Frequency Therapeutics — Hearing Loss Regeneration

LaBel addresses the possibility of getting further into the cochlea with phase 2a dosing:

https://www.fiercebiotech.com/biotech/frequency-s-hearing-loss-treatment-shows-long-term-promise

"FX-322 is two small-molecule drugs and once injected, they essentially diffuse into the inner ear. We can imagine a wave of two drugs washing through a particular region of the cochlea,” LeBel said. “One week later, we come back. Maybe that second injection gets a bit further throughout the cochlea, maybe it hits an additional number of progenitor cells and we get a bigger benefit. Or, maybe with additional injections, we will get more people with the same benefit. We don’t know which it might be—that’s the reason we designed it this way.”

 

Fair but in order for intratympanic Gentamycin to be effective for Meniere's patients, for instance, it has to reach the inner ear.

 

I think the question around what benefit someone would get from various dosing options has probably got to be the biggest unknown with FX-322. Having said that, it is reassuring to see Carl LeBel come out and say that Frequency Therapeutics have clear direction and purpose in their methods when it comes to dosing practices. It appears that Frequency Therapeutics knows that dosing is an issue because they don't have certainty around what dosing combination or method should be utilised to deliver the largest benefit.

I think that an interesting, previous comment from Carl was about how there are some very talented people in the drug delivery industry. I could be wrong, however I interpret this cryptic comment as possibly meaning that Frequency Therapeutics is going to pass this off to one of these firms to try and improve dose delivery, in order to get better outcomes from each dose of FX-322?

Looking to improve dose delivery would be prudent, especially if it turns out that the issue with FX-322 not working as well as it could is due to it not getting far enough into the cochlea. Obviously we will need to wait and see what the outcomes from the phase 2a trial are before we can determine if this is the issue.

Nevertheless, I wouldn't be at all surprised if Frequency Therapeutics gave FX-322 to a firm to improve the delivery of a single dose. It really seems that the biggest issue with FX-322 is now not about whether it will provide a benefit to someone, but rather how to get it to work most effectively in order to produce the best possible outcomes.

 

Would you be able to speculate on how FX-322 could work above 8 kHz? Is improving hearing above 8 kHz likely to be a linear degree of difficulty up to 20 kHz?

 

I agree. It is still unknown what happens with additional doses and whether with each additional dose it has a better effect improving each frequency or if it only works on high frequencies and additional doses do nothing and they will need to find a better delivery method.

 

What do y'all think about the tone of this article on Frequency Therapeutics?

Don't Shout Yet: Drug To Regenerate Hearing Shows Early But Muted Promise In New Trial

 

It is pointless to speculate since we will know this exactly when the phase 2a results are out but I think it is heavily implied that Frequency Therapeutics thinks the reason word scores improved so much was because of a big improvement in this area. The "how much" will be known Q2 of 2021.

 

Scroll back a page for discussion about it.

 

Well, here is a more optimistic article!

https://www.fiercebiotech.com/biotech/frequency-s-hearing-loss-treatment-shows-long-term-promise

An encouraging excerpt on the 10 dB improvement...

“A 10-decibel improvement is really a tripling in the ability to hear a tone at that particular pitch,” said Frequency Chief Development Officer Carl LeBel, Ph.D. “They came into the study with permanent hearing loss. After a single injection, they tripled the ability in those ears to hear the tone at that highest frequency.”

 

I just want to point out that FREQ stock went up 18% today but I don't think it really means anything (just like when it goes down) as it tends to fluctuate with the IBB index among other things. People only seem to post about it when it goes down, so I thought I'd make a counter post .

 

The article implies not so much a skeptical perception of the early trial involving 23 participants, but one of a guarded and reserve observation. It takes into account deviations of the variance involving audiograms that could, perhaps, be plausible in early clinical trials. Conquering hearing loss I suppose could be looked upon as the 'final frontier' in solving a common malady among humans. It's easy to imply "I'll believe it when I see it".

 

I do think the limits of intratympanic injections come into play with FX-322. Those limits have been pretty well established in the literature. I am, however, optimistic about efforts Frequency Therapeutics is making on drug delivery/reformulation. I’m also confident that any approved drugs for the inner ear that work partially (e.g. the higher frequencies) will be a huge stimulus for research on inner ear drug delivery. A lot of companies would want to be the first to get the drug in the entire cochlea. Or better yet: control where the drug gets depending on where the hair cell damage is located.

 

Yeah, but contrast that with the following quote from https://www.wbur.org/commonhealth/2020/09/13/frequency-therapeutics-regenerate-hearing-drug:

An improvement of 10 dB at 8000 Hz is also almost a negligible gain, adds University of Iowa's Gantz, "within test, retest variability of an audiogram," he says.

