Frequency Therapeutics — Hearing Loss Regeneration

[Zugzug]

Alternatively, if you decide to tank your score again at baseline in the interests of staying consistent, your score is going to increase regardless of whether you get placebo or FX-322, because at that point you certainly have no reason to tank.

Not true. See my Bear Thesis 1

 

[Diesel]

I read that different. It sounded like they thought the asker didn't understand audiograms and they just explained it poorly to them.

I guess I've never heard of improving at BANDS before? I've had my audiologist and ENT tell me that my threshold AT a certain frequency improved/declined. The tone is a single pure-tone frequency. It isn't a collection of sound from 4 kHz - 8 kHz.

 

[Gb3]

Could you ask if he felt the burning in the first 2 shots or the last 2 shots?

Their response:

One and third. I ask them to tell me when they find out what group I was in. They will not know that until the 2nd quarter of 2021... they just finished the last patients with the trial 2 weeks ago.​

They also told me they called the clinic and told them the tinnitus was basically gone and they said "thanks".

 

[Tezcatlipoca]

FREQ, if you're reading this, contact all the trial sites and trial participants and ask for the tinnitus outcomes.

 

[Lucifer]

Their response:

One and third. I ask them to tell me when they find out what group I was in. They will not know that until the 2nd quarter of 2021... they just finished the last patients with the trial 2 weeks ago.​

They also told me they called the clinic and told them the tinnitus was basically gone and they said "thanks".

Thanks for the reply. That is going to be tough to know if it was placebo or FX-322. If the burning sensation was first and third injections, maybe he got three FX-322 shots and one placebo.

 

[Diesel]

They also told me they called the clinic and told them the tinnitus was basically gone and they said "thanks".

RING RING

HEY I'M CURED OF THIS TORTUROUS SOUND THAT'S BEEN INSIDE MY HEAD FOR YEARS.

...

"Thanks."

 

[Lucifer]

FREQ, if you're reading this, contact all the trial sites and trial participants and ask for the tinnitus outcomes.

Agreed, this could give FX-322 a better chance at convincing the FDA for the pivotal phase early next year. Even if only 25% of patients experienced an improvement in their tinnitus, it should be enough.

 

[Zugzug]

Nice work. Here's the thing... how do you think the makeup of the Consonant-Nucleus-Consonant Word Lists used in the Word Recognition Test may have played a factor? It seems like many are overlooking the makeup of the test itself. There's been a few discussions on how people think the "just memorized it" and that's how they did better. Based on my understanding of the setup of the lists, and that there are 10 lists of 50 that are commonly used, I don't buy it that anyone is memorizing lists and regurgitating anything from memory between a 30-day time period. Also, if they truly did have poor hearing going into the Phase 2A, or any phase for that matter, how could they have possibly memorized words that they didn't hear accurately the first time, or words that they starting hearing accurately because of the treatment, but heard incorrectly prior?

Link:
An Examination of Sources of Variability Across the Consonant-Nucleus-Consonant Test in Cochlear Implant Listeners

I have an interest in this topic. We need to start thinking about the differences in test outcomes as if people aren't robots.

So, if you read the original Thornton and Raffin paper, everything was justified because the data was pulled randomly. In other words, no one felt like pressure to get a word right or wrong (it was veterans so maybe there's some disability motivation -- queue Jastreboff -- a joke)

The Binomial assumption is not bad if:

• No memorization
• True binary: Person either hears the word or they don't and refuse to guess
• Trials are independent

I hate to say it, but unconscious bias sounds like a real thing for this test. It's quite simple: there's motivation to not guess the first time around and varying degrees of motivation to guessing based on which group you think you are in. A lot of this is a true design problem.

It's also not easy to fix because Frequency Therapeutics is dealing with the problem of having to prove significance against established clinical criteria. Not an easy thing to do. They are sort of victims of their own scientific breakthroughs.

Okay, done shilling. The drug still wouldn't have cleared Phase 2a and needs a ton of work.

 

[FGG]

Their response:

One and third. I ask them to tell me when they find out what group I was in. They will not know that until the 2nd quarter of 2021... they just finished the last patients with the trial 2 weeks ago.​

They also told me they called the clinic and told them the tinnitus was basically gone and they said "thanks".

This makes me think the burning is only a side effect of how well lidocaine was applied.

No one in the trial was dosed that way. If you got two doses, they were consecutive and the first two.

So we can't use "burning" to figure out which cohort someone was in.

 

[Zugzug]

Agreed, this could give FX-322 a better chance at convincing the FDA for the pivotal phase early next year. Even if only 25% of patients experienced an improvement in their tinnitus, it should be enough.

