Frequency Therapeutics — Hearing Loss Regeneration

You make a point here, but it is relatively unfair to use anecdotal evidence as an argument in a debate about new medicine exploring a completely new approach in treatment for hearing research.

It may very well have a positive impact on tinnitus sufferers. If someone had told you they have hopes that Trobalt would cure their tinnitus back when it was not yet in Phase 2, you'd probably have been sceptical about it as well.

But of course, there are so many theories and so many propositions about tinnitus that it is impossible to know if this new drug will improve any of us in advance.

Let's just not start giving up or taking down each other's enthusiasm.

 

Frequency Therapeutics has made a nice move off the recent bottom as expected, but most stocks that hit a recent low moved up. Most of the FREQ recent buying has been non-institutional and I don't see those that attended the Oppenheimer conference buying yet. Most buying has been from us as this can be seen on NASDAQ.com.

It's best to use DCA-ing as @Diesel mentioned on the investment board. I'd be careful not to fully invest until we get some read-outs. Stock sites are still showing caution ⚠ as of today with FREQ. Do hope they will be proven wrong in the next couple of years.

 

I'm sure we'll find a cure in a century or two.

 

I’m more interested in the other discoveries Frequency Therapeutics is making at the same time. There’s no telling how their research still might help others.

 

I doubt the subjects in the clinical trials so far that have been statistically significant responders would agree with you. In the Phase 1/2 trial, Subject 1 went from qualifying for a cochlear implant surgery to being able to live with hearing aids. Subject 4 went from needing a hearing aid to possibly being able to get by without one. Those results are absolutely life changing for them. And these results are from a drug that is barely touching the first 15% to 20% of the cochlea.

I don't understand why WR tests are seen as subjective but audiograms aren't. I could sit there all day long and wait to push the button until it hurts my ears if I want to and I will look functionally deaf on an audiogram. Or I could try and jump the gun and hit the button before I hear anything and if I time it right, I might look like I have better hearing than I do. Both tests are subjective.

 

Given the fact that it has been over a year since the failed trial and they haven't issued shares yet indicates they are likely waiting for the new Phase 2 results to be in before they do. They have enough cash to keep them financed until the end of 2023 so they will have results from both FX-322 and FX-345 trials before they run out. If those come back positive, there should be a significant share price recovery and dilution wouldn't be a major concern then.

 

Pinning down the cause is a good first step. Many of the experimental medicines are focused on the nerve component, which is tricky but sensible. Biggest hurdle is money.

 

Exactly - I think Retigabine could definitely provide symptomatic relief but at the end of the day it's not a curative drug or repairing the underlying structural damage that has led people to develop tinnitus. It will also probably come with side effects even though it's been made safer. It's still a hardcore anticonvulsant and you'd probably need to be taking it daily.

Whereas with a lot of the regen drugs it could just be an annual/biannual thing which is obviously a lot more appealing.

 

The thing is, the DCN theory is that noise exposure, or ototoxic drugs, has caused dysfunction in the potassium channels. Repairing synapses and hair cells will not cure this hyperexcitability so I honestly can’t understand the reasoning why fixing auditory input will stop tinnitus if potassium channels are still not fixed. Great, it might prevent tinnitus in the future but fixing existing tinnitus, I just don’t get it.

Plus, I must add the DCN hyperactive fusiform, malfunctioning potassium channels is the only theory that has had proof behind it. Susan Shore’s work plus lots of information on Tinnitus Talk on tinnitus suppression using Trobalt.

Correct me if I’m wrong but it is the only drug to suppress tinnitus.

There is zero evidence that restoring hair cells will fix tinnitus.

 

Yes there is zero evidence because they haven’t been able to do it. But if you believe that tinnitus is a symptom of hearing loss, then correcting it would solve tinnitus. Just like cochlear implants make some people's tinnitus go away.

 

How come then most of us don’t have hearing loss and still have tinnitus? I don’t get it.

But for those with hearing loss it would help yeah.

 

One problem is the rudimentary audiogram which often only goes up to 8 kHz. Extended high-frequency audiogram can show hearing loss in those upper frequencies but this test is rarely carried out. If you get perfect result from that too, you can still have hidden hearing loss.

