Frequency Therapeutics — Hearing Loss Regeneration

Oh wow. Interesting. You may be on to something. All groups got 4 shots with variable level of placebo. They could have washed away drug before full effect.

But it would also mean repeat injections may have disturbed the lawn too much too otherwise 4 injections should have an effect.
@FGG Here's the original study, can you confirm or disconfirm as maybe I'm reading it wrong?

"The tissue was then treated identically to the mouse tissue to isolate single cells for culture. The single cells formed clonal colonies after 12 days under EFICVP6 conditions"​

For everyone else's reference, EFICVP6 = FX-322.
 
Oh wow. Interesting. You may be on to something. All groups got 4 shots with variable level of placebo. They could have washed away drug before full effect.

But it would also mean repeat injections may have disturbed the lawn too much too otherwise 4 injections should have an effect but that group may need more time.
The cochlea is full of perilymph all the time. Why can't the perilymph wash the drug away but a second shot of placebo/drug can?
 
I'm starting to cool off and forcing myself to think more critically here.

I think I'm going to ignore the biased sample population argument for now because clearly that wasn't the case in the supplementary Phase 1b (111) study as those patients had been made known about the same WR score criteria ahead of time. That trial went on to see stat sig improvements that were not observed in the Phase 2 trial. So I think that's a red herring and we should focus our attention elsewhere, although I don't deny that trial design is critical moving forward.

I posted this some time ago, but I do remember reading somewhere that the cochlea, being a very delicate membrane, has physical limitations to what can be injected into it before it breaks. Chris Loose also said today that they hadn't trialed multiple doses in animals before because the cochlea would be overwhelmed/break. I'm wondering then whether that analogy - that when you re-seed the lawn you must stay off the grass - does carry some weight. Because regardless of whether someone received 1 dose or 4 doses, EVERYONE received 4 doses of the carrier gel, regardless of whether it was carrying the small molecules or not. I also recall reading in Will McLean's paper that a colony took 12 days to form, which begs the question: why the hell did they only give it one week in between each dose? Even two weeks would be pushing it.

Is it possible, for example, that 4 doses of FX-322 was actually equivalent to 1 dose, because each previous dose washed away the other? On this point, do we have any historical data to glean from regarding multiple dosing for any ear-related condition? For example, is there a study out there that looked at multiple weekly injections of intratympanic steroids against placebo? I'm pretty sure this is a discussion some of us had over on the Otonomy thread about Meniere's and I don't remember finding anything other than maybe one study. In any case, if the lawn analogy is true, this could explain why they didn't see differences between 1x, x2 and x4 FX-322 groups. Unfortunately, this still doesn't explain the lack of difference between placebo within each category. The only explanation we have for that is the failed trial design.

So we have some plausible explanations given the above, but how does one still reconcile this with the failed EHF audiogram in the Phase 1 study which showed no placebo effect? The only explanation we seem to have, as @FGG and @Diesel have pointed out, is that there is preferential IHC regeneration over OHCs in vivo - the idea being that IHC regeneration will not appear on an audiogram. But again, if IHCs restore clarity, why have we not found statistically significant results in the WIN scores? The only answer again is design error and a biased sample of patients.

To put things simply, for this Phase 2 outcome to have happened, it would have taken a catalogue of errors and unique set of circumstances. So I'm going from "this drug doesn't work" to more of a "perfect storm" take on this. Is it possible this was the perfect storm? We just don't know yet, but obviously things don't look too good right now.

This may seem like a tangent, but I have an interest in air crash investigations. What you find in almost all cases of air crashes is that there is almost never just one cause. You find that there are a catalogue of errors, one after the other, usually combined with a unique set of circumstances, that all together lead to the crash. Perhaps this is one of those occasions.
Does this work?

Intratympanic dexamethasone injection for refractory tinnitus: prospective placebo-controlled study
 
Why does it still sound like they are proceeding to the next phase in the press releases too?
Ok so hear me out on this one...

They could argue that since they're positioning it as a single dose drug... they're going to request that the multi-dosing efficacy used in the Phase 2A be excluded from consideration to start the pivotal trial. Lucchino noted that there were no notable safety issues from the 75 that got FX-322. So, that counts as a single successful primary endpoint.

By the end of Q3/2021 they're going to have 3 Phase 1bs completed by the end. All single-dose, all similar outcomes. I don't know if the open-label trial will count to the FDA. At this point.. .

From a safety standpoint, they've got data from just about 200 patients.
From a single dose efficacy standpoint, the Phase 1b (they're hoping) might continue to look significant for WR, improving for WIN, some Audiogram improvements.

At that point, they can request a Phase 2B/3 as a single-dose drug. And basically run it like another Phase 1B, with maybe some lead-in filters (to eliminate the fucking liars/fakers) and possibly a longer tail of follow-ups to prove durability.

And that's it.

Loose mentioned on the call a "parallel" multi-dose trial strategy. I don't know if that's parallel to the Phase 2B/3, or if its in parallel to the product post-approval...
 
