Frequency Therapeutics — Hearing Loss Regeneration

[Jack V]

Interesting find - when Carl LeBel was on the Tinnitus Talk Podcast he made an interesting comment when discussing cochlear synaptopathy. He was talking about the process of FX-322 working:

"It wouldn't be the first drug if it gets approved, where one didn't fully understand the mechanism of action." (on page 12 of the transcript).

I'm probably just reading too much into this but it's a slightly ambiguous comment and I wonder if it possibly suggests that the drug could also stimulate synapse growth?

That's something I've heard drug scientists say before, and I really wouldn't read too much into it.

Even the mechanism of action for something as common as aspirin is probably not fully understood.

 

[100Hz]

Oh ok.

I took @Orions Pain's anecdote as a loudness one (which is definitely uncomfortable and unpleasant but absolutely not in the way noxacusis is) and it seems that this is similar. Once again, I wish there was a standard terminology because it gets very confusing.

Yeh, it makes me wonder that although the insertion of a cochlear implant is obviously very damaging to what's left of natural 'good' hearing mechanisms, it may also be wiping out the 'bad' mechanisms of hyperacusis, maybe noxacusis as well. I'll be interested to see more of these sort of cases in the future.

 

[PeteJ]

If FX-322 is approved and works as advertised, it will likely become a common procedure and easy to find.

What does the above mean?

The vague statement "works as advertised?"

What's the chance of improved hearing and elimination of tinnitus from FT? 10%? 20%? More? Less?

Will it treat one of tinnitus or hearing or hyperacusis or a combination?

I know everyone has their own hope but mine is elimination of my loud, high-pitched tones... the tinnitus. If it 'cures' my ear pain (hyperacusis?) and improves my hearing, that's a bonus. But, I don't consider a treatment a success unless it dramatically reduces or "cures" loud tinnitus. And since everyone's tinnitus is different, doesn't it have to "cure" it, universally? It needs to be applicable to all sorts of tinnitus or at least tinnitus caused by acoustic trauma or noise-induced tinnitus (from noise-induced hearing loss?), right?

 

[Orions Pain]

Oh ok.

I took @Orions Pain's anecdote as a loudness one (which is definitely uncomfortable and unpleasant but absolutely not in the way noxacusis is) and it seems that this is similar. Once again, I wish there was a standard terminology because it gets very confusing.

Here are some direct quotes from his post:

"During my most recent mapping, I asked my audiologist how much mid range was present in my map. Astonished with her response, I asked her to add a significant amount. I also asked for a little more treble.

Much to my surprise, the higher sounds are not hurting. There is too much treble, but it is not intolerable.

My low and high frequencies were amplified with hearing aids, but with no mid, there was not an appropriate balance. This explained the excessive muffling on the low end, excessive sharpness on the high end, and a hollow sound in the middle"​

So as you guys can see he said higher sounds "hurt" but we don't know if he meant that they just sounded overly piercing or if they actually hurt like a stab in the ear or a burn. My personal speculation is that it was the former.

Also just to clarify, if you guys re-read my post I didn't make any claims that it stopped his noxacusis/pain, just that he said "higher sounds were no longer hurting" . Of course we all know people in the Hyperacusis world when people use the words "hurting/pain" they often don't mean ice pick stabbing or burning.

 

[Michael01]

The FX-322 ClinicalTrials.gov page has the list of clinics that participated in the trial, and when Phase 3 comes around it should get updated/expanded. That could be a good place to start looking for doctors. Now's the time to build relationships with the right doctors because once FX-322 gets released it's going to be a crap show and a scramble, and I for one am not waiting to get it when it comes available.

Thing is most of those clinics are in the U.S right now which stinks for those of us that don't live in the U.S. Once they roll out Phase 3 I'm really hoping that they get more international clinics and ENTs to join in the trials, as traveling to the U.S right now is something I'd prefer to avoid, due to cost and other factors.

 

[tiredofit]

Do you retain any natural hearing function that runs alongside an implant or is it now purely the implant acting as the ear? I believe it wipes out what's left.

Yeah most of the cochlear implant patients lose their remaining hearing.

