Frequency Therapeutics — Hearing Loss Regeneration

[Sunshine007]

I'm going to propose the same type of question I've asked before.

Say the safety studies were fine for all three placebo controlled Phase 1, but efficacy was minimal. Then Phase 2 was a huge success. Would we say, "well the lack of efficacy in the Phase 1 studies overrides the Phase 2?" No, we would say what really matters is the efficacy study.

I've learned my lesson with regards to pushing the drug deeper. The lawn effect doesn't exist until it is proven to exist. Successful trials with different designs is not a proof.

On the following hypothetical:

If Phase 1 showed safety and no effect but Phase 2 did show efficacy, Phase 2 would have shown a multiple dose schedule was the optimal way forward. My point is we are finding the therapeutic dose, it is a question of finding what works best.

Based on all available data to date, we could say drug does nothing or the lawn effect impacted results. If we go with the drug indeed did nothing explanation then we must explain the significant WRS improvements in the single dose trials.

The fact that multiple dose did not produce an effect does not suggest that the effect we saw with single dose is invalid.

I do agree that the lawn effect needs to be proven but successful single dose trials could prove that.

 

[FGG]

Can anyone answer my question about the same person getting placebo or the real thing randomly for their four injections?

Here were the Phase 2a groups:

1) 4 placebo shots
2) 4 FX-322 shots
3) 2 FX-322 shots first, then 2 placebo shots
4) 1 FX-322 shot, then 3 placebo shots.

 

[Cernuto]

Here were the Phase 2a groups:

1) 4 placebo shots
2) 4 FX-322 shots
3) 2 FX-322 shots first, then 2 placebo shots
4) 1 FX-322 shot, then 3 placebo shots.

Ok, thank you. I got it now. It makes sense although I'm not sure the purpose of groups 3 & 4. Seems like unnecessary confusion and overall dilution of the ending outcomes, good or bad.

 

[Zugzug]

On the following hypothetical:

If Phase 1 showed safety and no effect but Phase 2 did show efficacy, Phase 2 would have shown a multiple dose schedule was the optimal way forward. My point is we are finding the therapeutic dose, it is a question of finding what works best.

Based on all available data to date, we could say drug does nothing or the lawn effect impacted results. If we go with the drug indeed did nothing explanation then we must explain the significant WRS improvements in the single dose trials.

The fact that multiple dose did not produce an effect does not suggest that the effect we saw with single dose is invalid.

I do agree that the lawn effect needs to be proven but successful single dose trials could prove that.

I think we might be talking about different things. You're talking about where out intuition will start going based on the remaining Phase 1bs, and I'm talking about what really constitutes a proof.

I'm suggesting that no matter what we think, a scientific process can't sample for safety and then show off the efficacy, then sample for efficacy and say there's enough safety to lean on the efficacy of the safety trials. The problem is that the sampling techniques are not the same because the inclusion and exclusion criteria is different.

Think of it this way. One thing we were all very optimistic about (I definitely was) was the thought of knowing that they were recruiting for Phase 2 with efficacy filters. Keep in mind, this trial had the advantage of them looking for people like the responders in Phase 1/2. It still was an abysmal failure. This makes us think that the drug is either really ineffective or that quadruple injections of something (drug or placebo) is super unsafe. Well, if we are going to cite efficacy from the Phase 1 trials, we should then cite a safety risk from the Phase 2a. Even then, why did the placebos improve? I guess the fact that the placebo group wasn't harmed makes us wonder about the lawn theory, but we really don't know.

I'm totally with you that we have to figure out what happens when the people double word scores. Is it all dishonesty (I doubt this is the case)? Is the drug working a lot on some people (what I suspect)? Do people fundamentally take the test differently when they want to fail versus want to succeed (i.e. more guessing)?

I'm rooting for the Phase 1b's. If they are successful, I will conjecture in my mind that the drug may sometimes work. But it still has to demonstrate that in a well-run Phase 2 repeat trial.

 

[FGG]

I think we might be talking about different things. You're talking about where out intuition will start going based on the remaining Phase 1bs, and I'm talking about what really constitutes a proof.

I'm suggesting that no matter what we think, a scientific process can't sample for safety and then show off the efficacy, then sample for efficacy and say there's enough safety to lean on the efficacy of the safety trials. The problem is that the sampling techniques are not the same because the inclusion and exclusion criteria is different.

