There is no reason to believe it's time sensitive and if it helps, "length of hearing loss" was not an exclusion parameter for any of the regenerative therapies so clearly they (regen biotechs) don't think so either.Can I ask, post-injury (let's assume for simplicity's sake we all have a one-time event or catalyst that induced our hearing loss / tinnitus), is there any part of the ear for which regenerative therapies are time-sensitive? Let's exclude steroid intervention - I mean while we wait for therapies, is there part of the ear which is deteriorating in a way that is irreversible.
As far as I can tell, hair cell regeneration isn't time-sensitive so long as you don't reach a profound level of hearing loss. Likewise, synaptic damage isn't time-sensitive so long as the spiral ganglions stay alive once detached, which also shouldn't be an issue as it sounds like they remain okay for years.
That being said I'm trying to sanity check assumptions as this seems like a critical issue to be aware of if it exists.
Frequency Therapeutics has made no mention of a "therapeutic window" that you're referring to. Also, if a therapeutic window were a concern, it would have likely been a recruiting criteria in the Phase 2A. To note: During the JP Morgan Q&A, a question was asked regarding how long some of the participants had hearing loss in the trial. Chris Loose replied that its likely that some of the participants had been living with hearing loss for many many years prior to receiving FX-322.Can I ask, post-injury (let's assume for simplicity's sake we all have a one-time event or catalyst that induced our hearing loss / tinnitus), is there any part of the ear for which regenerative therapies are time-sensitive? Let's exclude steroid intervention - I mean while we wait for therapies, is there part of the ear which is deteriorating in a way that is irreversible.
As far as I can tell, hair cell regeneration isn't time-sensitive so long as you don't reach a profound level of hearing loss. Likewise, synaptic damage isn't time-sensitive so long as the spiral ganglions stay alive once detached, which also shouldn't be an issue as it sounds like they remain okay for years.
That being said I'm trying to sanity check assumptions as this seems like a critical issue to be aware of if it exists.
It was also stated that Frequency Therapeutics would consider compassionate access and usually this means a release post phase 2. If their next trial is the pivotal one, then there is a reasonable level of feasibility that this will mean a release after this trial.Carl LeBel said that if the results warranted, they would discuss the possibility of the next trial being pivotal with the FDA. He didn't say anything about a possible release of the drug after this trial. Compassionate use could happen now if Frequency Therapeutics wanted to make it available. That's not the same as releasing the drug.
Do you really think there's a chance that you could go to an ENT in Melbourne in December next year and get FX-322 when they finish their first efficacy trial in May? Hope you're right then.
I think that there has not been a therapeutic window mentioned in not only the information released relating to FX-322 but also actually in relation to any of the other treatments too. Thus this tends to indicate that regeneration can consequently happen at any time.Frequency Therapeutics has made no mention of a "therapeutic window" that you're referring to. Also, if a therapeutic window were a concern, it would have likely been a recruiting criteria in the Phase 2A. To note: During the JP Morgan Q&A, a question was asked regarding how long some of the participants had hearing loss in the trial. Chris Loose replied that its likely that some of the participants had been living with hearing loss for many many years prior to receiving FX-322.
Where and when was this stated?It was also stated that Frequency Therapeutics would consider compassionate access and usually this means a release post phase 2. If their next trial is the pivotal one, then there is a reasonable level of feasibility that this will mean a release after this trial.
In one of their talks. They said that compassionate use after a completion of phase 2 might be granted if it is looking like the treatment is promising. Obviously they couldn't commit to it definitively because they have a really keen interest in not making unverifiable statements on trials or any things which will get them in trouble with the FDA. Fairly likely that this comment was simply a hint that this would be something they would look at and also be something that they are interested in.Where and when was this stated?
Generally speaking, I don't think compassionate use of FX-322 is going to occur, for the most part, and should not be expected. Frequency Therapeutics are focused, I believe, on the successful completion of the clinical trial process before anyone has access other than trial participants.The only way they accept compassionate use and not have a recruitment delay is to have a very large international pool for phase 3, but I think it's possible.
Otherwise, their trial might mostly include people who couldn't afford the drug and would have at least some delay.
FX-322 can theoretically improve all frequencies. It is just an issue of getting it to work throughout the cochlea across all frequencies. This is why in the current trials Frequency Therapeutics are looking at multi dosing and may also look at a different dosing technique to improve drug delivery.I heard many times that FX-322 is more likely to improve higher frequencies. But what frequencies specifically are we talking about? 2kHz+, 8kHz+, 15kHz+?
This current phase will answer that question more. Results next spring.I heard many times that FX-322 is more likely to improve higher frequencies. But what frequencies specifically are we talking about? 2kHz+, 8kHz+, 15kHz+?
In the Tinnitus Talk Podcast, Carl LeBel was asked specifically about this.Where and when was this stated?
We won't have data on this until the end of Phase 2a. In Phase I/II, 4 of 13 patients saw a 10dB increase at 8kHz [1], however, this was deemed statistically insignificant. It's theorized that the frequencies above 8kHz saw greater improvements. In Phase 2a Frequency is testing the extended high range frequencies [2] (most likely up to 20kHz), so we'll have a better idea of what the drug can do.I heard many times that FX-322 is more likely to improve higher frequencies. But what frequencies specifically are we talking about? 2kHz+, 8kHz+, 15kHz+?
Firstly, the testing is only being done to 16000 Hz in the current trials.We won't have data on this until the end of Phase 2a. In Phase I/II, 4 of 13 patients saw a 10dB increase at 8kHz [1], however, this was deemed statistically insignificant. It's theorized that the frequencies above 8kHz saw greater improvements. In Phase 2a Frequency is testing the extended high range frequencies [2] (most likely up to 20kHz), so we'll have a better idea of what the drug can do.