You mean fortunately! Lol I wish I could hear better and understand better what I hear.

Nah, I find the newest CIs to be pretty cool looking and they would free up my ears finally, plus they are just wayyy more powerful than hearing aids.

 

[FGG]

Yeh, it makes me wonder that although the insertion of a cochlear implant is obviously very damaging to what's left of natural 'good' hearing mechanisms, it may also be wiping out the 'bad' mechanisms of hyperacusis, maybe noxacusis as well. I'll be interested to see more of these sort of cases in the future.

It seems that damaging either the IHC or the IHC synapse with the SGNs increases cebtral gain and contributes to loudness hyperacusis so it's more likely the CI just re-establishes the input to resolve the issue.

Inner Hair Cell Loss Disrupts Hearing and Cochlear Function Leading to Sensory Deprivation and Enhanced Central Auditory Gain

If CIs did improve noxacusis that would be an entirely different pathophysiology, though, and maybe destruction of the remaining hair cells and associated afferents would treat noxacusis. Interesting.

Yeah most of the cochlear implant patients lose their remaining hearing.

They make shorter implants now that, in particular, preserve more low frequency natural hearing which is a lot of why modern implants sound better, particularly with music.

 

[patorjk]

Frequency Therapeutics' stock now has a market cap above $1B. It's kind of strange there was such a run-up in the last month. I take that as a sign that people are becoming more and more optimistic about FX-322. It'll be interesting to see where the company ends up after the Phase 2a results.

 

[Paulmanlike]

Frequency Therapeutics' stock now has a market cap above $1B. It's kind of strange there was such a run-up in the last month. I take that as a sign that people are becoming more and more optimistic about FX-322. It'll be interesting to see where the company ends up after the Phase 2a results.

Much higher stock price, that's for sure. If FX-322 fails, it will crash miserably.

 

[FGG]

Frequency Therapeutics' stock now has a market cap above $1B. It's kind of strange there was such a run-up in the last month. I take that as a sign that people are becoming more and more optimistic about FX-322. It'll be interesting to see where the company ends up after the Phase 2a results.

Anyone who bought at IPO almost doubled their money already.

 

[LAnative]

I bought in. I figured God nerfed my ears to make me rich off this stock.

So when the results come out it'll be double jubilation or double agony.

 

[ThomasRobert]

This is all I could have:

 

[tommyd87]

Thing is most of those clinics are in the U.S right now which stinks for those of us that don't live in the U.S. Once they roll out Phase 3 I'm really hoping that they get more international clinics and ENTs to join in the trials, as traveling to the U.S right now is something I'd prefer to avoid, due to cost and other factors.

I don't think that this will be too much of an issue in the end because basically I think what will happen is either Frequency Therapeutics or Astellas on behalf of Frequency Therapeutics will arrange to conduct sessions with relevant overseas bodies about things like joining as a clinic, how to dose, what the processes are etc when the time is right. I believe this is what is happening in Europe with their trials too.

The thing is that like redosing is a fairly expensive exercise so is arranging consultations with overseas clinics to organise and engage in treatment. Thus I don't think that they will do anything about this until there is certainty that FX-322 will deliver benefits.

There is no way where we will see Frequency Therapeutics and also Astellas keep this as a US only treatment since they would lose too much money from possible sales.

 

[Princebeyel]

So what's the main focus on the severe hearing loss trial if you're only receiving one shot of FX-322?

 

[tommyd87]

So what's the main focus on the severe hearing loss trial if you're only receiving one shot of FX-322?

That isn't the trial to see if there is an effect from FX-322. It is the safety trial that's the same set up as the Phase 1/2 trial was.

 

[Diesel]

That isn't the trial to see if there is an effect from FX-322. It is the safety trial that's the same set up as the Phase 1/2 trial was.

Primary is safety and suicide assessment. Secondary is audiogram, word score, TFI.

Could still be some interesting outcomes.

 

[Diesel]

@FGG, and others... I had a thought I wanted to raise:

The Phase 1/2 resulted in significant word score improvements BUT not audiogram improvements. Could this be due to inner hair cell regrowth in some areas, but not significant enough outer hair cell regrowth?