Think of it this way. One thing we were all very optimistic about (I definitely was) was the thought of knowing that they were recruiting for Phase 2 with efficacy filters. Keep in mind, this trial had the advantage of them looking for people like the responders in Phase 1/2. It still was an abysmal failure. This makes us think that the drug is either really ineffective or that quadruple injections of something (drug or placebo) is super unsafe. Well, if we are going to cite efficacy from the Phase 1 trials, we should then cite a safety risk from the Phase 2a. Even then, why did the placebos improve? I guess the fact that the placebo group wasn't harmed makes us wonder about the lawn theory, but we really don't know.

I'm totally with you that we have to figure out what happens when the people double word scores. Is it all dishonesty (I doubt this is the case)? Is the drug working a lot on some people (what I suspect)? Do people fundamentally take the test differently when they want to fail versus want to succeed (i.e. more guessing)?

I'm rooting for the Phase 1b's. If they are successful, I will conjecture in my mind that the drug may sometimes work. But it still has to demonstrate that in a well-run Phase 2 repeat trial.

Based on their statements, this was how I interpreted the situation:

-- All groups improved their word scores including placebo (the company cites "inconsistency" they found later in histories for this lack of difference). They didn't have any big WS jumps as in the single dose studies.

-- Multi dosing reduced efficacy in all treatment groups compared to single dose but did not result in no word improvements, just a dampened effect which would confuse it further in placebo comparison.

Remember, some people *again* doubled word scores in Phase 1b and Frequency Therapeutics did not cite the same "inconsistencies" with that trial. So those participants got a single injection and no inconsistency was reported.

As far as audiograms, correct me if I'm wrong, but they didn't say individuals didn't improve just that the group did not statistically improve.

What this would mean, for instance, if that anecdote were correct hypothetically, that person got 3 different 5-10 dB improvements (including in the EHF), while others did not (which makes sense with the IHC theory, for instance). But it also may look better on the single arm.

They did also seem to say (can someone else verify this?) that the more injections of drug you got, the efficacy worsened vs one injection of drug period.

In other words: 4 rapid injections were detrimental across the board regardless of what they contained but it was even worse when they contained drug.

They also said, and this may be key to understanding why this is depending on what they were, that there were more side effects with more drug doses.

It actually seems like the problem with Phase 2a dosing may be multi factorial: fluid overload or imbalance and some factor with the drug itself when given that way, either inflammatory, biochemical, signaling, etc, who knows.

Perfect shit storm that would require a "re-do" hopefully as a single dose with better trial design.

The severe group data could at least test both potential issues, though: rapid multi-dosing lowering effectiveness and inconsistency in word scores.

It's funny because "the drug may work great but only for some people" is an assumption only because first you have to figure out why they got the results they did. There are scenarios where it could help across the board with hair cell loss but has to be given differently.

I really hope they release the individual results for Phase 2a (including audiograms) but especially word scores with notes on which patients inconsistencies were found in.

 

[kiki]

I'm so sorry. I never thought FX-322 would make or break my situation (good chance it does nothing).

One reason why I think I can adjust to the "long-term" approach more is because it's always been long-term for me. I really wanted FX-322 to succeed because it would clear an important barrier, allowing for more cash flow and further advancements. I need a cure for autoimmunity and probably a host of regeneration type of drugs to try to see what sticks.

What I'm the most shaken by is just how hard it is for these things to succeed. I read the papers; this thing was (and really still is) legit. I share your sentiment about all of the calculations. If the best case scenario is 5 years, it's probably more like 10-20. So depressing.

If I believed this drug was picture perfect for my problems, I would be so much more devastated. Really sad stuff. Sorry everyone.

Dear @Zugzug,

It's great that you are an authority on mathematics and statistics.

But it's too difficult for me.

What is the mathematical and statistical basis for 10 to 20 years?

Please tell me, please.

Don't get depressed if you don't have a basis.

I don't know the future.

 

[Sunshine007]

I think we might be talking about different things. You're talking about where out intuition will start going based on the remaining Phase 1bs, and I'm talking about what really constitutes a proof.

I'm suggesting that no matter what we think, a scientific process can't sample for safety and then show off the efficacy, then sample for efficacy and say there's enough safety to lean on the efficacy of the safety trials. The problem is that the sampling techniques are not the same because the inclusion and exclusion criteria is different.

