Frequency Therapeutics — Hearing Loss Regeneration

[Diesel]

The hire of Kevin Franck now appears to be because they were looking at preliminary data and were surprised by the results, not just audiology educating. Kevin was the one who did an audiologic post mortem on the population data and said "looking at these results, the word scores don't match the medical records..."

He can't do this at an individual level until he is unblinded but it's possible to separate out the suspect individuals when it's unblinded and maybe that's part of the reason he was hired.

Interesting thought. I just wonder how they didn't have the medical records to begin with? If they required at least 6 months of stable deficiencies, then there would need to be patients that had hearing loss for more than 6 months, but at least faked the past two visits.

 

[HootOwl]

Can we like, maybe not call the drug dead until we have the full readout, and can parse through all the data? Just a thought.

I swear this forum sometimes gives me whiplash. If the drug shows some efficacy it's the greatest Cure in the world!!! And if it hits difficulties, well then it's fucking dead as dirt.

This is where I really appreciate all of the analytics coming from the cooler heads. Today was rough, but I really want to see that full readout before making any sort of definitive conclusion about phase 2a and the future of FX-322 (which is still somewhat optimistic imo).

 

[Diesel]

Is that still possible to do, get rid of the people that lied about their hearing results and then reassess the data? Could reassessing the data show that there were actually substantial improvements?

If they do... man they need to be 110% transparent about the method to do so.

 

[tommyd87]

I just can't figure out how you can *double* word scores in Phase 1 and have all the pre-clinical findings. Based on historical data that seems literally impossible.

Maybe in vivo conditions preferentially draws binding to IHCs to a great degree. IHC function is linked to both speech and WIN and isn't measured on audiograms.

If people falsified their performance to get into the trial, then genuinely demonstrated their performance during the trial then these results are completely plausible.

The thing is that no one during the trial would have known if they obtained the placebo or treatment. Hence, if there was widespread fudging to get into the trial and then the participants decided to perform correctly during the trial tests then both the placebo and treatment groups would have demonstrated improvement.

This would legitimately sum up why the results of the current trial have been compromised and cannot be used for demonstrating anything about the medicine because there is no certainty that the participants in either group were legitimate to begin with.

 

[VeryUnfortunate]

I see that this is a failure for hearing loss, but was tinnitus mentioned anywhere in the release? Was there any improvement with it? Sorry, there is just so much activity on this thread that mention is hard to find.

 

[Aaron91]

This assumes that the 2x and 1x groups got their real injections before the placebo injections. For keeping the end result times aligned, they might have started with placebos.

FX-322 was front-loaded in this trial for all groups. In other words, if you were only scheduled to get one dose of FX-322, your first dose was FX-322 and then you got three doses of placebo. You can imagine then how the lawn theory might stack up. It means you only get one week of a therapeutic drug in your ears before wiping it out with three consecutive doses of jello.

The more I think about it, the more retarded it gets.

 

[FGG]

@FGG Back to your point on audiologists saying ears don't do this (which I fundamentally agree with), are we aware of any previous study where something similar has occurred i.e. where both placebo and the drug have shown efficacy? Frequency said it's unprecedented but I want to know if there's evidence in the literature to the contrary. If there is I'm certainly not aware of it. Also, is there anything in the literature to suggest that the process of an intratympanic injection could have some kind of positive effect on hearing?

There are of course drugs that show a placebo effect, but I'm not aware of an effect so strong it obliterates historic controls (the "unprecedented" is because people literally can't double their word scores by believing no matter how much they want to).

Intratympanic injections may help with Menière's vertigo because grommets do (although unlike hearing, Menière's vertigo episodes are highly subject to the placebo effect) but that's totally different. And that was the context I discussed it before.

In the hypothetical case it preferred IHCs, it would just mean those have to be treated first (but definitely not a week apart...).

 

[FGG]

We have to assume that many honest people enrolled in the study who wanted to help progress the treatment, and did everything right and proper. It may have only taken 10%-20% of the participants to fake some scores to get in, and that was enough to muddy the outcomes. It's really unfortunate.

Right, and that's why you need the unblinded individual data and not the population data.

 

[Diesel]

Edit: I did learn from an former associate that it's not uncommon to exclude patients from a clinical trial after all are unblinded. There has to be very specific reasons and data to reinforce the exclusion. So, it's possible they could find a clear reason to reject each participant where the medical records are blatantly different than the day 0 baseline. I'm not sure this will inspire confidence though with the FDA.

 

[Koz]

FX-322 was my only hope. I have waited over 2 years, tortured to no end by tinnitus, only to learn this drug doesn't do anything or work at all, with no proper candidate to alleviate my suffering anytime soon.

