Frequency Therapeutics — Hearing Loss Regeneration

I know I'm probably beating a dead horse by now but I have a slight feeling that there might be long-term improvements in the trial subjects, maybe as far off as 3 years.

It's possible that these drugs start off a very long and slow healing process and it wouldn't be reasonable to expect improvements in 90 days. It seems that hearing restoration is a 3-step process of hair cell regrowth, nerve repair and forming connections, and getting your brain to process these sounds again maybe with time, brain supplements, BDNF, shock therapy, etc. There can be severe tinnitus flare-ups while the brain is trying to figure out how to do it and it all can take months or years.

There might be a lot of progress if Spiral Therapeutics or another company continues this research and has the money/resources to be in it for the long haul and see through regrowing hair cells, repairing nerves/connections, and helping the brain remember how to process.

Frequency Therapeutics had a good thing going but it's not enough to regrow hair cells without following the other steps. It's like a whole package.

 

They did a one-year follow up on the Phase 1/2 trial participants and the effects at 90 days had significantly lessened. They did a similar long term follow-up for the Phase 1b open-label study (I think it was at the 6th or 9th month mark) and a similar thing was observed, though I think 1 person moved to the statistically significant category (while others fell out of it).

FX-322 doesn't work in humans. And if it does, there's some important piece to the puzzle that hasn't yet been figured out. I think it's telling that Spiral Therapeutics said they wouldn't bother with it.

 

Gradually - left-sided hearing loss that has progressed to severe/profound across its entire range. My right ear is almost fully in normal range, I'll only consider a cochlear implant if my right (good) ear can't hack it anymore either and/or future iterations of a cochlear implant are significantly better than the current one. In other words, when I can't function whatsoever due to hearing. That is not currently the case.

Tinnitus is annoying but it's something I got used to. Let me put it this way - I have a dip in my right ear of 25 dB at 4 kHz, that's my worst drop on that ear, I have more fears over that one than any kind of care or anxiety over my left ear by this point (because that's already been medically examined thoroughly - tests, MRI scans, etc.). That is how perfectly capable I have been living life with just one hearing ear since my other ear went to shit.

 

I think what was needed is a separate drug after to help with nerve connections and then something for the brain to help it process the new sounds again.

 

If that’s the case, I would like to see Spiral Therapeutics take some patients who got a single dose of FX-322 to see if the efficacy is better with OTO-413 & FX-322 combined or the same with just OTO-413 only, but unfortunately that won’t happen.

I wonder what criteria Spiral Therapeutics might add. I don’t think they would let anyone in the trial who had FX-322.

 

Can anybody give me a brief summary where the biotechs are heading next with hair cell regeneration?

I lost money on the first FREQ failure and did not buy in a second time. I have followed tinnitus research loosely for 10+ years and have seen the massive increase in research, although it’s not unusual for me to be disappointed for each failure.

It’s almost like Dr. Susan Shore is the last person left to save us from this affliction.

Forget XEN1101, that won’t be here for years.

I need some hope!

 

Growth factors and molecular therapy still seem like the most popular solution.

Perhaps you'd be interested in doing some research on IGF-1. It's already FDA approved for other purposes, and research on humans has shown it is more effective for SSHL recovery than steroids. Other research on mammals shows that it's effective at hair cell and support cell proliferation, as well as repair of hair cells and ribbon synapse.

...Now if only there was clinical research on IGF-1 for chronic hearing loss that has lasted for years. People really should push for that.

 

It's possible that FX-322 was successfully restoring hair cells but the brain is not able to pick up that new input without some kind of external stimulation.

 

There is absolutely no reason to assume that the reason FX-322 failed is because the supposed regenerated hair cells had no nerve endings. Hair cells without nerve endings result in hidden hearing loss. So you would expect a shift in audiogram results, but problems with hearing-in-noise for patients who got FX-322. Instead, FX-322 did not result in any shift in neither metric. It’s thus far more likely there was no regeneration in the first place.

 

Gene therapy is one avenue that's being explored. The two main companies (that I'm aware of) in this space are Decibel Therapeutics and Akouos. Akouos got acquired by Eil Lilly last year for a huge premium, which tells me that the major players see this as a fruitful avenue. Both companies are taking the same approach of going after lower hanging fruit first (smaller diseases), learning from it, and then advancing on to tackle larger diseases (with both aiming to have something for general hearing loss). This can be kind of frustrating, as it means a cure isn't on the horizon in the next 2-3 years, but I think its a smart approach and it ultimately gives us a higher probability of a cure being found in the next 5-10 years. Decibel Therapeutics has an interesting patent on OHC regeneration, I think if DB-OTO is successful (we'll know early next year), we'll start to hear more about their OHC regeneration program (just my own speculation though).

 

To add to that, studies show that stereocilia proliferation include new ribbon synapses... So it's unlikely that a serum that's supposed to turn progenitor cells into stereocilia wouldn't have them, unless I am mistaken.

 

Seems like someone has thrown a curse at the inner ear pharma field. First Auris Medical, then Otonomy, and now Frequency Therapeutics. That's +10 years of developments wiped away just like that. Hard to believe...

 

This post perfectly sums up what many of us have been saying for years. People were convinced about FX-322, believing it to be a miracle cure before any of the results had even come out. I still remember the days of @JohnAdams wanting a petition for its immediate release on special measures because of the overwhelming “evidence.” This is the unfortunate effect of getting all one’s information from an echo chamber. Even though their results were terrible, and the management had dumped all their shares on the retail traders, many continued to defend the company.