Think of it this way. One thing we were all very optimistic about (I definitely was) was the thought of knowing that they were recruiting for Phase 2 with efficacy filters. Keep in mind, this trial had the advantage of them looking for people like the responders in Phase 1/2. It still was an abysmal failure. This makes us think that the drug is either really ineffective or that quadruple injections of something (drug or placebo) is super unsafe. Well, if we are going to cite efficacy from the Phase 1 trials, we should then cite a safety risk from the Phase 2a. Even then, why did the placebos improve? I guess the fact that the placebo group wasn't harmed makes us wonder about the lawn theory, but we really don't know.

I'm totally with you that we have to figure out what happens when the people double word scores. Is it all dishonesty (I doubt this is the case)? Is the drug working a lot on some people (what I suspect)? Do people fundamentally take the test differently when they want to fail versus want to succeed (i.e. more guessing)?

I'm rooting for the Phase 1b's. If they are successful, I will conjecture in my mind that the drug may sometimes work. But it still has to demonstrate that in a well-run Phase 2 repeat trial.

Ultimately the proof that the drug works and is safe is confirmed in a pivotal trial.We need to know the dose to do that. It's not clear to me that a Phase 2 trial needs to demonstrate a level of efficacy to advance to pivotal. While Phase 1 was designed to explore safety it demonstrated efficacy. Phase 2 was designed to find the therapeutic dose and demonstrate safety on a larger n and it was not designed or powered to demonstrate efficacy either.

What is the safety risk you are alluding to in the Phase 2a? Based on my understanding there were no adverse events reported. While clearly quadruple injections were not effective, am not sure we can say they were unsafe.

Regarding lawn theory in placebo argument, the placebo mechanism of action is different from the drug, so am not sure we can reason that the lawn theory argument must apply to the placebo.

I definitely agree we don't yet know the responder population. I also agree we do not have a good explanation on what might have caused the placebo improvement.

 

[GBB]

The evidence against this not working is substantial.

Change my mind. I wish you could.

Well for one this is a double negative, so you said the evidence it is working is substantial, so do we even have to try?

 

[Zugzug]

Dear @Zugzug,

It's great that you are an authority on mathematics and statistics.

But it's too difficult for me.

What is the mathematical and statistical basis for 10 to 20 years?

Please tell me, please.

I arrived at the 10-20 year thing off of conservative, pessimistic feelings. To be honest, if there isn't something out within 20 years, that is really hard to believe.

Here's some math for you:

Phase 1/2 started on July 3, 2018 and ended on April 1, 2019 (Clinical Trial). The press results were released on April 9, 2019. Hence, it took about 9 months to complete the study and announce plans for a Phase 2a.

Phase 2a started on October 4, 2019 and ended on October 6, 2020 (Clinical Trial). Hence, it took about 12 months. The time between the end of Phase 1/2 and the beginning of Phase 2a was 6 months. The press results were released on March 23, 2021, with anticipated full 210 day results to be released late Q2, 20201 so (let's say) July 1, 2021. Hence, time from end of study to final press release is 9 months. This is when they would have announced plans to start Phase 3, which would probably start 6 months after the press release.

If those numbers repeat, the total time until a Phase 3 would start (best case scenario) would be:

9 months (3 months for day 210 readout, then 6 more months until recruiting for second Phase 2a starts)
+ 12 months (completion of trial)
+9 months (final press release on second day 210 Phase 2a results)
= 30 months.

In other words, if the exact same timeline repeated, starting from ~today, it's about 30 months just to releasing plans to eventually start a Phase 3 trial.

Then let's say 6 months (best case scenario) until Phase 3 recruiting starts. Then the trial itself will take, best case scenario, 1 year. Then another 9-12 months until results are released. Then if successful, presumably they would file for Breakthrough Therapy status when they applied for their NDA (New Drug Application), which if approved, passes things along in about 2 months. From there, I have no idea.

The total amount of time is 30 + 6 + 12 + 12 + 2 = 62 months. In other words, a best case scenario, with successful trials and Breakthrough Therapy status granted, is about 5 years.

Where does this shoot up?

If Phase 2a repeat is another failure, presumably, the operation fails. If it passes Phase 2a repeat, but then fails Phase 3 the first time, we are looking at another long delay. So if the company makes it through the finish line with more major setbacks, that probably pushes it to about 7-10 years.

If FX-322 just fails completely, we would be looking at OTO-6XX (pre-clinical) to then have the same path that FX-322 had. Decibel Therapeutics also has a drug for hair cell regeneration in the discovery phase. Hough Ear Institute has a silencing RNA hair cell regeneration drug that's preclinical. Who knows how long at least one of those takes (by who, I mean @FGG)?

