Frequency Therapeutics — Hearing Loss Regeneration

Just checking in to say I still love you guys and that I’m sorry that I’m not nearly as active as I once was.

IIRC, it was Chester and his ears were cleaned by hand.

 

I’ll have to find it but I don’t believe so, it just gradually faded after the wax removal but took a long time to resolve. I want to say it was a manual cleaning.

 

You have your finger truly on the pulse of forum anxiety.

 

Ya this was the same one - nice recall.

 

They don't. I wish people would stop calling them ototoxic as well. I remember a Doctor in the Doctor's Corner section (one with tinnitus himself) and a tinnitus expert clarified that antidepressants aren't ototoxic.

Drugs that are actually ototoxic (i.e - cause hair cell death) are actually not that many.

Drugs that can induce tinnitus is a whole other thing altogether, but inducing brain noise (that even normal people can encounter under certain circumstances) isn't technically toxicity.

 

That's interesting but how was he able to make the connection to the ear wax he removed a year prior in that case? There must have been some initial fading, no?

 

It has to be, otherwise I do not think I can go on.

 

The good thing about this trial is that it will show whether IHC and OHC will be fixed in the areas where FX-322 does reach. If it significantly increases the audiogram in the area above 8 kHz it may mean that only the delivery method needs to be refined. Without deep understanding of the topic I really hope, that this is only a very small problem compared to finding actually a drug that works. On the other hand: why has FREQ not already sooner worked on extended release gels if it would significantly increase the benefits of the drug and might be comparable easy...

In this regard: if the FX-332 1.0 (with current delivery method) were already on the market, how hard would it be to just make an updated version with higher concentration but much slower release in the future? Will it take as long as the current trials or will it be very quick to release?

One thing that still bugs me is how my grandfather has in his audiograms -60 dB hearing but no tinnitus whatsoever. And here I am with only at most -30 dB in the standard range audiogram with a bothersome tinnitus...

 

Does anyone think that regular head movements and listening to various sounds can help FX-322 to penetrate further in the cochlea and target more frequencies?

 

This has been up for 19 hours on Frequency Therapeutics' Twitter but I don't recall seeing it in the thread; another mini-animation, this time about how the ears tune and filter sound.

 

@spacehunter, maybe tinnitus occurs when the loss of hair cell is immediate and the brain amplifies the signal to hear better?

 

They have stated that they are indeed looking at alternate/upgraded delivery methods.

 

Probably not.

 

When I first started on this forum I became paranoid over everything being ototoxic. I do wonder how many of the items fingered for this actually are rather than being just paranoia on tinnitus sufferers' part.

 

I once had a fully 100% impacted ear from ear wax; literally zero sound could get in and as a result I was 100% deaf in that ear. It was maddening and made the tinnitus seem much louder because it removed ambient noise. After a week I had it cleaned out (the one time microsuction didn't spike me) and after that, it felt like blissful silence for a little while afterward--days or weeks, I forget how long. I doubt the person you're referring to had it that bad though.

 

The forum is teeming with non-scientific anecdotes. Everyone's spike or recovery is due to the last thing that person did. That's what happens when research is too scarce; we're in the dark ages. Hopefully not for too much longer.

 

The main culprits for true ototoxicity seem to be limited to select drugs, e.g. certain antibiotics, mostly the aminoglycoside class but also Azithromycin, as well as certain chemotherapy drugs, e.g. Cisplatin.

 

Hi guys, I'm relatively new here and I only have mild tinnitus but I would be lying if I said it hasn't affected me.

I wanted to ask, for someone like me with -5 dB hearing loss at 4 kHz, what are the chances of FX-322 helping me? As you can see, I have minimal hearing loss. Does FX-322 have a higher chance at helping bigger hearing losses or is it the same?

Sorry for the clunky English, I'm from Greece!

 

I read the paper along with the supplemental materials to gain a better understanding of the PK methods. Basically, they used the guinea pigs to (more invasively) draw perilymph from the apex after 1 and 3 hours in successive samples in order to compute the half-life elimination rate in the Scala Vestibuli (SV) and Scala Tympani (ST). They also used the guinea pigs to gather middle ear data such as the elimination half-life from the Round Window (RW) niche, as well as RW Permeability (into ST) and Stapes Permeability (into SV).

From the humans undergoing cochlear implant surgery, they really only gathered the gel from the middle ear and 1-2 microliters of perilymph. They used this small sample of perilymph and middle ear gel to compute the same parameters that they did for the guinea pigs -- namely, middle ear half-life, RW Permeability, and Stapes Permeability. However, importantly, they assumed the elimination half-life in the SV and ST were the same as for the guinea pigs (Supplemental Figure S3). This appears to be the biggest value of the guinea pigs, if I am understanding this correctly.

