Frequency Therapeutics — Hearing Loss Regeneration

[twa]

Who would have thought that by being exposed to loud noise we would have gotten tinnitus and hyperacusis. The only thing we knew about loud noise is that it can cause hearing loss, but tinnitus and hyperacusis... I had no idea these conditions even existed.

I never imagined! I didn't know that you could get hearing loss by something like a child yelling in your ear! I've never known anyone who had anything like this. It's heartbreaking.

 

[FGG]

I said the same thing to my 80-year-old father and he said it probably won't be ready in time for him. I wish it was, he has hearing loss and it is hard to communicate with him between his hearing loss and my hyperacusis. Can you imagine? He is yelling and I'm holding my ears!

It's too bad he missed the recruiting for his age group for the current trial but the age-related cohort might be included in the Phase 3 trial next year (and travel should be easier then).

 

[Jrblovsky]

It blows me away to hear of all these people with normal hearing thresholds that have tinnitus. I'm guessing for them hidden hearing loss is the culprit. I absolutely believe that restoring lost hearing stops tinnitus. I have had my hearing return to normal which in turn stops the roaring I hear. I can also hear very very soft tones when this happens. When I have the roaring I cannot hear those tones.

 

[Lucifer]

If I understand correctly, I agree that they won't come out and make a blanket claim that FX-322 treats tinnitus. Meaning, tinnitus in the broad sense of "ringing in the ears," without disclosing the cause.

They may however begin to comment on how noise-induced hearing loss sometimes also causes tinnitus.

They may also be able to draw specific correlations between their data, which if statistically significant, they can make more specific claims to FX-322 treating tinnitus as a symptom of hearing loss. Or treating hearing loss, or tinnitus and thereby improving quality of life.

For example, if significant:

Overall significant improvements in primary endpoints positively correlate with a reduction in TFI score, and increase in QOL measure.

A stepped improvement in primary endpoints and stepped reduction in QOL measure. For example: 1 dose population saw an average of 7 point TFI reduction, 2 dose: 14 point, 4 dose: 28 point.

With this type of data, if statistically significant, it provides enough evidence that regenerating inner and outer hair cells is connected to treating tinnitus when the condition is acquired SNHL. At that point, they can make certain claims.

I can certainly see the general public thinking, "oh yay this will fix my tinnitus" and they will need to consult their doctor at that point to understand whether their tinnitus is a symptom of SNHL or something else.

Also I don't think they can guarantee that it cures tinnitus. You may need both, a hair cell drug like FX-322 and a synapse drug like OTO-413 to get rid of tinnitus completely.

 

[Gb3]

It seems like everyone here has noise-induced tinnitus?

 

[Pulsing Ear]

No, there is no drilling of a hole in the cochlea to put a gel in the middle ear.
Now, if you were undergoing a stapedotomy (like me), then yes, you would have a whole in your cochlea, and a piston (prosthesis) in there too.

Did you have stapedial myoclonus like I do? I'm wondering what kind of results you got from having it done? Are you glad you had it done, or do you have regrets?

 

[Diesel]

This is a really good point.

If they market it for tinnitus more generally, people who have other causes (apart from hair cell damage) will be potentially misled by the promise of a "tinnitus treatment" that wouldn't benefit people who have: middle ear disease, ETD, TMJ, iron deficiency, hydrops without hair cell loss, etc. It would be up to the ENTs and audiologists to do a better job determining the cause and educating people but I also think the marketing of this needs to be very specific.

Yes. If there is a favorable outcome on the TFI, they will have to use wording that describes FX-322 being able to "treat" SNHL hearing loss AND tinnitus. Or possibly just a specific 'treatment for noise-induced tinnitus.' They will certainly avoid referencing FX-322 as a cure for tinnitus or SNHL. Even though the media will spin it that way; but that's out of Frequency Therapeutics' control.

I also highly doubt we'll see anyone's TFI score go all the way to ZERO. Indicating that they no longer experience any tinnitus at all. But perhaps a low, single-digit level that most of us would cut off a limb for right now.

 

[tommyd87]

It seems like everyone here has noise-induced tinnitus?

No. I will have jaw caused tinnitus remaining even if it is the case that the cochlear issues get treated.