Trust me, I say this with the only intentions of being kind. This is not going to pivotal as a result of Phase 2a. No matter what. It's almost surely not going there regardless, but knock-your-socks-off results from both Phase 1bs would be required.

 

[Tezcatlipoca]

Even if FX-322 shows minimal improvements with its current formulation, if the positive tinnitus outcomes are somewhat common (let's say 1/4 people improve), it's a homerun.

 

[MarkRule]

Has anyone else seen this? It has been getting some exposure in my hometown of Melbourne.

The Bionics Institute seem to have been flying under the radar. From what I hear this nano delivery technology seems to be what FREQ is missing. I feel like these organisations should be working together.

 

[Diesel]

Has anyone else seen this? It has been getting some exposure in my hometown of Melbourne.

The Bionics Institute seem to have been flying under the radar. From what I hear this nano delivery technology seems to be what FREQ is missing. I feel like these organisations should be working together.

Sounds like another synaptopathy treatment. Seems like that route may get to market sooner than regeneration, imo.

 

[Zugzug]

Even if FX-322 shows minimal improvements with its current formulation, if the positive tinnitus outcomes are somewhat common (let's say 1/4 people improve), it's a homerun.

Tinnitus was a secondary end point so it's not going to play a massive role in pushing the drug through. My guess is the results are going to be very simple: Person is a "responder" or not based on if their TFI decreases by a certain amount.

For an idea of the statistical testing, see the open-label study (FX-322-111) style like this:

Both trials were statistically significant based on the percentage of responders in treatment relative to placebo. A positive result from Phase 2a will be something like those results. It will be encouraging, but probably won't play any meaningful role in pushing the drug through.

 

[Lucifer]

Trust me, I say this with the only intentions of being kind. This is not going to pivotal as a result of Phase 2a. No matter what. It's almost surely not going there regardless, but knock-your-socks-off results from both Phase 1bs would be required.

Even if both age-related and severe hearing loss trials have positive outcomes, you don't see the pivotal trial happening early next year?

 

[FGG]

Trust me, I say this with the only intentions of being kind. This is not going to pivotal as a result of Phase 2a. No matter what. It's almost surely not going there regardless, but knock-your-socks-off results from both Phase 1bs would be required.

@Lucifer, they aren't going to pivotal based on an experimental arm endpoint. Tinnitus results are not a factor in this. Regardless of suffering.

They need to repeat Phase 2a. As much as you don't want to hear that, it's extremely unlikely they can go straight to pivotal even with great age-related and severe arm results (which would be absolutely required though).

For going to pivotal, Day 210 results won't be a factor and neither will tinnitus, unfortunately. But tinnitus results will help emotionally.

 

[Zugzug]

Even if both age-related and severe hearing loss trials have positive outcomes, you don't see the pivotal trial happening early next year?

Someone more knowledgeable than me may have a feeling for how often drugs make it to Phase 3 with weird Phase 2s and brilliant Phase 1 outcomes. Some of it comes down to Breakthrough Therapy status and other things.

The only thing I feel a high level of understanding of is how fucked the Phase 2 was. Even if they unblind and say "well, Patient X looks like a faker, blah blah blah," this is all super weak stuff. Phase 2 failed.

Could insane results from Phase 1b push this to Phase 3? I think the probability is very, very low.

 

[MarkRule]

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I thought that they said there were no improvements in the audiogram in any participants in the readout?

 

[FGG]

Someone more knowledgeable than me may have a feeling for how often drugs make it to Phase 3 with weird Phase 2s and brilliant Phase 1 outcomes. Some of it comes down to Breakthrough Therapy status and other things.

The only thing I feel a high level of understanding of is how fucked the Phase 2 was. Even if they unblind and say "well, Patient X looks like a faker, blah blah blah," this is all super weak stuff. Phase 2 failed.

Could insane results from Phase 1b push this to Phase 3? I think the probability is very, very low.

I have seen drugs fail even Phase 3 and later get approved. Just happened with Posimir most recently. I don't know what the percentages are, though, but it obviously depends on what went wrong.

 

[FGG]

I thought that they said there were no improvements in the audiogram in any participants in the readout?

Over the group. They didn't say there weren't individual improvements to my knowledge.

 

[sensualmosquito]

I have seen drugs fail even Phase 3 and later get approved. Just happened with Posimer most recently. I don't know what the percentages are, though, but it obviously depends on what went wrong.

I agree with you that we need to see another Phase 2a study done.

 

[Diesel]

Someone more knowledgeable than me may have a feeling for how often drugs make it to Phase 3 with weird Phase 2s and brilliant Phase 1 outcomes. Some of it comes down to Breakthrough Therapy status and other things.

