinnitus is the main lane for FX-322, it just happens to be the case that high frequency hearing improvements should help a lot of tinnitus cases.

Although, you are right that if they are going for people at least in the moderate end, they will incidentally catch a lot more moderate to severe tinnitus cases. I just don't know if it will be enough.

 

[Diesel]

Don't get me wrong, if TFI improvements are "iffy" due to participants coming in with a wide range of tinnitus symptoms, but extended audiograms show a really good improvement, I will still believe in the treatment. It's a question of to what degree others, who make important decisions, will be convinced.

If it turns out there is a correlation between restoring hearing on the EHF audiogram and clinically meaningful TFI improvements, Frequency Therapeutics will certainly isolate those participants in the Q2 full data release and put it on a PowerPoint slide.

The nice thing is, the "powers that be" are measuring the drug on its primary outcomes: Word in Quiet, Word in Noise, Standard Audiogram, Safety.

If they can reproduce the Phase 1/2 in greater numbers, FX-322 should continue meet those primary outcomes effectively.

TFI, QoL, EHF Audiogram is all experimental and wont weight at all on the decision-making by the FDA.

 

[Zugzug]

I agree, but you would think if something worked for real, the kind of worked that we all are looking for where you couldn't hear it any more or it was suddenly actually maskable it would be pretty unambiguous right?

You make a good point, but this goes to my point about a trade off between "ability to override the placebo effect" and "ability to recruit." It would be wonderful if they could recruit n=95 people with moderate to severe hearing loss with high TFI. I see it as a recruiting challenge.

Certainly, if someone has horrific, high TFI tinnitus, it's unlikely that "believing in the drug" would be enough to override that. I'm more referring to people in that 14-30 TFI range that are just eligible for the >= 13 TFI improvement to be clinically meaningful.

 

[Piet]

I hope the results will be good. I don't know about you guys, but I'm 20 years old and can't hear properly above 12-13 kHz so I hope FX-322 will fix this

 

[Diesel]

To maybe make my original point more clear, I think I was more concerned about 90 day readouts. You're right that 6 months is a lot more time for things to stabilize.

Regarding "additional filters," it sounds nice, but is it hard to achieve in practice? So far, it looks like we know that their additional filters are based on the responders in Phase 1/2. If their filter also includes people with bad tinnitus, I would imagine recruiting would be hard.

This forum is a very biased set of data, with people with reactive brains. Plenty of people have hearing loss without highly debilitating tinnitus. I don't think tinnitus is the main lane for FX-322, it just happens to be the case that high frequency hearing improvements should help a lot of tinnitus cases.

Although, you are right that if they are going for people at least in the moderate end, they will incidentally catch a lot more moderate to severe tinnitus cases. I just don't know if it will be enough.

I don't think it's so far fetched.

Let's do a hypothetical:

There's about 5-10 million people with moderate+ hearing loss in the US. Let's assume that as hearing declines, the prevalence of tinnitus increases. Most of the clinical sites were at or within about 30 minutes of a major city, which provides favorable access to a majority of this group.

Average age in the Phase 1/2 was 55. Plenty of time to wear out hearing from working a noisy career. Plenty of these patients were already well known by their doctors before being referred to the trial.

It also took Frequency Therapeutics almost a year to fully recruit the trial, they were going slow even before COVID-19, which tells me they took the luxury of being really selective.

It may not be that the tinnitus had to be debilitating, but perhaps on the north end of the annoying scale to give ample room for improvement.

 

[FGG]

I don't think it's so far fetched.

Let's do a hypothetical:

There's about 5-10 million people with moderate+ hearing loss in the US. Let's assume that as hearing declines, the prevalence of tinnitus increases. Most of the clinical sites were at or within about 30 minutes of a major city, which provides favorable access to a majority of this group.

Average age in the Phase 1/2 was 55. Plenty of time to wear out hearing from working a noisy career. Plenty of these patients were already well known by their doctors before being referred to the trial.