 

[FGG]

@FGG, and others... I had a thought I wanted to raise:

The Phase 1/2 resulted in significant word score improvements BUT not audiogram improvements. Could this be due to inner hair cell regrowth in some areas, but not significant enough outer hair cell regrowth?

That's one of many possibilities. The other is that the ultra high frequency hearing really does make that much of a difference. There was one study I posted a while ago which showed when profoundly deaf people in a standard audiogram have normal audiograms above 8 kHz --very rare but happens-- they have "unusually good speech."

I had wondered that too, though. If the IHCs preferentially get treated first since there are more LGR5+ cells around them to activate.

 

[sensualmosquito]

That's one of many possibilities. The other is that the ultra high frequency hearing really does make that much of a difference. There was one study I posted a while ago which showed when profoundly deaf people in a standard audiogram have normal audiograms above 8 kHz --very rare but happens-- they have "unusually good speech."

I had wondered that too, though. If the IHCs preferentially get treated first since there are more LGR5+ cells around them to activate.

I feel like my brain is working harder to understand people, at least on the side of my bad ear. Most -s, -sh, -f , -th sounds are a bit more difficult to understand, especially through noise. I'm deaf in the 6-8 kHz range so I'm right at the end there.

 

[Princebeyel]

Primary is safety and suicide assessment. Secondary is audiogram, word score, TFI.

Could still be some interesting outcomes.

So should I be honest about having suicidal thoughts or could that exclude me from the trial?

 

[tommyd87]

@FGG, and others... I had a thought I wanted to raise:

The Phase 1/2 resulted in significant word score improvements BUT not audiogram improvements. Could this be due to inner hair cell regrowth in some areas, but not significant enough outer hair cell regrowth?

I believe that should Frequency Therapeutics see benefits from one shot in severe patients, it would show that FX-322 works and therefore this will be sufficient to instigate and explore further testing. The fact is if there is no benefit shown with one shot, then there will need to be further playing around with dosing numbers in the subsequent trial(s) or before subsequent trials to demonstrate that there is benefit for this group. Either way it is likely that there will be no issue with proceeding further with this cohort as long as the medicine is shown to be safe.

I think we can be fairly confident that Frequency Therapeutics will work with this cohort comprehensively until they can either show benefit or completely rule out that there is no benefit from FX-322 for patients having severe hearing loss.

 

[Diesel]

So should I be honest about having suicidal thoughts or could that exclude me from the trial?

The Columbia-Suicide Severity Rating Scale (C-SSRS) is a Measurement used as a primary outcome; not an entrance criteria. They are measuring if patients "feeling better" about life correlates to receiving FX-322. It's actually an interesting measurement, and may help tighten the association between other co-morbidities (depression, etc).

Link: https://clinicaltrials.gov/ct2/show/NCT04629664

Inclusion Criteria:

1. Subject has read and voluntarily signed the Informed Consent Form (ICF) after all questions have been answered and prior to any study-mandated procedure.
2. Adult aged 18-65 years inclusive.
3. Documented medical history consistent with severe sensorineural hearing loss (documented audiogram at least 6 months prior to screening required).
4. A pure tone average of 71-90 dB at 500Hz, 1000Hz, 2000Hz, and 4000Hz at Screening in the ear to be injected.
5. Ability to communicate well with the Investigator and is willing to comply with and complete all the study procedures.

Exclusion Criteria:

1. Subject has previously participated in a FX-322 clinical trial.
2. Perforation of tympanic membrane or other tympanic membrane disorders that would interfere with the delivery and safety assessment of an intratympanic medication or reasonably be suspected to affect tympanic membrane healing after injection in study ear. This includes a current tympanostomy tube.
3. Any conductive hearing loss of greater than 15 dB at a single frequency or greater than 10 dB at two or more contiguous octave frequencies in the study ear at the Screening visit or on the prior audiogram (if the Investigator feels there is not a true conductive hearing loss, the Medical Monitor should be consulted).
4. Active chronic middle ear disease or a history of major middle ear surgery, as an adult, in the ear to be injected.
5. Subject has had an intratympanic injection in either ear within 3 months of the screening visit.
6. History of clinically significant vestibular symptoms at the discretion of the investigator. For example, BPPV may be considered acceptable whereas Meniere's would not.
7. History of clinically significant systemic autoimmune disease (e.g. rheumatoid arthritis, Sjogren's syndrome, multiple sclerosis, psoriasis).
8. Exposure to another investigational drug within 28 days prior to injection of study drug.
9. Evidence of any active or chronic disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator following a detailed medical history, physical examination, and vital signs (systolic and diastolic blood pressure, pulse rate, body temperature).
10. Females of childbearing potential (those who are not surgically sterilized or post- menopausal) may not participate in the study if any of the following conditions exist:
    • Pregnant or intend to become pregnant
    • Nursing (lactating)
    • Does not agree to use adequate birth control methods for the duration of the study (adequate birth control methods are: hormonal- oral, implantable, transdermal or injectable contraceptives; mechanical- spermicide in conjunction with a barrier such as a condom or diaphragm, IUD, or surgical sterilization of a partner.
    NOTE: all female subjects of childbearing potential must consent to a urine pregnancy test as described in the Schedule of Assessments. Male subjects should use condoms with spermicide during the study or remain abstinent. Subjects should not donate sperm or ova during the study period.
11. Any known factor, condition, or disease that, in the view of the Investigator, might interfere with treatment compliance, study conduct or interpretation of the results.

 

[Ozwel]

I can't wait for that moment when people will figure out FX-322 is efficient at restoring frequencies above 8 kHz and no ENT in the world will find that relevant as frequencies above 8 kHz are considered useless or pretty much "meh, who cares?".

Some marketing work will have to be done, A LOT. That might be the only time I wish marketers do their job at their best.

 

[Born To Slay]

I can't wait for that moment when people will figure out FX-322 is efficient at restoring frequencies above 8 kHz and no ENT in the world will find that relevant as frequencies above 8 kHz are considered useless or pretty much "meh, who cares?".

Some marketing work will have to be done, A LOT. That might be the only time I wish marketers do their job at their best.

Or perhaps it'll make ENTs wake up to the fact that above 8 kHz is relevant after all.

 

[Diesel]

Or perhaps it'll make ENTs wake up to the fact that above 8 kHz is relevant after all.

Agree. I largely think this "above 8 kHz doesn't matter" has the hearing aid industry partly to blame. They can't provide a product to meet the need so conditioned the market that it is not important.

If Frequency Therapeutics can correlate ultra high frequency improvements to word score improvements (quiet or in noise). Then, another antiquated belief in this field will be debunked.

Come to think of it, 2021 may be a rough year for the hearing industry status quo.

 

[Born To Slay]

Come to think of it, 2021 may be a rough year for the hearing industry status quo.

Damn right it is, time to knock the whole fucking industry down and start over.

 

[Diesel]

Damn right it is, time to knock the whole fucking industry down and start over.

No need for violence. Parts of the industry will be in decline while new entrants fill the space as preferred alternatives.

Hearing aids and other coping treatments will just slowly start to go extinct and become a niche player like the cassette tape and dial-up internet.

 

[FGG]

No need for violence. Parts of the industry will be in decline while new entrants fill the space as preferred alternatives.

Hearing aids and other coping treatments will just slowly start to go extinct and become a niche player like the cassette tape and dial-up internet.

Nah, there would still be a need as (bone anchored) hearing aids are still the only treatment for conductive losses.

 

[tiredofit]

Damn right it is, time to knock the whole fucking industry down and start over.

There are still people that rely on hearing aids, people like me that were actually BORN profoundly hard of hearing and not because they decided to stand next to a concert speaker... Since FX-322 seems to be tackling acquired loss only, for me the ''cure'' is still a long way to go.

 

[Born To Slay]

No need for violence. Parts of the industry will be in decline while new entrants fill the space as preferred alternatives.

Hearing aids and other coping treatments will just slowly start to go extinct and become a niche player like the cassette tape and dial-up internet.

I mean, I wasn't trying to call for violence. Just a peaceful transition of power.