Of course, there are other drugs, but I believe these are the hair cell drugs to watch for.

Upon further analysis, it's probably more like 10-15 years, but I am padding it 10-20 years with extra bear padding.

 

[Sunshine007]

Based on their statements, this was how I interpreted the situation:

-- All groups improved their word scores including placebo (the company cites "inconsistency" they found later in histories for this lack of difference). They didn't have any big WS jumps as in the single dose studies.

-- Multi dosing reduced efficacy in all treatment groups compared to single dose but did not result in no word improvements, just a dampened effect which would confuse it further in placebo comparison.

Remember, some people *again* doubled word scores in Phase 1b and Frequency Therapeutics did not cite the same "inconsistencies" with that trial. So those participants got a single injection and no inconsistency was reported.

As far as audiograms, correct me if I'm wrong, but they didn't say individuals didn't improve just that the group did not statistically improve.

What this would mean, for instance, if that anecdote were correct hypothetically, that person got 3 different 5-10 dB improvements (including in the EHF), while others did not (which makes sense with the IHC theory, for instance). But it also may look better on the single arm.

They did also seem to say (can someone else verify this?) that the more injections of drug you got, the efficacy worsened vs one injection of drug period.

In other words: 4 rapid injections were detrimental across the board regardless of what they contained but it was even worse when they contained drug.

They also said, and this may be key to understanding why this is depending on what they were, that there were more side effects with more drug doses.

It actually seems like the problem with Phase 2a dosing may be multi factorial: fluid overload or imbalance and some factor with the drug itself when given that way, either inflammatory, biochemical, signaling, etc, who knows.

Perfect shit storm that would require a "re-do" hopefully as a single dose with better trial design.

The severe group data could at least test both potential issues, though: rapid multi-dosing lowering effectiveness and inconsistency in word scores.

It's funny because "the drug may work great but only for some people" is an assumption only because first you have to figure out why they got the results they did. There are scenarios where it could help across the board with hair cell loss but has to be given differently.

I really hope they release the individual results for Phase 2a (including audiograms) but especially word scores with notes on which patients inconsistencies were found in.

Based on my understanding Frequency Therapeutics is saying all arms, all doses behaved the same. All treatment arms were impacted by the lawn theory. There is just a lot riding on lawn theory here because ordinarily we would expect to see the 1 dose cohort perform the same as past trials. They did say it's unlikely that day 210 would be much different from the day 90.

 

[FGG]

I arrived at the 10-20 year thing off of conservative, pessimistic feelings. To be honest, if there isn't something out within 20 years, that is really hard to believe.

Here's some math for you:

Phase 1/2 started on July 3, 2018 and ended on April 1, 2019 (Clinical Trial). The press results were released on April 9, 2019. Hence, it took about 9 months to complete the study and announce plans for a Phase 2a.

Phase 2a started on October 4, 2019 and ended on October 6, 2020 (Clinical Trial). Hence, it took about 12 months. The time between the end of Phase 1/2 and the beginning of Phase 2a was 6 months. The press results were released on March 23, 2021, with anticipated full 210 day results to be released late Q2, 20201 so (let's say) July 1, 2021. Hence, time from end of study to final press release is 9 months. This is when they would have announced plans to start Phase 3, which would probably start 6 months after the press release.

If those numbers repeat, the total time until a Phase 3 would start (best case scenario) would be:

9 months (3 months for day 210 readout, then 6 more months until recruiting for second Phase 2a starts)
+ 12 months (completion of trial)
+9 months (final press release on second day 210 Phase 2a results)
= 30 months.

In other words, if the exact same timeline repeated, starting from ~today, it's about 30 months just to releasing plans to eventually start a Phase 3 trial.

Then let's say 6 months (best case scenario) until Phase 3 recruiting starts. Then the trial itself will take, best case scenario, 1 year. Then another 9-12 months until results are released. Then if successful, presumably they would file for Breakthrough Therapy status when they applied for their NDA (New Drug Application), which if approved, passes things along in about 2 months. From there, I have no idea.

The total amount of time is 30 + 6 + 12 + 12 + 2 = 62 months. In other words, a best case scenario, with successful trials and Breakthrough Therapy status granted, is about 5 years.

Where does this shoot up?

If Phase 2a repeat is another failure, presumably, the operation fails. If it passes Phase 2a repeat, but then fails Phase 3 the first time, we are looking at another long delay. So if the company makes it through the finish line with more major setbacks, that probably pushes it to about 7-10 years.