I will now start putting my things in order and put an end to my suffering. It is sad it has come to this but I can't live like this.

I have heard Pegasos does accept tinnitus sufferers as potential candidates.

Hello my friend, I developed tinnitus back in 2009 when I was just 17, entering adulthood and just about to start my life. My passion has always been music production and playing music. I went on and did it with one good ear, which is still my normal ear to this day. The left one is now in the severe range, my tinnitus on good days cannot be masked by anything, never mind the bad days.

There is still scope to make something out of life and as much as I dislike TRT and habituation, there is some merit in shifting your attention as best you could to other areas of your life after already ruling out anything dangerous medically with your Doctor. This should at least provide a small level of comfort.

The more you are able to do this the more you are able to get quieter tinnitus days and are able to deal with the harder tinnitus days if you do your best to occupy your time and attention on other things. Some people find this pointless, I understand, but my perspective is — if life served you a shit sandwich, then season it and at least enjoy the bread. I know there is still a lot I want to do in life despite my hearing loss and tinnitus and I hope you find it within you for yourself and for your loved ones to do so. I can't bring myself to end my life and hurt all my loved ones in the process, even if I end up living a limited life. A limited life is better than no life in my opinion and who knows what the future holds.

Before you say just because I could do it doesn't mean you can, its at the very least worth trying and taking inspiration from others. You have nothing to lose by this point.

 

[tommyd87]

I wonder now if the OTO-413 trial had a similar issue... did they ever disclose why they want to re-run the Phase 1?

They want to utilise a bigger dosing/volume of the medicine to analyse and observe whether the medicine produced bigger and better outcomes than they achieved in the inaugural phase 1/2 trial. The FDA rejected their request to use a bigger dose in the second trial without going back to the start.

I actually fear I might have been unknowingly complicit in the whole fraud thing, if that turns out to be truly legitimate. Most people were not given the reason for their rejection from the Phase 2a trial, but I was.

They point blank told me that although my audiogram qualified me, my WR scores did not, and I shared that here on the forums... my intention was to save people the hassle, money, and mental stamina of getting a HF audiogram if they (like me) had no WR issues. Because it ultimately wouldn't matter even if you had measurable notches.

But now I see why most testing sites would not disclose the reason why people were rejected... because if you knew that the WR scores were the lynch pin you could more easily lie your way into the trial.

God I feel like I really fucked up.

This really has Otividex phase 3 — trial 1 written all over it, because they chose a subjective and very falsifiable measure to be the key testing point too.

 

[Lucifer]

Thinking back they should have continued with one dose of FX-322 instead of multiple dosing. I think this was their mistake at doing multiple doses with this phase. They should have done one dose of FX-322 with more people to see if the results are the same as Phase 1b to confirm that this drug does work. 15 participants in Phase 1b and only 6 of them were substantial improvements is not big enough.

If the other trials are positive at the end of the year with severe category improving substantially we could see a pivotal phase early next year. All hope is not lost just yet. If we can see improvements with one dose with mild, moderate and severe categories then pivotal phase will happen.

I just hope now that one dose is needed for it to go through pivotal phase and release it out in the market. It should be even quicker now with one dose only.

 

[Philip83]

The thing that's still nagging me is that lack of EHF audiogram performance in both studies, especially the Phase 1 study which had stat sig WR scores.

Is there a possibility that restoring even both IHC and OHC simply doesn't have any effect on sound loudness in vivo? Has it been proven without a doubt in for example animal models that restoring these does in fact improve "volume"? Maybe the solution to improved audiograms is found elsewhere?

 

[Christine2222]

Has anyone considered that maybe the hair cells grow back but simply don't function?

 

[Tezcatlipoca]

You beat me to it, I had been thinking about this too. Let's hope they're able to figure this one out and see who the suspects were.

The thing that's still nagging me is that lack of EHF audiogram performance in both studies, especially the Phase 1 study which had stat sig WR scores. Like @Zugzug, I just can't for the life of me reconcile this with the pharmacokinetic models where we know the drug is concentrated. Even if we go with the preferential IHC thesis, that hardly bodes well for most of us moving forward, let alone the commercialisation of the drug.

I'm just finding it really difficult to spin this. Even if you have a population bias issue, I'm not sure you can still explain what's happened here.

@FGG Back to your point on audiologists saying ears don't do this (which I fundamentally agree with), are we aware of any previous study where something similar has occurred i.e. where both placebo and the drug have shown efficacy? Frequency said it's unprecedented but I want to know if there's evidence in the literature to the contrary. If there is I'm certainly not aware of it. Also, is there anything in the literature to suggest that the process of an intratympanic injection could have some kind of positive effect on hearing?