Actually no. The final phase 2a results in late Q2 this year will be the final nail in the coffin if they say there has been no improvement in tinnitus. That's what most of us here care about, not fixing a tiny bit of ultra high frequency hearing loss... If at Day 90 there was no tinnitus improvement, I doubt there will be at Day 210.
IIRC, they said they haven't analyzed tinnitus results yet. They did say anecdotally that one patient did not see improvements, though, but you cannot infer anything from that.

Someone please correct me if I am wrong.
 
On this point, do we have any historical data to glean from regarding multiple dosing for any ear-related condition?
The only data point I can think of off-hand is Ebselen, which becomes far less effective for ear inflammation at higher doses. But that drug is unfortunately not specifically targeted to the inner ear nor injected into the middle ear (it just has very high penetrance systemically) so the applicability of that to this situation is very ymmv.
 
Oh wow. Interesting. You may be on to something. All groups got 4 shots with variable level of placebo. They could have washed away drug before full effect.

But it would also mean repeat injections may have disturbed the lawn too much too otherwise 4 injections should have an effect but that group may need more time.
I was thinking about this too... was the cochlea absorbing the placebo in shots 2, 3, 4 and that was messing with FX-322 doing its work half-way through... sort of a coitus-interruptus type deal.
 
IIRC, they said they haven't analyzed tinnitus results yet. They did say anecdotally that one patient did not see improvements, though, but you cannot infer anything from that.

Someone please correct me if I am wrong.
I mean how could they though. If people definitely lied about word scores...
 
I think the next/first step in hearing restoration really has to be figuring out an efficient and safe way to deliver drugs deep into the cochlea. At least reaching the mid ranges. I think only then will drugs (at least non oral) be able to work. It could be that FX-322 would work if able to be delivered into the cochlea instead of sitting outside of it hoping some will get through.
Personally, I really don't see how one could get into the cochlea without causing more damage to the hair cells. The diffusion method was our best hope. The only other option seems to be making a hole but that's going to be extremely difficult to do without it being very high risk. I know a guy who had a benign tumor removed from his ear. It wasn't even touching his cochlea but he still lost all hearing in that ear after surgery. It's just too sensitive to damage.
 
I feel like people need to see this. This person was in the trial and 5 months after the injections they sent me this. They also told me they have had improvement in three different frequencies during the study. This is why I'm surprised today and I was very optimistic.

846FDEC3-8B37-4131-B3FD-88DBC84F394A.jpeg
 
Ok so hear me out on this one...

They could argue that since they're positioning it as a single dose drug... they're going to request that the multi-dosing efficacy used in the Phase 2A be excluded from consideration to start the pivotal trial. Lucchino noted that there were no notable safety issues from the 75 that got FX-322. So, that counts as a single successful primary endpoint.

By the end of Q3/2021 they're going to have 3 Phase 1bs completed by the end. All single-dose, all similar outcomes. I don't know if the open-label trial will count to the FDA. At this point.. .

From a safety standpoint, they've got data from just about 200 patients.
From a single dose efficacy standpoint, the Phase 1b (they're hoping) might continue to look significant for WR, improving for WIN, some Audiogram improvements.

At that point, they can request a Phase 2B/3 as a single-dose drug. And basically run it like another Phase 1B, with maybe some lead-in filters (to eliminate the fucking liars/fakers) and possibly a longer tail of follow-ups to prove durability.

And that's it.

Loose mentioned on the call a "parallel" multi-dose trial strategy. I don't know if that's parallel to the Phase 2B/3, or if its in parallel to the product post-approval...
Right now you have a drug that doesn't perform that great. The Phase 1/2 trial that they published today? Around 30% responded to the drug with at least 10% increase in word scores, a small subset doubled their word scores (we don't know what they started with). We might differ on this, but I'm not over the moon about that.
 
The cochlea is full of perilymph all the time. Why can't the perilymph wash the drug away but a second shot of placebo/drug can?
Washing away probably isn't the correct terminology. Displaces is probably more correct. The polyoxamer in the gel is a surfactant.
 
I feel like people need to see this. This person was in the trial and 5 months after the injections they sent me this. They also told me they have had improvement in three different frequencies during the study. This is why I'm surprised today and I was very optimistic.

View attachment 44212

There was also other person, someone that communicated with @Princebeyel

Thats two people that had their T go away. Im sorry for those that struggle with hearing loss but I dont give a crap about that, it could do nothing for hearing loss but if it does help with T thats a homreun for me

@Princebeyel could you share those screenshots with us again
 
I feel like people need to see this. This person was in the trial and 5 months after the injections they sent me this. They also told me they have had improvement in three different frequencies during the study. This is why I'm surprised today and I was very optimistic.

View attachment 44212
Wait... it took 5 months? That could explain a lot in and of itself...
 