If FX-322 just fails completely, we would be looking at OTO-6XX (pre-clinical) to then have the same path that FX-322 had. Decibel Therapeutics also has a drug for hair cell regeneration in the discovery phase. Hough Ear Institute has a silencing RNA hair cell regeneration drug that's preclinical. Who knows how long at least one of those takes (by who, I mean @FGG)?

Of course, there are other drugs, but I believe these are the hair cell drugs to watch for.

Upon further analysis, it's probably more like 10-15 years, but I am padding it 10-20 years with extra bear padding.

I couldn't even begin to speculate on anything with Hough Ear Institute. They are the true wildcard imo.

Another company with a hair cell regeneration drug listed on their website in pre-clinical is Akouos (this is separate from their genetic hearing loss treatments). I don't know anything more about it. Both Akouos and Decibel Therapeutics are now publicly traded so it's easier to monitor their progress.

My guess is if FX-322 runs another Phase 2a: 3-5 years. I still don't see them going straight to pivotal even with great remaining Phase 1b results. They have too much to work through (would be great to be wrong though).

These other companies, if successful, would be 6-8 years depending on how long trials are and when they file their INDs.

 

[kiki]

I arrived at the 10-20 year thing off of conservative, pessimistic feelings. To be honest, if there isn't something out within 20 years, that is really hard to believe.

Here's some math for you:

Phase 1/2 started on July 3, 2018 and ended on April 1, 2019 (Clinical Trial). The press results were released on April 9, 2019. Hence, it took about 9 months to complete the study and announce plans for a Phase 2a.

Phase 2a started on October 4, 2019 and ended on October 6, 2020 (Clinical Trial). Hence, it took about 12 months. The time between the end of Phase 1/2 and the beginning of Phase 2a was 6 months. The press results were released on March 23, 2021, with anticipated full 210 day results to be released late Q2, 20201 so (let's say) July 1, 2021. Hence, time from end of study to final press release is 9 months. This is when they would have announced plans to start Phase 3, which would probably start 6 months after the press release.

If those numbers repeat, the total time until a Phase 3 would start (best case scenario) would be:

9 months (3 months for day 210 readout, then 6 more months until recruiting for second Phase 2a starts)
+ 12 months (completion of trial)
+9 months (final press release on second day 210 Phase 2a results)
= 30 months.

In other words, if the exact same timeline repeated, starting from ~today, it's about 30 months just to releasing plans to eventually start a Phase 3 trial.

Then let's say 6 months (best case scenario) until Phase 3 recruiting starts. Then the trial itself will take, best case scenario, 1 year. Then another 9-12 months until results are released. Then if successful, presumably they would file for Breakthrough Therapy status when they applied for their NDA (New Drug Application), which if approved, passes things along in about 2 months. From there, I have no idea.

The total amount of time is 30 + 6 + 12 + 12 + 2 = 62 months. In other words, a best case scenario, with successful trials and Breakthrough Therapy status granted, is about 5 years.

Where does this shoot up?

If Phase 2a repeat is another failure, presumably, the operation fails. If it passes Phase 2a repeat, but then fails Phase 3 the first time, we are looking at another long delay. So if the company makes it through the finish line with more major setbacks, that probably pushes it to about 7-10 years.

If FX-322 just fails completely, we would be looking at OTO-6XX (pre-clinical) to then have the same path that FX-322 had. Decibel Therapeutics also has a drug for hair cell regeneration in the discovery phase. Hough Ear Institute has a silencing RNA hair cell regeneration drug that's preclinical. Who knows how long at least one of those takes (by who, I mean @FGG)?

Of course, there are other drugs, but I believe these are the hair cell drugs to watch for.

Upon further analysis, it's probably more like 10-15 years, but I am padding it 10-20 years with extra bear padding.

Thank you.

I hope it will be the best scenario.

I think the second Phase 2a will be multiple injections at long intervals.

I think it will be possible to shorten the preparation period and eliminate bias by making future clinical trials "catch all," which @Diesel used to say.

 

[Lucifer]

Based on my understanding Frequency Therapeutics is saying all arms, all doses behaved the same. All treatment arms were impacted by the lawn theory. There is just a lot riding on lawn theory here because ordinarily we would expect to see the 1 dose cohort perform the same as past trials. They did say it's unlikely that day 210 would be much different from the day 90.

This is why I'm on team bull. They have done two Phase 1b trials that showed that FX-322 was safe and patients improved their word scores, where a few of them doubled their word scores. This has never happened before in the history of regenerative medicine for the ear.