I've seen a couple of trials with ITI and none of them have the gains that phase 1 had. I'm starting to believe the short period of time between injections was the reason for the screw up.

 

[Lucifer]

This assumes that the 2x and 1x groups got their real injections before the placebo injections. For keeping the end result times aligned, they might have started with placebos.

I think this was their mistake. They should have injected placebos first then FX-322 as the placebo could be flushing out FX-322.

 

[Street Novelist]

Why can't they do back-to-back injections? Push the first, then immediately push the second. That way the first injection goes deeper inside the cochlea.

 

[ThomasC]

So what may happens now? Will they continue the trial? Will they have to stop ?

Edit: My bad, there are still ongoing tests for more severe hearing loss.

 

[Lucifer]

I've been reading the press release again. I did not realise that they also released results from another Phase 1b trial. I thought this was the Phase 1b trial from 2019 but this is a completely new trial that showing meaningful improvements.

"The Company also announced preliminary results today from a recently completed open-label, single-dose study of FX-322 (FX-322-111) designed to evaluate the impact of injection conditions on tolerability. In the multi-center, randomized study, subjects with mild to severe SNHL (n=33) were injected in one ear with FX-322, with the untreated ear as the control. Hearing function was tested over the course of 90 days following dosing.

At day 90 following dosing, thirty-four percent (34%) of subjects achieved a ten percent (10%) or greater absolute improvement in WR scores in the treated ear, which was clinically meaningful and statistically significant compared to the untreated ear (p <0.05). This included a subset of subjects that more than doubled their WR scores. The single dose had a favorable safety profile and was well tolerated. These latest results are supportive of the data reported in the prior single dose Phase 1/2 (FX-322-201) study, recently published in the peer-reviewed journal Otology & Neurotology.

"We now have two independent, single-dose studies showing a hearing signal with FX-322 and with statistically significant improvements in speech intelligibility".​

Which trials are they referring to when they mean FX-322-111 and FX-322-201?

FX-322 in Adults With Age-Related Sensorineural Hearing Loss

FX-322 in Adults With Severe Sensorineural Hearing Loss

 

[Guywithapug]

My hopes are temporarily crushed. I was aware of the news early this morning but have refrained from posting because I have been processing everything that has been said here.

I, like others, refuse to believe that the drug is a dud based upon Phase 1 results. Perhaps a longer time between administering doses or reformulated version that can penetrate deeper into the cochlea along with additional time between dosing would yield a more positive result?

Also, with the larger number of participants, how do we know that many had synapse issues? Or that the placebo affected efficacy?

This is all under assumption of a well structured trial to eliminate liars, which has appeared to skew the overall result. How can this be achieved though? People can always sham not hearing a tone or word and then later, surprise! They can hear it...

 

[Emgee]

Not a good day by any stretch, but I am not fully convinced the drug is dead. Could FX-322 not be efficacious after all? Absolutely, but I think more due diligence must be performed before drawing that conclusion.

Clearly, there was a case of issues that could have prevented a successful readout. Between the dishonesty of participants, excessive dosing, dosage not being spread out enough in terms of timeframe, and other related factors, there is a lot to investigate. Also, something seems odd to me about the placebo in this study. Lucchino and company seem to view it this way as well. While it doesn't look good right now, I think it's worth waiting to see how Frequency Therapeutics respond and react.

 

[tomytl]

After Phase 1 results were released, I discussed it with a top notch hair cell regeneration scientist. He wasn't that excited about, maybe to keep me optimistic, he said, it's probably the right direction FREQ is going in. He knows every important researcher in this field... and he isn't working in some competition.

He was also right with the bad outcomes of the CFG-166 trial from Novartis.

I hope we are all wrong and there was really a problem with delivery. If FX-322 is not dead, I would feel much better.

 

[hopetohear]

Hi all, long time follower of this thread, but I am nowhere near as intelligent as many of you so prefer to just read and learn from afar! However I'm just wondering if someone can confirm if my understanding of the results is correct? Because the placebo group showed an increase in WR and the test group also showed an increase, they basically cancel each other out? It's not that the test group showed no increase?

So if the placebo group had actually been a 'proper' placebo, showing no increase, would the FX-322 group have shown a statistically significant increase?

Hope that makes sense. From a tired mum of a newborn who was up all night feeling sorry for myself over the results.