 

I also think journalists feel they need to present "both sides" equally to appear objective to lay readers.

 

That's the only person I have ever seen say 10 dB is within test/retest variability. After reading that, I spent a half am hour looking and every other source and publication seems to say 5 dB (which is what Frequency Therapeutics says). I'm tempted to write him and ask for his source.

 

I haven't seen it posted yet, but here are the slides from Sunday's presentation:

https://investors.frequencytx.com/static-files/47014168-736e-4a25-9435-b1a8bf19599e

Very neat to see the actual data!

 

Maybe, but if 5 dB is within test/retest than 10 dB can't be that much. I asked an audiologist to choose between this guy's statement and LeBel's tripling of ability to hear a tone. He was scratching his head over LeBel's claim. Labelled it nonsensical. Unless LeBel has an interesting take on the phrase 'ability to hear a tone'?

 

4/13 subjects with noticeable improvements in a controlled trial doesn't seem like a lot :/

 

The wording of his quote is odd. He says it’s almost a negligible gain. So it seems he’s not saying that it’s within test/retest variability, but it’s not much of a gain when factoring in test/retest variability. He should have phrased it more clearly.

 

I thought it was the other way around, that they start delivery in the high frequency region of the cochlea and work down, which, conveniently, is good for tinnitus patients.

 

Half of these people had a "high" dose and half had a "low" dose [1]. This is a point Frequency Therapeutics hasn't really talked about much, which I find a bit confusing. For Phase 2a, everyone is getting a High dose, so High must have performed better (though maybe 1 of the 4 had a Low dose, so they're playing that aspect down?). Someone on here has mentioned that Frequency Therapeutics said there was no difference between the High and Low groups, but I haven't been able to verify that information myself (I can't find any info online about it).

Additionally, half of the subjects had mild hearing loss and half had moderate to severe hearing loss. The 4 people with statistical improvements came from the latter group, and all people in this group had some improvement.

I do find it curious that people in the mild group didn't see much of a pure tone improvement. It's probably because not all 10 dB improvements are equal (i.e., it's a logarithmic scale, so each 10 dB improvement is double what the previous improvement would be). For Phase 2a there will be no mild group, only moderate to moderately severe patients. So the end results will (hopefully) look like the 4 people who saw improvements.

Another thing that's crossed my mind: Would Frequency Therapeutics be able to do internal tests on humans? I wonder if they've already tried additional doses in internal tests to see what would happen. Intuitively one would think additional doses would help, but part of me thinks they would have done something previously to verify this before putting it in their Phase 2a trial (sort of like how they added a test for tinnitus after patients from Phase 1/2 reported a benefit). Maybe they had groups of mice that got different doses and saw better results with the mice that got more doses?

[1] https://clinicaltrials.gov/ct2/show/NCT03616223

 

All the moderate hearing loss patients had increased word scores (some doubled) and the mild ones already had good word scores, so didn't have room for improvement. I would say that's pretty noticeable. Unless you mean standard audiogram changes but this is why they are measuring the extended audiogram in this phase because given the dramatic word score changes, they suspect big changes here.

 

Did he say double or triple? It seems that double is actually accurate if you are talking about loudness.

http://www.sengpielaudio.com/calculator-levelchange.htm.

Though it depends on what metrics you are using.

 

That's the way that I read into it too. The higher frequencies are much more accessible as they are on the outer "rings" of the cochea spiral and the lower frequencies on the inner of the spiral are much harder for the drug to reach.

 

Herd instinct/idealism/we're all in this together.

No question about it that we tinnitus sufferers are living in an exciting time.

But I emphasize: Decide how much you can afford to lose. That's the amount you can invest.

 

No, a doubling of loudness is 10 dB. It's actually in the section of your source that breaks down the differences between volume, sound pressure, and acoustic energy.

He said triple. He's referring to the acoustic energy which doubles in increments of +3 dB. How that relates to his statement I'm looking at, but I'm homeschooling three kids...

 

That is what I was saying, that doubling of loudness is 10 dB which is definitely not negligible.

If he said triple, I'm not sure why unless he was referring to acoustic energy but I'm not sure why he would express it that way. What was the full quote?

 

Sorry I misread what you said.

Here it is from @serendipity1996 above.

 

You're talking about the stock, right? I had a feeling there would be a post-presentation bump, though I didn't think it'd be as big as it is. They have 3 more presentations in the next 30 days, so I imagine the stock is going to stay high.

However, after their October presentation, it seems like there's going to be a drought of new information. I'm not sure what they have planned for the time period between November and April 2021, but they're definitely going to do something (interim results? new study announcement? new hydrogel?), it'd be unlike them to just go quiet.

 

It definitely seems like doubling is more accurate unless "acoustic energy" is what he means by "ability to hear" but that's not a metric I have really seen used.