 

Really? I didn’t know about that. I’ve done several audiograms, but only the normal ones and they have always come back normal.

May I ask what’s the better audiogram called? Might ask my doctor about it.

If there is hearing loss in those high frequencies, can hearing aids help? Or nah?

 

Dr. De Ridder mentioned on the Tinnitus Talk Podcast that he thinks regenerating hearing loss is an important component of total treatment, where if tinnitus can be "cured", repairing hearing might be necessary to maintain the cure.

 

I think unfortunately hearing aids only cover up to 8 kHz.

 

I think it's often called "extended high-frequency audiometry":

Extended high-frequency audiometry (9,000-20,000 Hz). Usefulness in audiological diagnosis.

Most hearing aids go to 8 kHz. But there are some models that go up to 12 kHz:

Siemens’ Newest Hearing Aid Platform Delivers a Natural, Uncompromised Listening Experience

 

Just an FYI -

Audiograms, even the extended high frequency ones are a very narrow and legacy method to assess the overall health of one's hearing. The biggest problem is that they're not representative of real-world hearing ability. Almost all top researchers reiterate this position re: Audiograms in any presentation about hearing health. If you really want to know how healthy your hearing is, take a look at the various hearing-in-noise tests including SIN, DIN, and AMET tests. These tests truly assess multiple functional capabilities of the cochlea.

 

Hearing loss is just one of the causes.

 

Hey, I don't mean to intrude or say something I'm not meant to say - but what's currently happened so far with FX-322? I've heard many good things coming out of it, but I'm anxious about what we can look forward to.

 

The tinnitus suppression using Trobalt faded away for most in the thread discussing it, leaving them with the nasty side effects of anticonvulsants and a drug that may leave big physical and psychological marks if not tapered off properly, and tinnitus.

There is still a need for a lot of research. Nerve, synapse and hair cell damage definitely must be researched and treated as it is a known precursor to tinnitus, even if not in all cases. It should also lead to further discoveries on the tinnitus model itself.

The problem with there being no evidence that hair cell regeneration will fix tinnitus is that we don't properly understand how the hair cells interact with the rest of the auditory system (on the subject of signal balance and brain activity) and we haven't been able to regenerate them before.

The potassium channels are better understood and allow for speculation. There is also no strict evidence for potassium channel regulation providing sustained relief without disproportionate side effects (lessened neuroplasticity, Visual Snow Syndrome, possible Complete Vision Loss, blue pigmentation in nails and skin, urinary retention, cardiac arrhythmia, increased risk of depression, essential tremors, ... -> taken from the Trobalt Notice and Trobalt spec sheet on Zivi[1] and this Pharmacology review).

I believe both approaches have a lot of potential and I do not understand why you seem to be determined to bring this approach down before enough time has passed to analyze short and long term results.

-- Notes
[1]: The documents are in French and Dutch, but I'm sure English spec sheets for Trobalt are widely available on the internet. Google Translate will also help.

 

I’m unfamiliar with the technical aspects of Cochlear Implants but do they bypass the DCN? Anyone here know?

I’ll keep it brief. XEN1101 is not Trobalt and the side effect profile is minimal vs that of placebo. I repeat, XEN1101 drug is NOT Trobalt.

But, in theory it should work for tinnitus like Trobalt did, especially as it is 16x more potent. Plus the info I read on here suggests that most discontinued or reduced dose of Trobalt due to unfortunate and sad side effects. It did show efficacy for tinnitus with continued use.

None of those serious side effects have appeared in the Xenon Pharmaceuticals studies.

I was a big believer in FX-322 and even invested in Frequency Therapeutics but let’s face it, the Phase 2 results were a complete and utter bomb. In the months leading up to the release of Phase 2 results the Frequency Therapeutics team were hyping the company like you would not believe.

I still have faith in the tech as Robert Langer has had 1 fail out of 40 spin off biotechs. I am more researched than most on here, and firmly believe there is no cure for tinnitus on the horizon via progenitor cell activation. Yes, potentially a cure for hearing loss and certainly speech intelligibility but there is zero evidence that it will suppress tinnitus. I am a hearing aid wearer up to 10,000 Hz and my tinnitus is lower than that. No effect on tinnitus when my hearing aids are in apart from amplification to mask it.