 

[Diesel]

FYI:

TFI = Tinnitus Functional Index. It is a tinnitus questionnaire that considered "clinically acceptable" by the FDA and other hearing-related academic/professional entities. Each participant of the FX-322 trial that indicates they have tinnitus is required to complete a TFI Questionnaire on each visit. So, prior to receiving any injections on Day-0, they'll fill out the TFI Questionnaire, then fill out another for each return visit up to Month 7.

The TFI is 25 questions totaling 100 points. It measures how a person's tinnitus is affecting their overall quality of life in 5 different categories: (1) discomfort caused by tinnitus; (2) interference of tinnitus with participation in social events; (3) interference of tinnitus with leisure activities; (4) fatigue caused by tinnitus; and (5) amount of time that overall quality of life was reduced by tinnitus.

There's a little bit a varied response on the TFI score, but generally, the higher the number, the worse the tinnitus is affecting quality of life.

TFI Score:
0 - 17: Not a Problem (Mean: 14)
18 - 31: Small Problem (Mean: 21)
32 - 53: Moderate Problem (Mean: 42)
54 - 72: Big Problem (Mean: 65)
73 - 100: Very Big Problem (Mean: 78)

Based on the research I have done; generally a TFI score dropping 12-14 points is considered clinically meaningful. So, should we see a 14-point drop or more at the 90-day Phase 2A read-out, or the final read-out; that would indicate that FX-322 regrowing hair cells does in fact have a clinically meaningful impact on treating tinnitus.

That does not make it a cure. But, it's highly likely that it makes the tinnitus much easier to live with. I'm sure people who consider their tinnitus to be a Moderate Problem would be delighted to have their tinnitus reduced to a Small Problem, or even into the higher range of the Not a Problem category.

 

[Jrblovsky]

Also I don't think they can guarantee that it cures tinnitus. You may need both, a hair cell drug like FX-322 and a synapse drug like OTO-413 to get rid of tinnitus completely.

You're absolutely correct.

 

[FGG]

It seems like everyone here has noise-induced tinnitus?

Macrolide antibiotic ototoxicity for me.

 

[ajc]

Based on the research I have done; generally a TFI score dropping 12-14 points is considered clinically meaningful. So, should we see a 14-point drop or more at the 90-day Phase 2A read-out, or the final read-out; that would indicate that FX-322 regrowing hair cells does in fact have a clinically meaningful impact on treating tinnitus.

TFI is bullshit.

I can have 90 TFI on one day, and 40 the next.

That's why we need an objective measurement for tinnitus. Subjective measurements suck donkey's balls.

 

[GregCA]

Did you have stapedial myoclonus like I do?

No. I suffer from otosclerosis.

I'm wondering what kind of results you got from having it done?

I regained a good chunk of hearing (closing the air-bone gap). Lost a little bit in the high frequencies. Overall positive. The disease also stopped progressing after that, but I don't know if it's because of the surgery or the heavy doses of Fluoride that I'm taking.

No change in tinnitus.

 

[Diesel]

TFI is bullshit.

I can have 90 TFI on one day, and 40 the next.

That's why we need an objective measurement for tinnitus. Subjective measurements suck donkey's balls.

It's not ideal, but it's the best we have right now that the FDA accepts. In the aggregate group, there may be a notable change across a 7 month timeframe.

Mine also swings. But, perhaps the range would swing lower on average over 6 months after treatment?

Same goes for the audiogram in my opinion. Crappy measurement that is too broad. Word scores are really the best we have, since words require so much detailed processing to understand.

 

[Danad]

FYI:

TFI = Tinnitus Functional Index. It is a tinnitus questionnaire that considered "clinically acceptable" by the FDA and other hearing-related academic/professional entities. Each participant of the FX-322 trial that indicates they have tinnitus is required to complete a TFI Questionnaire on each visit. So, prior to receiving any injections on Day-0, they'll fill out the TFI Questionnaire, then fill out another for each return visit up to Month 7.

In order to arrive at a better understanding of what FX-322 can do for tinnitus, they really needed to shoot up both ears in Phase 2a. Results will fall short of the drug's potential.

 

[Diesel]

In order to arrive at a better understanding of what FX-322 can do for tinnitus, they really needed to shoot up both ears in Phase 2a. Results will fall short of the drug's potential.

Completely agree. I hope they're strongly considering dosing both ears in the pivotal phase.

