Frequency Therapeutics — Hearing Loss Regeneration

Yes. They keep a presentation updated on their website regarding the Phase 1/2 trials from a single dose (now they are testing up to 4 in the Phase 2a).

https://investors.frequencytx.com/events-and-presentations

In the Phase 1/2, significant improvements were seen in word score both in a silent background and noisy background. Some participants also showed a 10 dB improvement as low as 8 kHz. Unfortunately they did not include a high frequency audiogram in the Phase 1/2, so cannot provide more data on the actual level of improvement.

I am not a scientist; but I would assume that restoring the hair cells at this high frequency would at the very least provide the auditory system with more fully functioning cells to work with; not amplify sound at those frequencies. So, with more working cells, the patient is able to be more sensitive at those levels, but also may notice a reduction in hyperacusis/tinnitus if it is in those frequencies. Or who knows, may notice a reduction in tinnitus wherever it is experienced just because the auditory system is receiving better quality signals from a larger quantity of new cells.

Two hypothesis that Frequency is hoping to learn from multiple doses in the Phase 2A, is whether FX-322 will penetrate more deeply into the cochlea, there by increasing growth in lower frequencies (Below 8 kHz); or will cause more patients to show improvements at the same ranges as the Phase 1/2 (8 kHz+). Or potentially both.

Some suspect that the delivery mechanism is the issue penetrating the cochlea and not the drug itself. Frequency has mentioned a number of times that they have been able to regenerate cells at all frequencies in cochlea in vitro. So, I would argue this is a pretty impressive first step.

 

Just wondering. Why don’t you think improving that range will make much of a difference? There weren’t reports about distorted hearing from patients who received FX-322.

 

First of all you have to remember that the limited frequency range stems from the vehicle they use to deliver the drug, not the drug itself. So even if 1. gen FX-322 doesn't reach sub 6.5 kHz, there's guaranteed room for improvement with reformulations (as other companies already managed to cover the whole cochlea).

Also improving high frequencies isn't useless at all. They play a big role in word recognition. And obviously there's the hope of eliminating or at least reducing tinnitus which for most people is in those ultra high frequency areas.

Some patients had a 10 dB improvement at 8 kHz (and probably more at the higher, untested frequencies).

However you have to consider that the trial wasn't for efficacy but for safety. So they only got one shot. Right now they are testing up to 4 shots.

And finally you have to remember that dB is logarithmic. A sound 10 times more powerful is 10 dB. A sound 100 times more powerful than near total silence is 20 dB.

 

Dude 6500 Hz-20,000 Hz is massive. I would imagine it's the majority of human hearing range.

 

@Xojo, Like you, I was hoping for improvements over a wider range of frequencies. On the other hand, doubling word recognition score isn't too shabby. I could really use some of that right now, even with hearing aids.

From memory, 4 out of 6 with moderate to severe loss showed about a 10 decibel improvement at 8 kHz. Someone will correct me if that's wrong.

Yeah, don't know how much I'd pay for that level of improvement. It might be out of my reach.

 

Intratympanic injections have the disadvantage of having the drug concentrate in the base of the cochlea (high frequencies). So it’s not so much a problem with the drug, but with the delivery method. The drug works with supporting cells and supporting cells are no different in the apex of the cochlea (low frequencies). A better deliver method down the line might yield better results in the lower frequencies. Also, it remains to be seen if four (or more) injections - which they are testing now - will result in hearing restoration in some of the lower frequencies.

I do agree that if this drug happens to only work for high frequencies (given the current delivery technology) and you have a patient with hearing loss across all frequencies, the sound quality as a result of this drug might still not be that great. You’d still have to wear a hearing aid with amplification for lower frequencies in order to have decent sound quality. But natural high frequency hearing is always better than hearing aid amplification.

 

In phase 2a they are giving 4 injections which should demonstrate deeper diffusion into the cochlea resulting in lower frequency restoration. The drug has shown to regenerate functional OHCs and IHCs; even a modest db boost using the natural biology of the inner ear and the modulating effect of OHCs will have some positive impact. Curing tinnitus is all about restoring input.

 

Is it safe to say that by 2025 we can expect several tinnitus drugs to be released to the public?

 

No. It's not safe to say anything. BUT, I'm optimistic, and I believe a good bit more knowledge will be had by then.

 

Safe? No.
Likely? Absolutely.
Sadly we can't predict the future and making empty promises is the last thing anyone needs.
But it does seem like most of the drugs that are developed at the moment aim for mid 2020s.

It would be ridiculous if all of them fail, especially since most of them have different approaches.

I assume that by 2025 we'll at least have FX-322 and maybe the Hough ear pill (since Justin told us they aim for 2023-2036 if I remember correctly).

 

I would not say it's safe to say that whatsoever... that's a very guarded expectation. I'm not sure that a 10 dB improvement is enough. I mean we are talking about hair cell regeneration, it should be like 30-40 dB at least, and not for 4 out of 6 people, but like 9 out of 10 people.

 

A 10dB improvement equates to 4x (4 times) the sensitivity in hearing. In the phase 1/2 it specifically was identified at 8kHz, the highest range tested in the standard audiogram used. Since the concentration was higher than 8kHz, at the end of the cochlea, it stands to reason that gains were higher than 10dB from 8kHz - 20kHz.

