Frequency Therapeutics — Hearing Loss Regeneration

My tinnitus fluctuates quite a bit. When my tinnitus is active I notice an increase in hyperacusis. My tinnitus has slowly improved since it started 20 months ago. As my tinnitus has improved the fullness in my more damaged ear has dissipated with a decrease in hyperacusis. If FX-322 can cure or lessen tinnitus it should take care of hyperacusis, at least in my case.

 

This is what I’m hoping as well. If you look at the Pipeline presentation the amount of synaptic regeneration was highly dependent on dose. Frequency could very well find that the 4 dose cohort show exceptional gains.

 

Will FX-322 work on someone that was born deaf or just on people with hearing loss?

 

That’s an interesting question that I’ve thought about myself. Some deafness at birth is the result of genetics, though I haven’t looked into the specific mechanisms. I would guess that if a person simply doesn’t have progenitor cells in their cochlea then FX-322 won’t do anything for them. If the deafness has some other cause not related to genetics then maybe it could work.

 

It would work for sensorineural hearing loss, but there are other companies which are developing treatments for genetic hearing loss, if that's the cause.

 

I’m hoping it will be based on the current theory driving the underlying pathology of both pain and loudness hyperacusis.

Loudness hyperacusis is thought to originate from synaptopathy of the A1 nerve fibers connecting with the IHC. Although FX-322 is not targeting synapses directly they have said that they have seen “meaningful connections” reestablish with the IHCs. Although for true synaptopthy we might see better results from Hough or Pipeline.

For pain hyperacusis, another forum member explained to me that sometimes when OHC are damaged they begin to leak ATP which affects the A2 fibers that connect to these OHC. It’s thought that this ATP stimulates the A2 nerves, which are involved with pain sensations. If you can repair the OHC hopefully the ATP will stop, and the stimulation of the nerve will cease.

I think someone mentioned a while back that a person in the REGAIN trial experienced improvement in both their hyperacusis and tinnitus, so I think there’s a good deal to be optimistic about.

 

I do not think this will work for cases of genetic deafness because that usually isn't due to just an absence of hair cell with progenitors in place.

 

So is FX-322 the only drug in the pipeline that shows promise?

The negative report of worsening of OTO-313... makes me wonder if OTO-413 will be the same animal with the same possible negatives.

So there are two nerve stimulators which attempts to reprogram a brain without an instruction manual... and one drug that shows promise and two drugs that may make things worse?

 

Hm, well not really. The good news is that OTO-313 has nothing to do with hearing regeneration of any kind. It is an analog of an NMDA antagonist they had been trialed in the past for tinnitus and either was ineffective or in some cases, was shown to have deleterious effects.

To clarify, OTO-413 is for synaptic repair. As is Pipeline and Hough. From what I understand it is also a byproduct of FX-322 but FX is focused more on OHC generation, rather than synaptopathy. These are not affecting the brain, but are addressing the physical damage in the cochlea. We don’t really know how the brain will react to increased input for tinnitus but Hough said their preclinicals were promising.

And now you have people like Chen who is trying to use our own DNA to regenerate both IHC and OHC. If you read the paper, this guy has found a way in animal models to takes a blasted on cochlea, flattened, with no supporting cells, and get it back to functional shape. I doubt he isn’t also looking at synapses and nerve fibers.

And while I’m leaning towards regenerative medicine I think you’re underselling the science that has gone into bimodal stimulation. I recommend reading Susan Shore’s papers where she explains the whole process or at least the YouTube video from 5 or so years ago that explains the underlying mechanism of bimodal stimulation. It’s nothing to sneeze at, and I think we should respect the amount of work that went into developing that technology.

 

In addition to the work being carried out by Hough and Pipeline there is the efforts of Rinri Therapeutics, a UK-based biotech firm founded last year by Professor Marcelo Rivolta! Their focus is also on researching and devising treatments to repair the auditory nerve. Looks promising! https://rinri-therapeutics.com/

 

Has anyone here been accepted to the trial for FX-322... or did I read the recruitment wrong?

Thanks.

 

Plenty of people here have been knocked back. If you're looking for a mole, I don't think it's going to happen. If I were accepted you wouldn't hear a peep out of me. You've got the NDA, and consider this: Frequency Therapeutics is now a publicly listed company. Any rumour about the current trial will shift the share price. Investors stand to gain or lose millions. I wouldn't want to be on the end of a multi-million dollar lawsuit. How about you?

 

Don't believe so, most likely maladaptive plasticity the brain trying to fill up the gap in lost hearing due to sudden damage to hair cells by turning up central input. Fix the cochlear damage, the hyperacusis should improve.