It also took Frequency Therapeutics almost a year to fully recruit the trial, they were going slow even before COVID-19, which tells me they took the luxury of being really selective.

It may not be that the tinnitus had to be debilitating, but perhaps on the north end of the annoying scale to give ample room for improvement.

They were focusing more on sudden and not age-related hearing loss ("wear and tear") for this trial though. The age-related trial was separate. I think that group probably has a much higher percentage of at least moderately bothersome tinnitus than just the average hearing loss population.

 

[Zugzug]

I don't think it's so far fetched.

Let's do a hypothetical:

There's about 5-10 million people with moderate+ hearing loss in the US. Let's assume that as hearing declines, the prevalence of tinnitus increases. Most of the clinical sites were at or within about 30 minutes of a major city, which provides favorable access to a majority of this group.

Average age in the Phase 1/2 was 55. Plenty of time to wear out hearing from working a noisy career. Plenty of these patients were already well known by their doctors before being referred to the trial.

It also took Frequency Therapeutics almost a year to fully recruit the trial, they were going slow even before COVID-19, which tells me they took the luxury of being really selective.

It may not be that the tinnitus had to be debilitating, but perhaps on the north end of the annoying scale to give ample room for improvement.

I hope you're right. It seems like the fact that audiologists don't keep up with research is a huge hurdle...

 

[Diesel]

They were focusing more on sudden and not age-related hearing loss ("wear and tear") for this trial though. The age-related trial was separate. I think that group probably has a much higher percentage of at least moderately bothersome tinnitus than just the average hearing loss population.

I should have clarified.. my perspective on age was more about patients who had accumulated noise damage from their career, and therefore displayed favorable symptoms for the Phase 2A. In the Phase 1/2, 12 patients had NIHL and 11 had SSNHL.

 

[Diesel]

I hope you're right. It seems like the fact that audiologists don't keep up with research is a huge hurdle...

Yeah this is very real concern, and hopefully Frequency Therapeutics sticks to their word and owns the education push for clinicians.

 

[AfroSnowman]

It seems like the fact that audiologists don't keep up with research is a huge hurdle...

Not audiologists but ENTs right? I don't think audiologists will be administering FX-322.

 

[tommyd87]

I hope you're right. It seems like the fact that audiologists don't keep up with research is a huge hurdle...

I don't think that this will be too much of a hurdle overall. Obviously some will be keen to learn about it immediately in order to provide best assistance to their patients. However those that don't then will face the possibility that if a medicine is successful (EG: FX-322) and they don't do anything to learn about it then they could end up being behind in the game quickly.

There is nothing stopping an ENT for example dealing with treatment themselves. All they would need to do is send someone suitable off to get the audiologist's tests done and bring them back to them completed in order to commence treatment. There's tonnes of ways to get around an audiologist's lack of following research and also attain treatment outcomes.

 

[Zugzug]

I don't think that this will be too much of a hurdle overall. Obviously some will be keen to learn about it immediately in order to provide best assistance to their patients. However those that don't then will face the possibility that if a medicine is successful (EG: FX-322) and they don't do anything to learn about it then they could end up being behind in the game quickly.

There is nothing stopping an ENT for example dealing with treatment themselves. All they would need to do is send someone suitable off to get the audiologist's tests done and bring them back to them completed in order to commence treatment. There's tonnes of ways to get around an audiologist's lack of following research and also attain treatment outcomes.

Sure, but the conversation is about the current ability to recruit good candidates that will produce beautiful TFI changes, QoL changes, PTA changes, SIN and WR changes, etc.

Also, I have just as much of a lack of faith in ENTs lol. When I asked my otologist about FX-322, he said to not even think about it because it's "decades away." Yet LeBel has conservatively shot out the date to 5-10 years from now. This otologist is good too, by the way.

 

[throwaway]

I suspect those with higher-pitched ringing would get more relief than those with lower tones, and the data won't show that.

Why would it only work on higher-pitched ringing?