Frequency Therapeutics — Hearing Loss Regeneration

[xyz]

Wall Street is treating it as if it doesn't work because FREQ shot themselves in the foot by switching from single dose to multi dose when they went from Stage 1 to Stage 2.

I guess nobody knew this and most thought the more shots you get the better.

Probably if you inject anything in the cochlear you are causing first irritation/inflammation and the drug has to make up for that. Maybe that's also the reason there were so many adverse side effects in the placebo group of OTO-313. But it could be that Otonomy has a gel that is more liked by the inner ear, let's see.

 

[Street Novelist]

If your synapses are fine but your hair cells are damaged, does that mean PIPE-505 and OTO-413 won't help you? Is FX-322 the main drug that regrows the hair cells?

 

[Pete88]

If your synapses are fine but your hair cells are damaged, does that mean PIPE-505 and OTO-413 won't help you? Is FX-322 the main drug that regrows the hair cells?

Your synapses are likely damaged. You have also lost hair cells. Both drugs that regenerate either synapses or hair cells will give you some benefit. It is argued that synapses are even more fragile than hair cells and may play a larger roll in hearing than they are credited for.

Point is, you'll need both to have excellent hearing but having one will likely still bring a lot of benefit.

To answer your last question though, yes, FX 322 grows the hair cells but you will benefit from either regeneration.

 

[serendipity1996]

If your synapses are fine but your hair cells are damaged, does that mean PIPE-505 and OTO-413 won't help you? Is FX-322 the main drug that regrows the hair cells?

FX-322 is focused mostly on hair cell regeneration - it only regenerates synapses if the corresponding hair cell is damaged. However, given that synapses are the most vulnerable to damage, I think it would be very unusual for someone to have hair cell loss but no synaptopathy. Certainly, when it comes to noise damage, synaptopathy has been shown to precede hair cell loss.

 

[Tezcatlipoca]

Your synapses are likely damaged. You have also lost hair cells. Both drugs that regenerate either synapses or hair cells will give you some benefit. It is argued that synapses are even more fragile than hair cells and may play a larger roll in hearing than they are credited for.

Point is, you'll need both to have excellent hearing but having one will likely still bring a lot of benefit.

To answer your last question though, yes, FX 322 grows the hair cells but you will benefit from either regeneration.

For noise-induced hearing loss synaptogenesis may be even a bigger deal than hair cell loss.

 

[Chad Lawton]

I guess nobody knew this and most thought the more shots you get the better.

Probably if you inject anything in the cochlear you are causing first irritation/inflammation and the drug has to make up for that.

If you think about it, the healing process of the body works through chemical messaging systems. Whether it's the blood coagulation cascade, bone osteoblasts or neural stem cells. In most instances of drugs we use today, we introduce said drugs through the digestive track or IV administration and they are absorbed through the blood stream and that is how they reach the target tissue.

In the case of FX-322, we are applying the drug directly to the tissue itself rather than letting the body handle the administration. It makes sense to me that multiple dosing could screw things up because you're interrupting the long and ongoing chemical processes for healing every time you try to introduce more drug or placebo. Like the analogy I used before, it would be like trying to bake a cake but opening the oven door every 5 minutes to add another egg and more flour.

 

[Tezcatlipoca]

If you think about it, the healing process of the body works through chemical messaging systems. Whether it's the blood coagulation cascade, bone osteoblasts or neural stem cells. In most instances of drugs we use today, we introduce said drugs through the digestive track or IV administration and they are absorbed through the blood stream and that is how they reach the target tissue.

In the case of FX-322, we are applying the drug directly to the tissue itself rather than letting the body handle the administration. It makes sense to me that multiple dosing could screw things up because you're interrupting the long and ongoing chemical processes for healing every time you try to introduce more drug or placebo. Like the analogy I used before, it would be like trying to bake a cake but opening the oven door every 5 minutes to add another egg and more flour.

Yup, that's why both single dose trials have been successful; get the goop in and let it do its work, don't fuck around with it until it's done its job.

 

[Pete88]

Yup, that's why both single dose trials have been successful; get the goop in and let it do its work, don't fuck around with it until it's done its job.

Sorry, I must have missed something. What are the two successful single dose trials? I only know of the Phase 1 safety trial from a couple of years ago. What are the Coles Notes of this second trial?

 

[ThomasRobert]

Sorry, I must have missed something. What are the two successful single dose trials? I only know of the Phase 1 safety trial from a couple of years ago. What are the Coles Notes of this second trial?