People’s analysis became too emotionally biased rather than objective, and that’s when I stopped following this thread.

I feel so sorry for all those who put all their eggs in this basket.

100%.

 

If you were going to put forward a cautionary view back in the day, first you had to get past @JohnAdams. He reacted aggressively to any "negativity". Then you were made to feel like you were messing with people'' mental health. So it was never the best environment for having a balanced discussion.

I really hope that for the really severe sufferers amongst us, the years of hope were worth the disappointment at the end.

 

His conspiracy theories were a bad influence on my anxiety back then and it really disturbed me how far he was willing to go to slander/insult people. Looking back, I'm amazed with how they tolerated with him for so long.

Although I'm now convinced he handled everything wrong, I'm grateful on how he was willing to try the PRP treatment. I just wish he properly did audiograms like everyone wanted.

Unfortunately, although I believe my research on PRP and stem cells is sound, his behavior seems to have tainted the reputation of them.

I've recently become convinced that molecular therapy likely might not work without PRP. What I read about growth factors being necessary for stem cells could likely apply to progenitor cells as well, and considering what growth factors do and how they seem to not be properly naturally provided to the cochlea, finding a way to properly distribute them in required levels may be necessary regardless of the method of stereocilia regeneration.

 

I personally know two people who have had stem cell exosomes administered intratympanically (1 week of IT shots, a shot every other day, so either 3 or 4 shots, I forget). No improvement. One shot was around 0.5 ml, containing 50-100 billion exosomes.

All that aside, the PCA approach worked with and without exogenous growth factors in vitro.

 

Stick this thread in the archives with Lipoflavonoid.

 

Principle Component Analysis?

 

This may be one of the reasons why FX-322 failed?

Defective mechanosensory transduction of the new inner hair cells prevents hearing recover in the damaged cochlea

New IHCs but no hearing improvement.

 

Was @JohnAdams heavily invested in the company? Just curious.

To your last point: We really do need something to look forward to. Life was so nice back then during the halcyon days of Frequency Therapeutics when we "knew" (ahem) that we would all be young again.

 

Progenitor Cell Activation, what Frequency Therapeutics were doing.

 

So is the next move for scientists to figure out how to bypass this? How long is that going to take?

 

Yes, this is a weird situation where much of the anecdotal reports on growth factors on Tinnitus Talk do not match the results of the scientific studies, including those that involved human subjects. I have wondered why this is. It would be unrealistic to assume all these studies were fake, but the reports here on the forums should also be respected whether anecdotal or not.

 

I don't think so. I think he was suffering. Paranoia and aggression was part of how he responded.

You know, thinking about it, I agree with you.

 

Could you please provide any publications on intratympanic exosomes then? I'm talking human trials, I do know they seem to be effective in animals. However, hearing-wise, they did nothing to me (systemically at very high doses). I will try growth factors (BDNF and/or NT-3) intratympanically eventually, do not get me wrong, but I do not have extremely high hopes.

 

I would give these American biotech vultures a wide berth. I've just had an email from the University of Sheffield who are starting trials on progenitor cells in humans in 1-2 years, using cochlear implant patients for delivery. They have a company called Rinri Therapeutics, who will be involved. We generally don't do stock markets in the UK. It's a vulture class of doing people over, it seems.

You will not be aware of this as the University of Sheffield spend money on research and not slick PR, which has done many over and left them feeling foolish and licking their wounds.

Stick with universities and public funded biotechnology, not these brain washing biotechs floating on the stock market.

Only the University of Michigan has delivered anything of value.

Bury this thread...

 

Re: "Was @JohnAdams heavily invested in the company?"

A few clicks by some knowledgeable 'puter-finance-geek/nerd/punter [that shure ain't me] would answer the question as to how much stock he owned back then when he was blasting away at the unbelievers.

But I'm sure you've observed in day-to-day life. People can play a game for fun and it's just fun.

But once they put down some money... a dollar, 50 cents... sometimes their pride gets involved and it takes on an atmosphere that's much more serious. They don't want to appear to lose. Their self-image gets involved, maybe.

Just something to bear in mind in the entrepreneurial approach to biotech startups.

Am I knocking this method of solving the tinnitus/hearing problem? Well what else have we got?

 

Thanks, I still remember the one or two who notoriously disagreed with me in this thread earlier on (as I personally lost faith in this drug during the initial Phase 2 readout) but there is no point in a "told ya so" approach because we're all losers in the grand scheme of things with this involved - financially, mentally, physically etc

That and the fact the people who tried to stretch the reality and every outcome to date in relation to their hopeful thinking did also try a scientific, logical but mostly hypothesis based approach with their reasoning. So really it's all good.

I did, however, find the phase of this thread when people were completely disregarding audiograms altogether stupid and mostly just showed that there are a lot of people with manifestations of this condition without showing much for it on an audiogram. I think Frequency Therapeutics shifting the goal posts at one point regarding audiogram improvement expectations from this drug also made people think a certain way. Try having visible loss on an audiogram relating to your hearing loss/tinnitus that has worsened over time and you'll understand why audiogram results do matter.

 

'Hypothesis based approach'. I don't know where you pulled that. If you were to ask us whether the earth is flat or ball-shaped, I bet we could produce evidence equally scientific and logical in support of both hypotheses. Since we're now doing a 'hypothesis based approach'.