The severe hearing loss trial will be the one that is going to determine whether FX-322 can move to the pivotal phase or not. The question is if it does restore high-mid frequencies for severe hearing loss sufferers like the previous Phase 1b trials have shown, what would be the things that severe hearing loss sufferers are able to hear when those high-mid frequencies are regenerated? Would restoring high-mid frequencies make a difference for a severe hearing loss sufferer?

 

[kiki]

I think it will be possible to shorten the preparation period and eliminate bias by making future clinical trials "catch all," which @Diesel used to say.

Append.

What is "catch all"?

I think it means that they do not select applicants for clinical trials.

 

[Lucifer]

What is "catch all"?

I think it means that they do not select applicants for clinical trials.

Catch all means to unblind some of the data. With the Phase 2a trial it was quadruple blinding and if Frequency Therapeutics could have looked at the data earlier on, it could have allowed them to remove those fakers in the trial.

I'm glad moving forward they are going to be using a single dose of FX-322 so this should make the trials a lot shorter and I expect it to show meaningful improvements like the 2 previous Phase 1b trials did.

 

[Zugzug]

Phase 2 was designed to find the therapeutic dose and demonstrate safety on a larger n and it was not designed or powered to demonstrate efficacy either.

Respectfully, this is just not true. The entire point of Phase 2 is efficacy. It's almost like a break from safety (relatively speaking, of course, safety is always a big concern). Phase 1 is almost entirely safety with flashy, exploratory statistics that aren't even intended for inference, and if efficacy is demonstrated in Phase 2, then Phase 3 returns to more safety and honing in on adverse effects for as many patient populations as possible.

There's just no argument that efficacy matters more for the n=23 safety trial than the n=96 powered up efficacy trial. We are only saying this because Phase 1 was effective, while Phase 2 wasn't.

What I was referring to about lawn theory and safety is more long-term, unknown effects. Sure, it sounds nice to say "some hair cells were developing and then a new injection just innocently stopped this process." Wait a minute. Why are my new growing cells dying? What does this mean for my chances of successful PCA in the future? What about successful transdifferentiation?

Don't get me wrong, I'm sure it's all fine, but we can't just always fit the narrative to what we want. Phase 1 is efficacy now, Phase 2 is safety now, but there's a weird, damaging theory to explain the safety concerns. This isn't science.

I'm really sorry to anyone who thinks I sound like an asshole. I really hate it, but it's just so wrong to pretend like top scientific reviewers are going to view what happened like this.

If there's a path forward with a butchered Phase 2, it's almost entirely based on a lack of current treatments and someone viewing a lower bar more favorably. It has nothing to do with rewriting the phases.

 

[Tezcatlipoca]

If there's a path forward with a butchered Phase 2, it's almost entirely based on a lack of current treatments and someone viewing a lower bar more favorably. It has nothing to do with rewriting the phases.

That's good enough for me lol, and I think for the FDA as well.

 

[Lucifer]

If there's a path forward with a butchered Phase 2, it's almost entirely based on a lack of current treatments and someone viewing a lower bar more favorably. It has nothing to do with rewriting the phases.

I know it's a long shot but I wonder if the FDA and Frequency Therapeutics had a similar discussion like that talking about the possibility of completing a pivotal phase on the outcome of the age-related and severe hearing loss trials. I wouldn't be surprised if it happened. Hearing loss is an unmet need and costing the whole world millions each year. Even with a 30-40% improvement it may be enough to get it approved. It doesn't have to be 100% perfect.

 

[mrbrightside614]

Trobalt is the drug that had visual snow as a side effect, right? And this new drug is similar to Trobalt and doesn't have that side effect?

Not sure yet, early days. Correct on the visual snow charge about Trobalt though. If it was on the market I would've tried it as it was, though. But that's another story for another thread.

There was a girl on here that claimed Lenire completely cured her tinnitus. This is the nature of anecdotes.

I'm still on the fence in all of this. I need to see something that makes me believe.

The difference is that Lenire seems very volatile. In terms of safety and efficacy risk/reward, I'd say FX-322 wins every time but I understand the sentiment.

 

[Street Novelist]

If Mr. Lucchino or McLean are reading this thread, we just want to get our hearing back. I don't care how much we'll have to pay. Whatever the cost... but please don't delay the upcoming phase/trial... so many of us are already on the ledge

 

[kiki]

I seriously want them to do a "Phase 2B" that is a single-dose "catch all" for all the different Phase 1B designations. IE: Mild-Severe SNHL/NIHL, Mild-Moderately Severe ARHL. Recruit a few hundred patients. 1 Dose, follow-up over 6 months. There needs to be larger efficacy data for each class of patient over a longer period. If this is the route, it may not take long to fill up recruiting.