[1] https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1 (slide 25)
[2] https://clinicaltrials.gov/ct2/show/NCT04120116
It was statistically significant. The placebo patients and control ears did not see this improvement.Secondly, where did you get the evidence from that 10 dB at 8000 Hz was statistically insignificant? It was also 4/6 of the big dose patients who had improvement at 8000 Hz.
The range wasn't listed on the clinical trial site so I used a number I got from Google (which is why I said "most likely" rather than stating it as a definite). However, digging deeper, you are correct, 16kHz is the upper range they are testing [1].Firstly, the testing is only being done to 16000 Hz in the current trials.
Secondly, where did you get the evidence from that 10 dB at 8000 Hz was statistically insignificant? It was also 4/6 of the big dose patients who had improvement at 8000 Hz.
Source?It was statistically significant. The placebo patients and control ears did not see this improvement.
I know we're going to be tripping over semantics... but I believe Frequency Therapeutics has called the 10-15 dB improvement at 8000 Hz by 4/6 patients in the Phase 1/2 "Clinically Meaningful."The range wasn't listed on the clinical trial site so I used a number I got from Google (which is why I said "most likely" rather than stating it as a definite). However, digging deeper, you are correct, 16kHz is the upper range they are testing [1].
Source?
From what I've seen, Frequency Therapeutics has not stated that this was statistically significant. They don't state anything about statistical significance on the Pure Tone slide (slide 31), while they do state it on the WR slide (slide 22). I'd love to be proven wrong though.
[1] https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1 (slide 31)
Sorry, you are correct.The range wasn't listed on the clinical trial site so I used a number I got from Google (which is why I said "most likely" rather than stating it as a definite). However, digging deeper, you are correct, 16kHz is the upper range they are testing [1].
Source?
From what I've seen, Frequency Therapeutics has not stated that this was statistically significant. They don't state anything about statistical significance on the Pure Tone slide (slide 31), while they do state it on the WR slide (slide 22). I'd love to be proven wrong though.
[1] https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1 (slide 31)
Have they though? I can't find anything where they say that. The closest I can find is that they say "clinically meaningful improvements in hearing function" - which is ambiguous and could refer to the WR score improvements (they also state the clinically meaningful line on the WR score slides).I know we're going to be tripping over semantics... but I believe Frequency Therapeutics has called the 10-15 dB improvement at 8000 Hz by 4/6 patients in the Phase 1/2 "Clinically Meaningful."
The P-Value on the Clarity of Sound slide (23) at 0.010 indicates statistical significance. While it can depend on N size (sample population), typically a p value below .05 is considered significant.
In my opinion, and i'm sure others would agree, that a P value below .05 from a N=23 sample size is actually impressive.
What you would expect to see from a small sample set is what they show on Page 24, where P = .211. Its possible that the N-value increasing (more participants) in the Phase 2A might drive down the P-value for hearing-in-noise.
Because it's super rare for the places to have the capacity to test 20 kHz. The cap at 16 kHz opens the trial up to more testing centers and speeds it along.I wonder why they don't test up to 20 kHz, but just to 16 kHz. I really wanted to know how FX-322 affects those ultra-high skull piercing frequencies, since that's where my hearing loss is. It seems like I have to wait a bit longer then.
They have. I can paraphrase Carl LeBel saying in an investor presentation about a year ago, that a 10 dB improvement at 8 kHz represents a roughly 3x improvement in hearing sensitivity; in a real world setting he referenced "hearing leaves rustling."Have they though? I can't find anything where they say that. The closest I can find is that they say "clinically meaningful improvements in hearing function" - which is ambiguous and could refer to the WR score improvements (they also state the clinically meaningful line on the WR score slides).
I don't doubt that the 10dB improvement was a good sign, and I'm sure we'll see bigger improvements at the higher frequency bands, but we should be careful in our interpretation of what they tell us.
As an aside, there is a Facebook group I'm in where they are much more negative on FX-322, and the 10dB improvement was derided as pretty insignificant. I haven't had my hearing tested since 2014 (I had the hearing of an 70-80 year old then, I'm sure it's much worse now), so I don't really have a feel for what 10dB would mean.
I think the assumption is that if patients show improvement in the 8 kHz -> 16 kHz audiogram, it's highly likely that 16 kHz+ are seeing improvement as well. FX-322 enters the cochlea starting at the highest range and works its way down, so it's not likely it can just skip over those ultra-high frequencies. I am also curious of the limitations for the testing facility to test at the ultra-high ranges. The 8 kHz-16 kHz test seems fairly available.I wonder why they don't test up to 20 kHz, but just to 16 kHz. I really wanted to know how FX-322 affects those ultra-high skull piercing frequencies, since that's where my hearing loss is. It seems like I have to wait a bit longer then.
That's a fair point.Because it's super rare for the places to have the capacity to test 20 kHz. The cap at 16 kHz opens the trial up to more testing centers and speeds it along.
It's also unnecessary to test 20 kHz because if you get improvements at 16 kHz, you would have them at 20 kHz.
Can anyone comment on the above?Would giving multiple shots at once push the first injection deeper into the cochlea, thereby hitting the lower frequencies?
The theory that if you have improvement at 16000 Hz, you will have improvement at 18000 Hz is also actually the same reasonable conclusion which can be drawn about why when we saw improvement at 8000 Hz in the inaugural trial, we could also assume an improvement was seen at those very high frequencies. Frequency Therapeutics cannot and will not declare that has happened however because it would be non-compliant with the FDA requirements.I wonder why they don't test up to 20 kHz, but just to 16 kHz. I really wanted to know how FX-322 affects those ultra-high skull piercing frequencies, since that's where my hearing loss is. It seems like I have to wait a bit longer then.