Also, 6 of 6 saw an improvement in word score after receiving FX-322. 4 of 6 were considered statistically significant. Frequency has mentioned numerous times that ALL (15/15) recipients of FX-322 (both with mild and moderate+ hearing loss) saw improvements over the testing period.

I bet they are kicking themselves for having so many participants with mild hearing loss; as the ceiling effect clearly reduced the improvement outcomes.

 

Wow, thanks for all of the replies! Your responses have given me a little more hope to hold on to.

I'm just basing it off of how things sound when you significantly boost that range on an equalizer. It makes the audio sound like it is coming out of a cell phone speaker.

Human hearing is about 20 Hz to 20,000 Hz and while 6,500 Hz to 20,000 Hz appears to be most of it, 1,000 Hz is actually the real middle of the full range. Low frequency range is around 20 Hz to 600 Hz and mid frequencies are 600 Hz to 2,000 Hz. 2,000 Hz and up is high frequency.

A treble dial on a stereo generally boosts from 2,400 Hz to 20,000 Hz so we're not reaching even the lower treble range at this point. The most important frequencies like speech are in the 300 Hz to 3,000 Hz range.

 

That’s ridiculous.

 

10 dB hearing loss on an audiogram is considered normal hearing...

 

I do agree that Frequency should at least address the problems with low frequency hearing loss and their drug and that it needs to be more than 10 dB improvement. If you have 10 dB PTA it is not even considered hearing loss.

 

They should give me a call

 

You have to consider that most people don't have equal hearing loss across all frequencies. Many people (including me) have good hearing in mid to low frequencies and a drop at higher ones.
For those with a ski slope audiogram FX-322 is perfect in its current form.

There is still critical information at higher frequencies. Frequency Therapeutics actually addressed that on page 17 of their June presentation.



In general id recommend you to check out their presentation as it's a nice little summary of most of the facts we have at the moment.

 

Goddamn, my bad. It really would be ridiculous.Thankfully that was just a typo

I meant 2026.

 

It was a 10 dB improvement. So the individual sensitivity at 8 kHz showed improvement from 40 dB to 30 dB, for example.

 

Perhaps you should call them! Help get this trial moving forward!

 

Actually, it is not quite like that: hearing works logarithmically. There are more "hearing octaves" below 6.5 kHz than above it.

 

Yeah I don't think going from 40 dB to 30 dB will put any significant dent in tinnitus. I don't think that will cut it. It would have to be like 40 dB to 5 dB...

10 dB improvement is like pissing in a jacuzzi.

The brain needs a jolt of new input to reset to a new "default" state.

So if they can't get 40 dB improvement, it is another pipe dream.

 

Unfortunately it's not that massive.

Most us have probably never even been able to hear close to 20 kHz (20,000). Certainly not too much past age 16 or so. There really isn't too much information up there anyway. You can probably cut out most sound above about 16 kHz without really noticing much of a difference. 6.5 kHz and up is not nothing, but it's sort of like the top 20% - 25% of our range (approximately).

Due to the logarithmic nature of how frequencies increase, it can give a warped perception of how our hearing is "balanced".

If you wanted to divide it into roughly even quarters, it would look something like this:

20 Hz to 500 Hz = low
500 Hz to 1000 Hz (1 kHz) = low mid
1 kHz to 5 kHz = upper mid
5 kHz to 15 kHz = high

Source: Before my hearing issues I used to work as an audio engineer.

 

True, though if you're at let's say 40 dB, going to 30 dB would be a significant improvement I would think. That is if it could improve frequencies lower than it does at the moment. If it could improve 10 dB from 1,000 Hz upwards, I'd definitely get the treatment once it's ready.

 

I agree 10 dB isn’t enough, I also think it is implied that more than 10db improvements were had above 8 kHz.

It may very well have been a higher dB of improvement in frequencies above 8 kHz where the drug concentration was the highest. Note in the current presentation, 8 kHz seems to be the edge of action for a single dose. And, as mentioned in a few threads above, they didn’t do a high frequency audiogram in the Phase 1/2.

However, word recognition improved significantly for patients who received the drug, in particular those with moderate to severe hearing loss. It stands to reason that those with moderate-severe hearing loss experienced gains of better than 10db to see word recognition increase by nearly double in some cases. Where word score puts them in a mild or no hearing loss class. I don’t see how it could be any other way.

As it relates to tinnitus. If you prescribe to it being a symptom of hair cell loss, then restoring hair cells should reduce the symptom. Frequency seems to think this is the case; according to the presentation, a secondary outcome of the Phase 2A is a test for tinnitus symptoms. Also, they’re doing a HF audiogram.

I would go as far to say that if they can demonstrate HF improvements that correlate with reduced tinnitus, especially in a case where the tinnitus is in the high frequencies, it will be very telling.

 

I am getting more skeptical about this tinnitus cure business.
So far there hasn't been an "omg" moment...

 

They are using the same dose in Phase 2, only four times. They are not using a higher dose per injection.

 

What if it's a combination of problems? FX-322 could help a bit and OTO-413 could finish up. Each treatment could deliver their own improvements increasing the quality of life with each treatment.

 

I think initially it may until your brain gets used to it. Plasticity.