 

[sssing]

In order to arrive at a better understanding of what FX-322 can do for tinnitus, they really needed to shoot up both ears in Phase 2a. Results will fall short of the drug's potential.

Even if the other ear is normal and doesn't have tinnitus?

 

[Drachen]

You may need both, a hair cell drug like FX-322 and a synapse drug like OTO-413 to get rid of tinnitus completely.

Can we touch on this a bit further?

My understanding was that regrowing the hair cells would also repair the synaptic connections beneath, as otherwise hair cells with no connection serve little purpose.

Is the need for a complementary synaptic drug meant to address those hair cells still intact but with broken connections? Can they not repair themselves over time? Do we know what causes you to lose hair cells sometimes and synapses otherwise?

 

[Gb3]

Macrolide antibiotic ototoxicity for me.

How do they go about diagnosing that?

 

[FGG]

How do they go about diagnosing that?

Hearing loss that was instantaneous with bilaterally extremely symmetric audiogram changes and my history.

 

[GBB]

Can we touch on this a bit further?

My understanding was that regrowing the hair cells would also repair the synaptic connections beneath, as otherwise hair cells with no connection serve little purpose.

Is the need for a complementary synaptic drug meant to address those hair cells still intact but with broken connections? Can they not repair themselves over time? Do we know what causes you to lose hair cells sometimes and synapses otherwise?

Yes, another drug is needed for the intact hair cells with broken connections.

 

[FGG]

Can we touch on this a bit further?

My understanding was that regrowing the hair cells would also repair the synaptic connections beneath, as otherwise hair cells with no connection serve little purpose.

Is the need for a complementary synaptic drug meant to address those hair cells still intact but with broken connections? Can they not repair themselves over time? Do we know what causes you to lose hair cells sometimes and synapses otherwise?

Someone else will beat me to this but regenerated hair cells will synapse without an additional drug.

Some people don't have hair cell loss though and will need a drug that addresses "cochlear synaptopathy" without hair cell loss.

 

[FGG]

I hope they're strongly considering dosing both ears in the pivotal phase.

I think it's better for hearing loss approval (which is what they are seeking FDA approval for) if they don't because you have a strong internal control.

 

[Drachen]

Some people don't have hair cell loss though and will need a drug that addresses "cochlear synaptopathy" without hair cell loss.

I think I already know the answer for this, but is there anyway to determine whether one's hearing loss is a result of hair cell or synapse loss? Given we may have two drugs for two different causes soon, it would seem it's important to gauge the correct one before starting treatment.

 

[FGG]

I think I already know the answer for this, but is there anyway to determine whether one's hearing loss is a result of hair cell or synapse loss? Given we may have two drugs for two different causes soon, it would seem it's important to gauge the correct one before starting treatment.

Testing isn't great but audiogram changes at least indicate hair cell loss. Diagnostics are years behind treatments in this case.

Many people will have to "trial treat" I suspect.

 

[Gb3]

Testing isn't great but audiogram changes at least indicate hair cell loss. Diagnostics are years behind treatments in this case.

Many people will have to "trial treat" I suspect.

So if you have sudden hearing loss in three consecutive frequencies, it's most likely hair cell damage?

 

[FGG]

So if you have sudden hearing loss in three consecutive frequencies, it's most likely hair cell damage?

Audiogram changes measure outer hair cell loss so yes, you have hair cell damage.

 

[katri]

Wait, I thought FX-322 treated hair cell damage and synaptic damage?

It only creates new hair cells where they're missing?

 

[FGG]

Wait, I thought FX-322 treated hair cell damage and synaptic damage?

It only creates new hair cells where they're missing?

It doesn't treat synapse damage if the hair cell is fine.

A lot of people (noise-induced especially) may have "cochlear synaptopathy" where only the synapses are damaged.

Hop over to the OTO-413 thread. There is a different drug in trial for this and they have had good Phase 1 results.

 

[katri]

It doesn't treat synapse damage if the hair cell is fine.

A lot of people (noise-induced especially) may have "cochlear synaptopathy" where only the synapses are damaged.

Hop over to the OTO-413 thread. There is a different drug in trial for this and they have had good Phase 1 results.

Didn't Carl LeBel semi-address that? I'm not 100% sure though. Just really wondering because he stated that you'd be surprised fixing one thing can be proven to fix others as well. I'm not sure exactly what he meant by that or if I'm interpreting it all wrong.