Dear @Diesel,

My understanding may be wrong.

Please tell me the meaning of "catch all".

I think it means that they do not select applicants for clinical trials.

I think it will be possible to shorten the recruit period and eliminate bias by making future clinical trials "catch all."

I'm thinking like a "catch-all" account in an email.

 

[Sunshine007]

Respectfully, this is just not true. The entire point of Phase 2 is efficacy. It's almost like a break from safety (relatively speaking, of course, safety is always a big concern). Phase 1 is almost entirely safety with flashy, exploratory statistics that aren't even intended for inference, and if efficacy is demonstrated in Phase 2, then Phase 3 returns to more safety and honing in on adverse effects for as many patient populations as possible.

There's just no argument that efficacy matters more for the n=23 safety trial than the n=96 powered up efficacy trial. We are only saying this because Phase 1 was effective, while Phase 2 wasn't.

What I was referring to about lawn theory and safety is more long-term, unknown effects. Sure, it sounds nice to say "some hair cells were developing and then a new injection just innocently stopped this process." Wait a minute. Why are my new growing cells dying? What does this mean for my chances of successful PCA in the future? What about successful transdifferentiation?

Don't get me wrong, I'm sure it's all fine, but we can't just always fit the narrative to what we want. Phase 1 is efficacy now, Phase 2 is safety now, but there's a weird, damaging theory to explain the safety concerns. This isn't science.

I'm really sorry to anyone who thinks I sound like an asshole. I really hate it, but it's just so wrong to pretend like top scientific reviewers are going to view what happened like this.

If there's a path forward with a butchered Phase 2, it's almost entirely based on a lack of current treatments and someone viewing a lower bar more favorably. It has nothing to do with rewriting the phases.

I meant in a Phase 2 trial we are looking for a signal and trying to find the right dose. I do not think a Phase 2 is powered to observe statistically significant effect vs placebo.

Usually there is an arm in the Phase 2 trial that does exactly what was observed in the Phase 1 trial but with a larger n. Unfortunately we do not have that here. Lawn theory aside, the 1X arm ought to be equivalent to the single shot studies.

I will point out though every single arm Phase1 and Phase 2 has about 24 people, we have the n=96 because because that trial had 4 arms. Really the only difference is placebo n=4 vs n=24. Bottom line is you got to go where you see the signal, it so happens this is in an earlier arm.

Hypothetically if in the 4X arm (n=24) we saw the same effect we saw earlier in Phase 1 (also n=24), we would say we saw a signal in the 4X arm. If am understanding you right you are saying this would be a valid signal but somehow the same signal is not valid from the earlier Phase 1 because of the difference in n in the placebo group?

Also, the safety issue due to multiple injections would only be an issue when we do the multiple dose not when pursuing the single dose. I sure hope we do not end up with a not enough seed theory to accompany the lawn theory in which case it might be front and center.

All the points you are making are valid, am just TRYING to present an alternate point of view

 

[Billy_Shears]

The science behind PCA is groundbreaking medical technology and FX-322 has been proven to increase audibility and clarity in trail participants with mild-moderate sensorineural hearing loss. In regard to Phase 2a, there was a bias within the trial design and it wouldn't surprise me if not the participants, but selective audiologists at trial centers being 'the fox watching the hen house'. FX-322 works and along its path to glory it will be 'stepping on some toes'.

FREQ is currently supported by three Wall Street analysts as a Strong Buy for the next 12 months with an average PT of $37/share within a year. The next two catalysts, severe hearing loss and the 66-85 year age group will speak volumes about the stealth of FX-322.

 

[ThomasC]

So hearing regenerative drugs are just not going to be available anytime soon. I'm really sad.

I guess our best luck are Kv7.2/3 channel modulators and maybe brain stimulation to a certain extent.

 

[Ed209]

The difference is that Lenire seems very volatile. In terms of safety and efficacy risk/reward, I'd say FX-322 wins every time but I understand the sentiment.

I wasn't comparing Lenire to FX-322. I was comparing the anecdotes. In both examples, they claimed that their tinnitus went away. If Lenire's efficacy is reportedly poor, or underwhelming, then you could argue that her improvement may not have been related to it. The same is true of the FX-322 anecdote, and that's why they are not proof of anything and must be taken for what they are.