From there, they used software to simulate and make predictions of CHIR and VPA concentration with respect to space and time for both humans and guinea pigs.

All of this is to say the following that's noteworthy:

• It was slightly unclear in the paper whether the concentration of CHIR and VPA in the EHF range was overkill or not. They say:

"CHIR99021 and VPA achieved concentrations in the most basal, or extended high-frequency (EHF) region (Supplemental Figure S3), that were consistent with reported regenerative activity in mammalian cell and cochlear explant culture (8)."​

Essentially, whatever was achieved in vitro was consistent with concentrations in the most basal region. It's still not clear to me whether or not it was more than they needed for sufficient PCA. I'm going to assume that since they are experts, it is probably right around the exact amount needed.​

• Unless I am misreading, they are assuming that the SV and ST flows in the perilymph are similar between humans and guinea pigs. The major difference (and why the graphs look different for CHIR and VPA) is the anatomy of the cochlea in terms of shape and volume. But the physics inside is assumed to be similar -- at least similar enough to use the same half-life elimination parameters inside the ST and SV.

I don't have nearly enough knowledge to know how justified this is. I'm assuming it's justified since they are doing it, but it does leave some uncertainty.​

• Regardless, there weren't 2 or 4 doses applied to the guinea pigs in cohorts so there's a lot of uncertainty, even under the assumption that humans and guinea pigs are similar.

I still see a lot of uncertainty, unfortunately.

 

Stapes permeability? Does that mean some of the gel flowed back out of the oval window or am I missing something here?

 

-5 dB is almost perfect hearing (perfectly normal). Anything down to -20 dB is considered normal hearing. Most audiogram tests aren't even accurate enough to differentiate -5 dB, your tests could vary from day to day.

I really doubt FX-322 would help you if that's what you think is the cause of your tinnitus (which I doubt it is).

I have -50 dB @ 4000 Hz in both ears from noise exposure, but only got tinnitus after I had a trauma (slap to the ear).

 

Yeah, the first sentence from the following section of the published paper seems to indicate so. I'll admit that I'm pretty confused though. It seems like the main focus is on the RW niche and ST perilymph. However, in Supplemental Table S3 (Kinetic Parameters for Humans, attached), it seems like the Stapes Permeability score (for both CHIR and VPA) is higher than RW Permeability. I have absolutely no understanding of what any of this means so I can't comment on what this means. It does appear that there is some interest in what happens at the Stapes though.


Measurement of Entry Rates Into Perilymph With RW Niche Application

Drug entry into perilymph at the round window (RW) and stapes is driven by the drug concentration in the middle ear (22). Drug concentrations in samples taken from the RW niche were found to decrease with time. Exponential curves fitted to these data indicated elimination half-times of 56.4 minutes and 48.6 minutes, respectively, for CHIR99021 and VPA (Supplemental Figures S2A & S2B). Exponentially declining middle-ear concentrations were used to derive simulations of drug movement into perilymph in which calculated perilymph concentrations were compared to perilymph sample data following RW niche applications.

Perilymph samples were collected from the guinea pig LSCC or cochlear apex at either 1 or 3 hours after CV application to the RW niche. For sampling from the cochlear apex, serial samples, each 1ml in volume, were collected as the perilymph emerged after perforating the apex. The serial samples allowed drug distribution along the length of ST from apex to base to be derived. Sample perilymph drug concentration data collected 1 hour after RW application are shown in Supplemental Figures S2C & S2D. The highest drug concentration of both FX-322 components was found in samples originating from basal regions and decreased apically. The gradient along ST was most pronounced for VPA.

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It's too early to tell. Let's wait for the Phase 2 results to draw conclusions.

 

They could have dips and loss in the frequencies higher than 8 kHz causing the tinnitus.

 

I wonder what happens to the drug in the endolymph? Assuming it enters at round window and stapes that it must also flow into the endolymph.

 

What else can it be? The only time I listened to headphones was in late January 2020 and it wasn't even particularly loud over a month period. Anxiety can't cause tinnitus on its own, right? You need hearing loss. I also did an MRI and it was clean.

Here is my audiogram from January 2021. There is no hearing loss in the 6 kHz or 8 kHz range.

 

Was your hearing tested in the extended high frequency range? IE: 8 kHz - 16 kHz.

 

Go to an audiologist and measure your hearing up to 16000 Hz or 20000 Hz. Then you will know for sure if you have hearing loss down to 20 dB at the higher frequencies.

 

Wow your audiogram is pretty good, but it tests very few frequencies and it doesn't get into much else. Remember the hidden hearing loss, and some of the other myriad frequencies that it doesn't test could have dips.