I mean how could they though. If people definitely lied about word scores...
That is why I have been repeating for hours that biased data produce biased results. You literally cannot extract anything helpful from biased data. Every piece of information is unreliable in one way or another.

Of course, this only applies if Phase 2a design was actually biased as they said in the PR and conference.
 
Right now you have a drug that doesn't perform that great. The Phase 1/2 trial that they published today? Around 30% responded to the drug with at least 10% increase in word scores, a small subset doubled their word scores (we don't know what they started with). We might differ on this, but I'm not over the moon about that.
I am realistic how the embarrassingly dog-shit low the bar is for hearing loss drugs. So, even if this reverses 10% of the damage in patient's cochleas, they'll buy it.
 
I think even the most optimistic of optimists can agree that these guys have one more major trial ahead of them to really get an idea of what to expect out of this.

Whether it's study design, drug delivery, higher dose in a single shot etc. Is there much hope? I would say the same level of hope when people hypothesized that "more shots = deeper penetration and more effective". That didn't really come off in the end. So, approach with scepticism by this point because everything up until today was hype based on strong science, terrific pre-clinical evidence and meh Phase 1 results that might look better if Phase 2 wasn't a flop.

For me personally, it was a reminder of a lesson I learned a long time ago when I first developed tinnitus and hearing loss in 2009 which went on to the severe range. Expect the worst, hope for the best.
 
I've been reading this thread since 2018. We started out with this drug being a cure. Then we went to this being complimentary to a hearing aid. Now this.

The rationalizing increased with every dataset that's been released. It's not deliberate, people here are suffering.
 
I feel like people need to see this. This person was in the trial and 5 months after the injections they sent me this. They also told me they have had improvement in three different frequencies during the study. This is why I'm surprised today and I was very optimistic.

View attachment 44212
For the sake of everyone's self-preservation, if you get any more out of her or anyone else for that matter I think we'd all appreciate it. I was previously against any leaks, but given how shit this readout has been I'm not sure what that's worth anymore. Did she say how long it took for her to see improvements in her hearing? I'm holding little hope for the 210 day readout but who knows.
 
Wait... it took 5 months? That could explain a lot in and of itself...
Yes it happened out of nowhere five months after their last injection. They also stated they had no more follow-ups with the clinic. My concern is what if this is happening with other people and they just aren't aware. I advised them to contact the clinic and update them.
 
Personally, I really don't see how one could get into the cochlea without causing more damage to the hair cells. The diffusion method was our best hope. The only other option seems to be making a hole but that's going to be extremely difficult to do without it being very high risk. I know a guy who had a benign tumor removed from his ear. It wasn't even touching his cochlea but he still lost all hearing in that ear after surgery. It's just too sensitive to damage.
There would have to be a leap in technology. We don't have it yet. But hopefully a company will be able to develop one.

Also, it doesn't have to be getting deeper mechanically. It could be a more complex development of drug. Finding something that's able to easily penetrate the bone that surrounds the cochlea.
 
For the sake of everyone's self-preservation, if you get any more out of her or anyone else for that matter I think we'd all appreciate it. I was previously against any leaks, but given how shit this readout has been I'm not sure what that's worth anymore. Did she say how long it took for her to see improvements in her hearing? I'm holding little hope for the 210 day readout but who knows.
Agree. I was worried anecdotes could affect trial recruitment but it looks like people did that on their own anyway...
 
Except that it isn't. Ask anyone with significant hearing loss. That's not to say that a perfect audiogram means that person has perfect hearing. But improvement on the audiogram as a result of this drug would've been huge.
Thank you for saying this. So tired of reading "audiograms mean nothing" by people with losses in the super high frequencies/hidden hearing loss or even one single minor loss at one frequency.

I have losses in all frequencies in the severe/profound range, audiograms and their results do matter.
 
Here's a thought...

I wonder if they could pinpoint when the recruiting might have started to get Fakers/Liars that muddied the baselines?

It seems like the early recruiting, pre-COVID-19, they had about 40 participants. And nobody knew about the drug, and not many were talking about it (aside from maybe here)... Even I didn't know about it until November.

So, I wonder if they look at the individual entrants, and reject those recruited past a certain date, they can get something remotely informative from it?
 
Easy Zugzug. There can only be one Toby™.
Haha, thanks for lightening the mood.

Honestly, a huge pet peeve of mine is retroactively assigning probabilities after the outcome comes out. The pathetic part is these people whine about how "blah blah blah, I don't care how unlikely it seems, I have HORRIBLE tinnitus or hyperacusis. Why doesn't any doctor believe me!??!"

Yet, if we looked at this problem without information, the probability of someone at random developing severe hyperacusis is like 1 in 50,000 or 1 in 100,000. Maybe the doctor who's doubting the sufferer is being smart by thinking the person is exaggerating.

This is, of course, nonsense. Life is about conditional probabilities. These dumb statistics about "X percent of Biotechs fail" is completely irrelevant to what happened here. Information updates.

/rant
 

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