FX-322 Phase 1b – 111 Study (Open Label).

 

[GlennS]

There are no successful trials if you're expecting improved audiograms.

 

[Diesel]

There are no successful trials if you're expecting improved audiograms.

View attachment 45125

"Three patients who had durable improvements in intelligibility also had pure tone audiometry improvements of 10-15 dB at the highest frequency tested (8 kHz)."

Is a pure tone audiometry improvement at 8 kHz part of the audiogram?

 

[Pete88]

"Three patients who had durable improvements in intelligibility also had pure tone audiometry improvements of 10-15 dB at the highest frequency tested (8 kHz)."

Is a pure tone audiometry improvement at 8 kHz part of the audiogram?

View attachment 45126

So I 100% think the Phase 1/2 results are very promising because when you look at the data, the people who had room to improve a lot, all improved a lot and the people who had room to improve a little, improved a little. I think it looked amazing. The only thing unfortunately missing was that they didn't do an extended audiogram to prove it increased the hearing ability at higher frequencies. If they had done that, it would have been a slam dunk.

Regarding this Phase 1b study, it seems very underwhelming when I read the statements without having the whole picture. So 34 percent of people had a 10% increase in word scores? That's it? Sure, a few people had near doubling, but how many people had poor audiograms that had room to double? To be fair, the Phase 1/2 data didn't look as impressive until all the data was broken down. Is that the same thing here?

What about extended audiograms? Did they again not test for higher frequencies using an extended audiogram?

 

[Kleiner]

"Three patients who had durable improvements in intelligibility alsohad pure tone audiometry improvements of 10-15 dB at the highest frequency tested (8 kHz)."

Is a pure tone audiometry improvement at 8 kHz part of the audiogram?

View attachment 45126

There was no improvement in the audiogram in the Phase 1b-111 trial. I have serious doubts.

 

[Diesel]

There was no improvement in the audiogram in the Phase 1b-111 trial. I have serious doubts.

Where do they actually say that? Can you show me? I see that they disclosed no improvements for FX-322-112.

 

[Pete88]

Where do they actually say that? Can you show me? I see that they disclosed no improvements for FX-322-112.

Where do you see them mentioning any kind of audiogram improvement? They only mention some word score improvements.

I'm all for the theory that multiple dosing neutralizes the benefit but we have to be realistic with the second single dose study, which so far to me seems not nearly as impressive as the Phase 1/2 trial. I admit I know very little about this study but so far it seems nobody knows much about it but seem to hang just as much confidence in it despite apparently only being a fraction as successful as the first one. I thought they were testing higher frequencies after the Phase 1/2 trial? Why is this not receiving any attention? Is it because there simply isn't much information released?

 

[Chad Lawton]

Where do you see them mentioning any kind of audiogram improvement? They only mention some word score improvements.

I'm all for the theory that multiple dosing neutralizes the benefit but we have to be realistic with the second single dose study, which so far to me seems not nearly as impressive as the Phase 1/2 trial. I admit I know very little about this study but so far it seems nobody knows much about it but seem to hang just as much confidence in it despite apparently only being a fraction as successful as the first one. I thought they were testing higher frequencies after the Phase 1/2 trial? Why is this not receiving any attention? Is it because there simply isn't much information released?

In the slide that @Diesel posted above, they mention the pure tone audiometry improvements in the bottom right corner in blue font.

Both single-dose trials had almost identical results, 33% of patients improved 10% or more in both trials so I'm not sure why you say one trial did better than the other.

 

[Tezcatlipoca]

In the slide that @Diesel posted above, they mention the pure tone audiometry improvements in the bottom right corner in blue font.

Both single-dose trials had almost identical results, 33% of patients improved 10% or more in both trials so I'm not sure why you say one trial did better than the other.

He didn't read the slide I guess. We have known this information for 2 months now.

 

[Pete88]

In the slide that @Diesel posted above, they mention the pure tone audiometry improvements in the bottom right corner in blue font.

Both single-dose trials had almost identical results, 33% of patients improved 10% or more in both trials so I'm not sure why you say one trial did better than the other.

That's Phase 1/2. I'm talking about Phase 1b. I know Phase 1/2 was successful and in my opinion, it was great. I'm concerned about this second "successful" Phase, mainly because the first one had tons of data that when broken down, shows how good it was.

Phase 1b simply says "34 percent had 10 percent or more word score increase" along with 3 people doubling. OK, 3 people or so had doubling in Phase 1/2 too but that number is impressive because those few made up 100 percent of the people who were given the drug and had significant room for improvement.