The only thing I feel a high level of understanding of is how fucked the Phase 2 was. Even if they unblind and say "well, Patient X looks like a faker, blah blah blah," this is all super weak stuff. Phase 2 failed.

Could insane results from Phase 1b push this to Phase 3? I think the probability is very, very low.

There will still need to be a "Phase 2B" after these next two Phase 1Bs complete. Even though it will essentially be a bigger version of a Phase 1, since it will be just one dose.

The only way around it I could see, is if they do a Pivotal Phase 2B/3 for Moderately-Severe and Severe hearing loss. This would clearly identify a patient population that may respond most consistently to the drug.

But this would mean that everyone that has "no" hearing loss but tinnitus, mild or moderate hearing loss would be treated off label.

 

[Lucifer]

I have seen drugs fail even Phase 3 and later get approved. Just happened with Posimer most recently. I don't know what the percentages are, though, but it obviously depends on what went wrong.

I think it's clear multi-dosing of FX-322 weekly was the problem and caused the Phase 2a to fail. I have hope that the age-related and severe hearing loss trials should show more improvement with the one dose of FX-322 compared to multi-dosing in Phase 2a.

Let's hope a repeat of Phase 2a will be shorter.

 

[FGG]

There will still need to be a "Phase 2B" after these next two Phase 1Bs complete. Even though it will essentially be a bigger version of a Phase 1, since it will be just one dose.

The only way around it I could see, is if they do a Pivotal Phase 2B/3 for Moderately-Severe and Severe hearing loss. This would clearly identify a patient population that may respond most consistently to the drug.

But this would mean that everyone that has "no" hearing loss but tinnitus, mild or moderate hearing loss would be treated off label.

That's a good point. They would have to have their larger trial include a much narrower population if it's possible at all.

 

[Zugzug]

I have a really weird question that I can't figure out from Googling:

What the hell is the difference between Phase 1/2 and Phase 1b?

The trial we keep referencing as Phase 1/2 is also called Phase 1b 201. Is the last trial (Phase 2a) considered a Phase 2/3? lol

 

[Lucifer]

There will still need to be a "Phase 2B" after these next two Phase 1Bs complete. Even though it will essentially be a bigger version of a Phase 1, since it will be just one dose.

The only way around it I could see, is if they do a Pivotal Phase 2B/3 for Moderately-Severe and Severe hearing loss. This would clearly identify a patient population that may respond most consistently to the drug.

But this would mean that everyone that has "no" hearing loss but tinnitus, mild or moderate hearing loss would be treated off label.

My biggest fear is the severe hearing loss trial with its current delivery method won't be able to reach deep enough in the round window for meaningful improvements which will cause more delays in the trials. While majority of people that have mild-moderately severe hearing loss have benefitted from the trials will be force to wait even longer.

 

[Diesel]

I have a really weird question that I can't figure out from Googling:

What the hell is the difference between Phase 1/2 and Phase 1b?

The trial we keep referencing as Phase 1/2 is also called Phase 1b 201. Is the last trial (Phase 2a) considered a Phase 2/3? lol

There isn't a completely standard protocol for the use of "a" or "b" or "1/2".

Typically though the 1/2 is used to establish a baseline of efficacy, but not a full large-scale efficacy like a Phase 2.

For some drugs, an "a" and "b" are used to categorize different patient population arms / disease designations / etc for the same drug. But not always, sometimes it's just the first half and second half of the overall phase.

 

[FGG]

I have a really weird question that I can't figure out from Googling:

What the hell is the difference between Phase 1/2 and Phase 1b?

The trial we keep referencing as Phase 1/2 is also called Phase 1b 201. Is the last trial (Phase 2a) considered a Phase 2/3? lol

I have seen Phase 1b referred to as "cohort expansion" before. My impression is it's a trial to expand Phase 1 over a bigger group of potential patients.

Phase 1/2 is combined safety/efficacy.

But that's the reason I am convinced they will need another Phase 2a regardless of the age-related and severe group results. Because the efficacy data (including Word Scores) are secondary end points in the Phase 1b studies.

But who knows, maybe the FDA allows that data to be used anyway since it's a secondary and not an experimental endpoint.

 

[ThomasC]

Assuming FX-322 only shows minor MEASURABLE improvements but is safe, could it hit the market considering there is no existing regenerative drugs?

 

[Street Novelist]

Has anyone else seen this? It has been getting some exposure in my hometown of Melbourne.

The Bionics Institute seem to have been flying under the radar. From what I hear this nano delivery technology seems to be what FREQ is missing. I feel like these organisations should be working together.

I read the article with the video. It says the drug repairs the connection between the hair cell and the synapse.

But, what if your hair cell is damaged? Would the drug still work?