 

Since October when the study opened, I couldn’t find anyone to say they were excluded, if that’s what “knocked back” means to you.

If you were accepted, you would be afraid of a lawsuit on an anonymous website?

On Dec. 2nd you said, “hey will bring this about how? The success or otherwise of FX-322 is in no way affected by any views expressed in this forum.”

So I take it no one has been accepted?

Or everyone that has been accepted is now in an underground bunker looking out for black helicopters?

Thanks.

 

What's the prevailing scientific consensus on hyperacusis, do you know? Is it said to be due to damage to the OHCs or the auditory nerve and cochlear synaptopathy? Or both? From the research I have done, it seems that a lot of progress has been made over the last decade in identifying the potential underlying mechanisms of hyperacusis and nose-induced pain (noxacusis) in particular.

 

Call me a heretic, but I think the entirety of tinnitus and hyperacusis originates at the ribbon synapse right at the cochlea in cases of noise damage.

 

This is the exact same thing I've experienced so far.

 

If you’re curious you can check out my comment above.

Basically -

Loudness hyperacusis = syanptopathy and loss of A1 nerve fibers.
Pain hyperacusis (noxacusis) = leakage of ATP from damaged OHC on A2 nerve fibers

But these are still theories at the moment made from a small number of (distinguished) researchers. I wouldn’t go so far as to say there is any true consensus because although hyperacusis has come a long way we still have a lot of work that needs to be done in the area.

 

@FGG and at least one other (@Rb86?) were not accepted.

That's right. It's not. The short-term share price of the company might be however. Markets respond to rumours of inside information.

No-one's said so.

Yeah, well some of us have to because we wouldn't hear them coming.

 

Ok fair enough... lol

They don’t have any recruitment sites in the state I live in so that’s why I asked because I didn’t know if there was any travel exclusion like Dr. Shore’s.

 

Yep. It was me and the other user you mentioned tried to enter the trial and were both rejected due to our audiograms. I got the impression there was a minimum average pure tone loss (or distribution) they were looking for and neither of us qualified.

I was told I would have to sign an NDA if I did qualify, though, so if there are users in the trial we likely wouldn't know.

 

I've been on the fence about applying because I'd have to drive from Miami to Boca Raton many times. I really wish they had put it down here. I would have applied as soon as it started. I'm still thinking about it.

 

Yep I was rejected. 35 dB loss at 6 kHz. Tinnitus in both ears. I don't know why I was rejected and they wouldn't say either.

 

Yikes, ok... thanks for bringing me up to speed... did they tell you that you were rejected... or did they simply never reply to you again? I’m new to these clinical trials and doing my best to keep up.

 

As in... your audiogram was too good?

 

I was also rejected but what’s interesting is they didn’t seem to care that my audiogram up to 8 kHz was completely normal (less than 5 dB across the board). I only have a single 30 dB notch at 16 kHz in both ears and 15 dB loss at 14 kHz and 18 kHz. Given that they might end up focusing on high frequencies this wasn’t entirely surprising but I was a bit shocked that I really only needed a single notch at 14 kHz to get past the audiogram screening.

They told me that I was rejected only because my audiogram was taken 3 months ago and they wanted at least 6 months of hearing loss that was documented. They also wanted me to pinpoint the source of the hearing loss (which I could) and we’re implying that if it wasn’t noise induced (mine was) they didn't really want to take you, but that was me trying to read between the lines.

Having tinnitus wasn’t a problem for me. I just brought it up casually and they were like yeah that’s not an issue.

 

It was implied, yes. I have 55-60 dB loss at 12000 Hz and mild loss at 250 Hz and nothing in between. I was never tested above 12000 Hz. There seemed to be an average they were looking for. I got no more info than that.

 

They told me I wasn't a match. I still don't know why not. I mean it's not like I can go back and fake an audiogram to make myself a perfect candidate. I just wanted to know why as I have all the requirements they list they're looking for. But, that's life. I'm just hoping I can hang tough until these drugs come out, at which point mine will have either faded to zero or they will know a lot more.

 

Maybe it's the way you got it? They're looking for mild to moderate loss due to noise exposure or idiopathic causes. However I feel that many causes get classified under idiopathic for lack of a clearer understanding or lack of the doctor's willingness to find out what was the cause.
Basically to me the inclusion criteria say: tinnitus because of noise or just about ANY other cause. So it would seem you would qualify.

 

What's interesting is they didn't get to that part of the interview before i was disqualified. I might have been disqualified based on that but my audiogram disqualified me first.