In Phase 1b, there were over 30 people and from what I understand, all 30 received drug in one ear with the other ear acting as the placebo. So that means 3 out of 30 had doubling of word scores, 10 out of 30 or so had a 10 percent increase. 20 out of 30 or so had nothing to report? That does not sound like a success to me.

If there were 30 people in this study who had scored 20 out of 40 for word scores or whatever and only 3 of those 30 doubled, that is not the same as Phase 1/2 success at all. The ratio of eligible people who saw amazing improvements is much smaller. FX-322 goes from helping 100 percent of eligible people by a lot to helping a measly 10 percent of eligible people.

Now maybe that's not the case and there were again only 3 people who had room for improvement. That's cool, just show it then.

All I'm saying is that Phase 1/2 had all the information required to come to the conclusion that it was solid. Phase 1b, by comparison, is very vague to the point the success it is implying could be very underwhelming.

And again, please provide the audiograms for Phase 1b. If they don't exist, that concerns me as well. You would think after Phase 1/2, they would be wanting to conduct extended audiograms and, if successful, show them off. The apparent silence is concerning.

I believe that 10 dB improvement at 8,000 Hz is great and is something to be excited about. I'm just worried that Phase 1b isn't even half as good. Maybe I'm wrong, I'm just not seeing the same kind of data and fancy diagrams like we saw from Phase 1/2.

I don't want this to be an echo chamber where people only grasp on to nuggets of good news and then invest so much into it.

I would love for someone to show me Phase 1b data that puts my skepticism to rest. No need to show me Phase 1/2 data. I'm very aware of it and I think it's promising. I just want to see data that proceeded it to follow up on the promise.

 

[Pete88]

He didn't read the slide I guess. We have known this information for 2 months now.

I did read the slide. Unless I'm totally off, it seems to refer to Phase 1/2.

Where does this 2 month old information that audiograms improved in the recent Phase 1b study come from?

 

[Kleiner]

The Phase 1/2 results gave us hope because the improvements were impressive.

The same single injection procedure in Phase 1b 111 worked in 34% of subjects, with 10% absolute improvement.

These is the real results of the FX-322, not those of Phase 1/2.

I'm sure Frequency Therapeutics' science works, but they are unable to complete FX-322. Too many preventable mistakes have been made.

Their Phase 2 was conceived completely at random, on an uncertain bet, without any alternative solution.

It was a game of Russian roulette with 5 bullets in the barrel.

Now we have to wait for more results. If FX-322 works, Frequency Therapeutics have to prove it.

I have long placed my hopes in the FX-322, but fortunately other solutions exist in the near future to provide relief until the arrival of hearing regeneration.

 

[Pete88]

The Phase 1/2 results gave us hope because the improvements were impressive.

The same single injection procedure in Phase 1b 111 worked in 34% of subjects, with 10% absolute improvement.

These is the real results of the FX-322, not those of Phase 1/2.

I'm sure Frequency Therapeutics' science works, but they are unable to complete FX-322. Too many preventable mistakes have been made.

Their Phase 2 was conceived completely at random, on an uncertain bet, without any alternative solution.

It was a game of Russian roulette with 5 bullets in the barrel.

Now we have to wait for more results. If FX-322 works, Frequency Therapeutics have to prove it.

I have long placed my hopes in the FX-322, but fortunately other solutions exist in the near future to provide relief until the arrival of hearing regeneration.

Yeah. I mean, maybe since it looked at "mild to severe hearing loss", they actually did replicate the same results as Phase 1/2, when broken down by the status of each individual's hearing.

When looked at vaguely, Phase 1/2 isn't that impressive. It's only when you look at the broken down data that you go "wait a second, this actually really works for higher half of our hearing!"

Maybe Phase 1b is the same, maybe everyone that could double, doubled. Maybe everyone that could gain 25 percent got it and the the people with extremely mild hearing loss only went up by whatever space allowed them to, which could have ranged from 2 to 12 percent. Maybe the 20 people who didn't fall into the "statistically significant" category had no room to fit in. That's fine then. That would replicate the success of Phase 1/2.

I hope that is the case here. All I'm saying is that we need that information before we hang our hat on it and act like it duplicated the success of Phase 1/2. Either way, it still looks like something is indeed happening, which is still awesome news. But let's not put so much faith in vague statements that could suggest success when they could also be covering for less groundbreaking results.

The lack of audiogram mention still concerns me and the fact that people keep mentioning it while referring to Phase 1/2 concerns me as well.

