Frequency Therapeutics — Hearing Loss Regeneration

Seeing an audiologist has literally zero medical credentials or experience with surgery, I wonder why they would say that. I'm sure it's no different than any other part of the body.

 

Scylla looks cooler!

 

Yeah that's true. And most of them don't know much of anything to be honest, haha. But this guy seems like a proper hearing-nerd and seemed to be knowing what he was talking about. Then again, nothing else than my intuition to back that up with.

 

I'm not sure any of us know this; but even if not, I'd be interested in informed speculation:

Do we think an individual hair cell, by itself, is like a binary push-button switch—either firing for "stimulated", or not firing for "not stimulated"—or that it has a range, like a pressure sensor? In other words, do we need a certain number of hair cells being stimulated in order to perceive different amplitudes at all, or will an individual hair cell sense and report a range of amplitude on its own?

 

I believe each individual Outer Hair Cell has a range like a pressure sensor / potentiometer. It seems like the inner cell works more in a binary fashion.

My crude understanding is the more OHC available, the better the brain is at "getting the correct response" to sound amplitude.

 

My admittedly uninformed speculation is that a single anything doesn't matter, whether it's a single hair cell, a single cancer cell, or a single virus. Things only matter when they start to add up.

I would therefore guess that we tolerate the loss of individual hair cells, but it only impacts hearing when the numbers grow. Similarly, I would guess that growing back a single hair cell wouldn't do anything, you'd need to grow a bunch.

 

Sorry for the newbie question, but given that tinnitus does not seem to be the main focus of the FX-322 drug, is there indeed good reason to suspect that FX-322 will be effective for tinnitus relief?

Also, is there good reason to suspect that those with tinnitus but without appreciable hearing loss will be able to access the drug once it is released?

I certainly hope the answer to both questions is "yes"!

 

Interesting job posting.

https://www.frequencytx.com/jobs/co-op-delivery-innovation/

"Work closely with project scientists to carry out experiments to develop novel polymer-based, small molecule inner ear drug delivery systems."

Sounds like they are working on a better gel.

 

You're right. I've met several of them and am blown away how stupid they are. Most of them are good for nothing more than doing a hearing test and fitting hearing aids. Hopefully drugs will eliminate this useless field of medicine soon enough.

 

Some only have hearing loss in one ear.

 

Will this delay the release of FX-322?

 

They have already reported that they saw anecdotal reports of tinnitus improvement from the Phase 1/2 trial. Noise-induced tinnitus is very likely to be either hair cell loss or synapse loss - it is most likely a combination of both to be honest. So yes, I think there's good reason to believe it will help with tinnitus.

I'm unsure about access - I presume this won't be a problem though.

 

Severe range.

 

No.

 

I seem to remember you at one point were considering cochlear implants. They said in a recent interview that @serendipity1996 posted that people in the cochlear implant range may still need hearing aids afterward (where people in the hearing aid range could potentially just get the drug).

A zero word score probably was flagged as in the cochlear implant range and as they don't give you hearing aids after to test your word scores, I could see why this would be an exclusion factor, unfortunately.

 

Yes. Yes.

 

No. I would highly doubt they would restart the whole trial with a new formulation. But it is possible they could work on a version 2.0 for an abbreviated trial after version 1.0. Or they need someone to plan mass production.

 

Thank you, @Diesel and @serendipity1996.

That gives me more hope.

 

It will certainly be nice once all those audiology/ENT offices with "tinnitus" listed on their websites and brochures are able to do more than just say, "welp, good luck!" and actually treat us.

 

No kidding. The large number of people who have this affliction and small number of people who seem to study it is a baffling disconnect.

 

I had an audiologist tell me that I would always have music in my heart and memory and that the human spirit transcends any condition. At least that was less useless than "it's all in your head" as some have gotten but still...

 

Ugh... in a way, that's kind of worse.

 

I dug through the paper by Thornton and Raffin (attached) that they cited in their Phase 1B paper that explained their methodology for assessing clinical meaningfulness of word recognition (WR). Basically, here's the issue:

The tests consist of n=50 words and are randomized. When comparing average performances (percent correct) across tests, the tests are deemed "equivalent" difficulty. However, it's not true that for each individual person, the tests are exactly the same difficulty. The further the percentage is from 0 to 100 (extremes), the more this is true. In other words, if I score 50%, I'm more prone to variation than if I scored 100%, as I could have scored 100% so easily that it doesn't matter if you change the test on me.

In their assessment of being "clinically meaningful" WR, they dropped the patients with baseline scores below 90% because of the ceiling effect. This is because if someone has, say, a 98% baseline performance and they receive the drug and improve to 100%, it's basically impossible to know if that improvement is just from changing tests.

In the following picture, the dot lines create a 95% confidence interval around the dashed line. Thornton and Raffin used a scheme to show the effects of repeating tests. They established 95% confidence interval ranges that Frequency Therapeutics basically just referenced for their data set. The dashed line is the assumption of no improvement. Notice all of the clustering on the top right. It is too difficult to put these people in the running for clinical meaningful because of the variation.



What you have is the opposite, which is the floor effect. Say you take the test at baseline and score 0% and take FX-322 and improve to 2% (1 word). How do we know it wasn't just luck or that you got the right test? Moreover, what if you're at 0% initially, but are no where close to even 2%. Maybe FX-322 helps, but you're so bad off that you only jump to 2% or even stay at 0%. For this reason, the floor effect is a problem. They took care of eliminating the floor effect by working it into their exclusion criteria.

 

It's absolutely hair cell or synapse loss. There is no doubt that it isn't.

 

Just saw a commercial for the COVID-19 vaccine where they said the vaccine went through all the safety precautions that any drug would. Why do FX-322 clinical trials have to take so long in that case?

 

I think people have been taking that snippet too literally. What he seems to be saying in a general way is that they expect FX-322 to improve hearing. The appropriate treatment option after that may change depending on where you end up on the curve. Like you, I'm encouraged that he thinks that FX-322 might help people with close to profound hearing loss.

You asked for an audiologist and you got Khalil Gibran? Cool.

 

What sources of cochlear damage would we not expect FX-322 to heal? I would imagine impact related trauma and congenital disorders it would not. Would we expect typical viral and ototoxic damage to improve with FX-322 or just noise induced damage?

 

I’m guessing anything that would cause hair cell loss would be helped by FX-322. If it’s not from hair cell loss, FX-322 wouldn’t help imho.

 

FX-322 is intended to treat Sensorineural Hearing Loss caused by Aging, Noise, Disease, and Ototoxic Medications.

 

Priorities. COVID-19 has honestly shown how disgustingly cruel the medical field is. I know of two people who died because the hospital would not do a simple surgery due to COVID-19. It's also disgraceful that multiple companies have various vaccines available and COVID-19 has been known about for roughly two years. A bunch of horseshit!