 

[FGG]

Is there a possibility that restoring even both IHC and OHC simply doesn't have any effect on sound loudness in vivo? Has it been proven without a doubt in for example animal models that restoring these does in fact improve "volume"? Maybe the solution to improved audiograms is found elsewhere?

Well, either it does or the Phase 1 super responders were lying since it's beyond what has historically been possible.

 

[kiki]

It seems that there was no dB improvement from 8 kHz to 16 kHz. In other words, is the improvement in dB at 8 kHz 0?

Where did the improvement effect of 10 dB at 8 kHz and 5 dB at 6 kHz in Phase 1/2 go?
Is this the result of being a "group unit"? If you look at the detailed data for each person, can the results be different?

As follows:
There are x people who have improved by 10 dB or more in this group, and y people who have improved by 20 dB or more, but since x and y are not significant numbers, they are counted as 0 people, and so on.

I'm not familiar with statistics...

 

[Aaron91]

I think this was their mistake. They should have injected placebos first then FX-322 as the placebo could be flushing out FX-322.

For readout purposes, I'm not sure that would work. It would seem to me that you have to frontload or the data can get messy.

On reflection, what I don't understand is why they had to give all cohorts four injections in the first place (regardless of how many FX-322 doses they were getting).

Would it not have been a better idea to just match the placebo to whatever the treatment group was having without the extra doses? For example, if a patient was assigned to receive two doses of FX-322, rather than inject two doses of FX-322 AND then two doses of placebo, you just inject two doses of FX-322 (and nothing else thereafter) while you inject the other patient with two doses of placebo.

Instead, what you have is one patient getting two doses of FX-322 and two doses of jello while another patient just gets four doses of jello. Surely that (the former) would seem to be a healthier approach to the cochlea. Honestly, the more I think about it the more retarded it gets.

Is there a possibility that restoring even both IHC and OHC simply doesn't have any effect on sound loudness in vivo? Has it been proven without a doubt in for example animal models that restoring these does in fact improve "volume"? Maybe the solution to improved audiograms is found elsewhere?

If I recall correctly, they did ABR tests in animals treated with FX-322 post noise-exposure and the results suggested their hearing came back.

 

[Lucifer]

If FX-322 is not dead, I would feel much better.

I don't think it's dead. I did not realise this but I read the press release again and they posted about their positive results in another Phase 1b trial. I originally thought they were referring to the one in 2019 but it was the one that was supposed to be completed soon.

This is what they stated:

At day 90 following dosing, thirty-four percent (34%) of subjects achieved a ten percent (10%) or greater absolute improvement in WR scores in the treated ear, which was clinically meaningful and statistically significant compared to the untreated ear (p <0.05). This included a subset of subjects that more than doubled their WR scores. The single dose had a favorable safety profile and was well tolerated. These latest results are supportive of the data reported in the prior single dose Phase 1/2 (FX-322-201) study, recently published in the peer-reviewed journal Otology & Neurotology.​

This is the clinical trial they are talking about:

FX-322 in Adults With Age-Related Sensorineural Hearing Loss

The clinical trial link I posted above is the one that just finish recently and was supposed to come out soon but they released them early. Now we are waiting for the severe hearing loss trial to finish. If the results are positive for that, I will expect them to start the pivotal trial early next year.

 

[Cernuto]

This assumes that the 2x and 1x groups got their real injections before the placebo injections. For keeping the end result times aligned, they might have started with placebos.

The FDA process is an overrated pile of dung and we ended up with this faulty result because of it.

 

[Philip83]

After Phase 1 results were released, I discussed it with a top notch hair cell regeneration scientist. He wasn't that excited about, maybe to keep me optimistic, he said, it's probably the right direction FREQ is going in. He knows every important researcher in this field... and he isn't working in some competition.

Being a "top notch hair cell regeneration scientist" would imply he knows how to regenerate hair cells, no? So what is his solution to there not being a viable treatment for it yet?

 

[d'Wooluf]

I'd hate to say it, but I hope there's a chance that someone that got FX-322 in-vivo during the trials dies so that Frequency Therapeutics can harvest their cochleas. I mean... some of these people are 65+ in the ARHL trial...

Not to be morbid... because it's for science.

Ok, replying now with about 6 pages of comments left to read which is kind of dangerous, but... what would that tell us? We might see things that look like hair cells, but do they work? All this pre-clinical stuff they did counting hair cells in vitro. Was there ever any way of knowing if they were working hair cells?

Here's my theory on increased word scores in Phase 1B. Go ahead and laugh if you feel like it. Hair cells were created but they were not working. These structures attracted synaptic growth in the general vicinity which then connected to some of the remaining 'real' hair cells. So synaptopathy improvement basically.