 

[serendipity1996]

David Lucchino will be presenting at 2 upcoming investor conferences - the Jefferies Conference on 2 June and the Goldman Sachs Conference on 10 June.

Frequency Therapeutics to Present at Upcoming Jefferies and Goldman Sachs Healthcare Investor Conferences

 

[Kleiner]

Yeah. I mean, maybe since it looked at "mild to severe hearing loss", they actually did replicate the same results as Phase 1/2, when broken down by the status of each individual's hearing.

When looked at vaguely, Phase 1/2 isn't that impressive. It's only when you look at the broken down data that you go "wait a second, this actually really works for higher half of our hearing!"

Maybe Phase 1b is the same, maybe everyone that could double, doubled. Maybe everyone that could gain 25 percent got it and the the people with extremely mild hearing loss only went up by whatever space allowed them to, which could have ranged from 2 to 12 percent. Maybe the 20 people who didn't fall into the "statistically significant" category had no room to fit in. That's fine then. That would replicate the success of Phase 1/2.

I hope that is the case here. All I'm saying is that we need that information before we hang our hat on it and act like it duplicated the success of Phase 1/2. Either way, it still looks like something is indeed happening, which is still awesome news. But let's not put so much faith in vague statements that could suggest success when they could also be covering for less groundbreaking results.

The lack of audiogram mention still concerns me and the fact that people keep mentioning it while referring to Phase 1/2 concerns me as well.

Personally, I'm curious about the Phase 2 results in detail, especially the 4-dose group of FX-322.

The x1 and x2 dose group was "washed" by the placebo, but not the 4 dose group.
Even if the chemistry of the ear has been altered, the last dose should benefit a minimum

Do we know if they will publish detailed results in June?

 

[Zugzug]

That's Phase 1/2. I'm talking about Phase 1b. I know Phase 1/2 was successful and in my opinion, it was great. I'm concerned about this second "successful" Phase, mainly because the first one had tons of data that when broken down, shows how good it was.

Phase 1b simply says "34 percent had 10 percent or more word score increase" along with 3 people doubling. OK, 3 people or so had doubling in Phase 1/2 too but that number is impressive because those few made up 100 percent of the people who were given the drug and had significant room for improvement.

In Phase 1b, there were over 30 people and from what I understand, all 30 received drug in one ear with the other ear acting as the placebo. So that means 3 out of 30 had doubling of word scores, 10 out of 30 or so had a 10 percent increase. 20 out of 30 or so had nothing to report? That does not sound like a success to me.

If there were 30 people in this study who had scored 20 out of 40 for word scores or whatever and only 3 of those 30 doubled, that is not the same as Phase 1/2 success at all. The ratio of eligible people who saw amazing improvements is much smaller. FX-322 goes from helping 100 percent of eligible people by a lot to helping a measly 10 percent of eligible people.

Now maybe that's not the case and there were again only 3 people who had room for improvement. That's cool, just show it then.

All I'm saying is that Phase 1/2 had all the information required to come to the conclusion that it was solid. Phase 1b, by comparison, is very vague to the point the success it is implying could be very underwhelming.

And again, please provide the audiograms for Phase 1b. If they don't exist, that concerns me as well. You would think after Phase 1/2, they would be wanting to conduct extended audiograms and, if successful, show them off. The apparent silence is concerning.

I believe that 10 dB improvement at 8,000 Hz is great and is something to be excited about. I'm just worried that Phase 1b isn't even half as good. Maybe I'm wrong, I'm just not seeing the same kind of data and fancy diagrams like we saw from Phase 1/2.

I don't want this to be an echo chamber where people only grasp on to nuggets of good news and then invest so much into it.

I would love for someone to show me Phase 1b data that puts my skepticism to rest. No need to show me Phase 1/2 data. I'm very aware of it and I think it's promising. I just want to see data that proceeded it to follow up on the promise.

Now's a good time to reiterate that the Phase 1/2 baseline data was imbalanced, greatly favoring the treatment group. The breakdown was n=23=15+8 into treatment and placebo. None of the placebo patients started notably low.

Everyone has a different opinion on the audiograms, but it's obvious that the current formulation and delivery, even in a single dose, can't help audiograms that much if there were no statistically significant differences between groups, despite the imbalanced data. They even followed up and checked EHF and didn't find anything.