 

[Tezcatlipoca]

Can Potassium ion channel openers be safe? Can they be a realistic long term medication for tinnitus?

 

[Diesel]

Dear @Diesel,

My understanding may be wrong.

Please tell me the meaning of "catch all".

I think it means that they do not select applicants for clinical trials.

I think it will be possible to shorten the recruit period and eliminate bias by making future clinical trials "catch all."

I'm thinking like a "catch-all" account in an email.

My opinion has been lately that it might be that they go with one of two strategies:

A new Phase 2 that includes all designations that have been trialed under the Phase 1Bs. This is the "catch-all" term. Because they're accepting basically all hearing loss classes, there is no incentive to cheat.

or

A Phase 2 that is super focused on a specific hearing loss class that have been observed a being consistently great responders, that are not able to cheat. Like the moderately-severe hearing group only.

 

[FGG]

Can Potassium ion channel openers be safe? Can they be a realistic long term medication for tinnitus?

We can at least say they are being developed for long term use because the indication they are being tested for (seizures) requires long term use.

The goal is to make them safe enough for that use.

 

[Zugzug]

In regard to Phase 2a, there was a bias within the trial design and it wouldn't surprise me if not the participants, but selective audiologists at trial centers being 'the fox watching the hen house'.

Oh, come on. I agree with you that PCA is groundbreaking and the long-term outlook is really positive. But there's no conspiracy of audiologists telling people to lie or trying to tank tests. They just failed the trial.

 

[Zugzug]

I meant in a Phase 2 trial we are looking for a signal and trying to find the right dose. I do not think a Phase 2 is powered to observe statistically significant effect vs placebo.

Usually there is an arm in the Phase 2 trial that does exactly what was observed in the Phase 1 trial but with a larger n. Unfortunately we do not have that here. Lawn theory aside, the 1X arm ought to be equivalent to the single shot studies.

I will point out though every single arm Phase1 and Phase 2 has about 24 people, we have the n=96 because because that trial had 4 arms. Really the only difference is placebo n=4 vs n=24. Bottom line is you got to go where you see the signal, it so happens this is in an earlier arm.

Hypothetically if in the 4X arm (n=24) we saw the same effect we saw earlier in Phase 1 (also n=24), we would say we saw a signal in the 4X arm. If am understanding you right you are saying this would be a valid signal but somehow the same signal is not valid from the earlier Phase 1 because of the difference in n in the placebo group?

Also, the safety issue due to multiple injections would only be an issue when we do the multiple dose not when pursuing the single dose. I sure hope we do not end up with a not enough seed theory to accompany the lawn theory in which case it might be front and center.

All the points you are making are valid, am just TRYING to present an alternate point of view

I appreciate your perspective. I just don't totally understand.

So where I can partially agree with you is that a Phase 2a often does have some exploratory aspect to dosing. But make no mistake about it -- this is not a big experiment. They definitely thought that multiple dosing would either help or do nothing more than 1x. There's no way they expected it to dampen the effects.

My main point about the phases is that the recruiting methods are different. Think of it like this. For Phase 1/2 recruiting, they don't have the knowledge of what responders look like. For Phase 2a recruiting, they do. Hence, between the larger sample size, nature of the fact that Phase 2 = efficacy, and the fact that they sort of got to hand select expected responders, means that this Phase 2a should have delivered the goods.

It did not, which means we have to have a really open mind about what's happening. The doubling of word scores is a huge part of the diagnostics. I'm sorry, but they can't say in the paper that the Phase 1/2 statistical analysis is "exploratory," but then conveniently fall back on it because the efficacy failed.

There's a reason why the phases are designed in the way that they are. Phase 1 is safety, safety, safety because that's the most important thing in medicine. Phase 2 then has a rise in efficacy interest with more safety monitoring. If these are both successful, more big picture things are considered for Phase 3, such as efficacy and safety over more diverse and numerous population types. Phase 3 is sort of a strong confirmation that Phase 1 safety and Phase 2 efficacy live up to the hype.

I agree that Phase 1 efficacy is exciting on an emotional level. But I'm just being honest, if the Phase 1 efficacy was really mediocre, while Phase 2 efficacy was a slam dunk, I would be writing letters to the FDA to allow compassionate use. I wish it wasn't the case, but the bad efficacy in Phase 2 overrides the efficacy in Phase 1. We still should make sense of super responders though.