The open label study just doesn't do much for me because we still don't know why people are doubling word scores. I do think it's essential to be on the lookout for placebos doubling. From the treaters, it can be 3/6 or 3/30 that are word score super responders. The fact of the matter is that it happens and doesn't happen in the placebo group. This all matters for diagnostics, more so than proving a widespread success of the drug.

My hope of the drug in its current form will simply die if I start seeing placebo super responders. That doesn't mean the science should be trashed, but yeah, definitely not good enough.

We're going to have to be very, very patient.

 

[Diesel]

Personally, I'm curious about the Phase 2 results in detail, especially the 4-dose group of FX-322.

The x1 and x2 dose group was "washed" by the placebo, but not the 4 dose group.
Even if the chemistry of the ear has been altered, the last dose should benefit a minimum

Do we know if they will publish detailed results in June?

Unfortunately, the 4x dose group had a "suppressed" effect according to the update from Frequency Therapeutics. So, the 4x dose group actually did WORSE than the other groups. I would suspect those patients were "overdosed" by getting the drug 4 times in 4 weeks.

There hasn't been any evidence of the subsequent placebo dosing "washing" any drug that has entered the cochlea.

If anything comes from the Phase 2A, it will be some cherry picking of patients that got drug and for some reason showed some improvements. Even that is unlikely.

 

[Kleiner]

Unfortunately, the 4x dose group had a "suppressed" effect according to the update from Frequency Therapeutics. So, the 4x dose group actually did WORSE than the other groups. I would suspect those patients were "overdosed" by getting the drug 4 times in 4 weeks.

There hasn't been any evidence of the subsequent placebo dosing "washing" any drug that has entered the cochlea.

If anything comes from the Phase 2A, it will be some cherry picking of patients that got drug and for some reason showed some improvements. Even that is unlikely.

OK, I hadn't seen that, thank you.

Study FX-322-113 is also likely to be a failure if we follow the logic of FX-322-112, an ear that is too damaged to be repaired.

We will have to wait for the new Phase 2 to get more information.

 

[Pete88]

So can anyone provide the audiogram data from Phase 1b? Or do we now admit that people were just repeating completely false information?

 

[ThomasRobert]

OK, I hadn't seen that, thank you.

Study FX-322-113 is also likely to be a failure if we follow the logic of FX-322-112, an ear that is too damaged to be repaired.

We will have to wait for the new Phase 2 to get more information.

FX-322-112 study (age-related hearing loss) cannot be compared with study FX-322-113 (severe hearing loss elated), they are a completely different situation.

The new Phase 2? There is no new Phase 2 yet. First we need to know which group FX-322 works for.

So far we can say that a future Phase 2 will be conducted on Moderate & Severe hearing loss cases.

If the study FX-322-113 (severe hearing loss related) is a failure, Phase 2 will be on moderate hearing loss patients only. And maybe they will have 2 studies:

1) Moderate - Single Dose.

2) Moderate - Multiple Doses (each dose 1 month apart).

So can anyone provide the audiogram data from Phase 1b? Or do we now admit that people were just repeating completely false information?

You need to be more specific, which study are you talking about? There are many Phase 1bs.

Phase 1b - 111 study
Phase 1b - 112 study
Phase 1b - 113 study

 

[Kleiner]

FX-322-112 study (age-related hearing loss) cannot be compared with study FX-322-113 (severe hearing loss elated), they are a completely different situation.

The new Phase 2? There is no new Phase 2 yet. First we need to know which group FX-322 works for.

So far we can say that a future Phase 2 will be conducted on Moderate & Severe hearing loss cases.

If the study FX-322-113 (severe hearing loss related) is a failure, Phase 2 will be on moderate hearing loss patients only. And maybe they will have 2 studies:

1) Moderate - Single Dose.

2) Moderate - Multiple Doses (each dose 1 month apart).

Biologically it's different, I misspoke. I was talking about Frequency Therapeutics' excuse following future study FX-322-113 results.

They announced the plan to start a new Phase 2 around the end of the year. I think it's official.

 

[Pete88]

You need to be more specific, which study are you talking about? There are many Phase 1bs.

Phase 1b - 111 study
Phase 1b - 112 study
Phase 1b - 113 study

I'm talking about the Phase 1b study that everyone has been quoting as "successful" because it replicated the same results as Phase 1/2, which apparently is the 111 study. Still, nobody has provided audiograms, despite constantly saying people's audiograms improved. They keep referring to the Phase 1/2 data.

I have a bad feeling that people are applying Phase 1/2 information onto Phase 1b-111 and there's a bunch of people parroting completely wrong information with so much confidence. I would love to be proven wrong.