Take Dr. De Ridder - ‘stuck in the brain,’ eliminate tinnitus, then regenerate.

Or take Dr. Shore - it’s the DCN.

Or take Professor Tzounopoulos - it’s the potassium channels.

Argue with them. As for now, the fact is that there is zero proof that hair cell regeneration will cure chronic tinnitus. None.

FX-322 is practically useless.

FX-345 sounds exciting but we have been down that ‘exciting’ road before.

 

Long story short, to date FX-322 has shown consistent improvements in speech perception in early clinical trials but FREQ had a hang up in their last trial in that there was an unprecedented placebo response in the trial and they were unable to make an accurate assessment of improvements in the FX-322 group (there were improvements) because they didn't have an accurate baseline to compare to so they had to throw the baby out with the bathwater and say that FX-322 showed no benefit over placebo which is true BUT that's because nearly 50% of both groups saw improvement.

The company's explanation for the placebo response is that they made the mistake of telling patients entry criteria to get into the trial and they didn't anticipate subjects lying on their hearing exams to make it look like they had worse hearing than they actually did to get into the trial. They are currently running a new Phase 2 trial with results expected around the end of the year.

So either FX-322 works and it was a poorly designed trial that allowed placebo responders, or placebo injections consistently improve hearing to a degree never before documented in history.

 

Ughhh... You're going to make me do this, aren't you? Evidence that FX-322 improved tinnitus for the millionth time:

CLAIM: [0664] In addition, three subjects reported an improvement in tinnitus. All three of these subjects were in the cohort that had improved word recognition scores.

REFERENCE: International Patent for FX-322

And if you're well studied on FX-322... You probably already know which 3 patients they're referencing.

Evidence.

 

We have to tackle this from ALL possible angles instead of putting our eggs in one basket. It's as simple as that.

 

ANECDOTAL. Not compared to placebo equals zero evidence. Ughhh.

Even the startling Korean study isn’t being taken seriously by researchers until placebo is in another trial.

Lenire. No placebo. Doesn’t work. Placebo averages 13 TFI in most trials. Lenire results match placebo.

Could it be the placebo effect? How much did their TFI improve? We don’t know as there was no TFI in Phase 1.

Probably under 13 which is PLACEBO but we don’t know. All it is is anecdotal. Probably placebo.

There was TFI in Phase 2. No positive TFI results announced. There must not have been anything significant. Scientific evidence = not present.

No offense but uggh there isn’t a shred of scientific evidence.

Also, I’m more than familiar with the Frequency Therapeutics hype machine. They are lucky that shareholders didn’t take class action (or did they?). Plenty of insider selling pre Phase 2.

Zilch, nothing, certainly nothing solid except anecdotal shite from a company prone to over hyping and unfortunately under delivering.

The share price doesn’t lie. What was it, -80% on Phase 2. Check out Xenon Pharmaceuticals’ share price after Phase 2.

Clutching at straws. Ugghh.

Nothing here yet for tinnitus sufferers 100% guaranteed.

FX-345, maybe, but again there is a shedload of time before we see that and zero evidence it will help tinnitus.

Please don’t make me state the bloody obvious again.

 

Of course. Hearing regeneration may help tinnitus and will help hearing but all I am saying is that there is zilch to put our faith in here yet. Better off focusing on:

Otonomy
Ebselen
XEN1101
Dr. Susan Shore

They should be here by 2024 at the latest, whilst FX-322 is crap and FX-345 might be optimistically in Phase 2A by then. That is if they can get cash. They have $140M and the market cap is c$80M. That shows the faith the market has in the company unfortunately. How they will raise funds is a mystery to me.

 

I thought the Dr. Shore device was only effective while using it and tinnitus returns after cessation.

 

Anecdotes are evidence. So, now you're just moving the goalpost and mocking? Nice way to minimize your argument on a public forum. Also, Frequency Therapeutics clarified that they rejected the data from the Phase 2B because it couldn't be distinguished from placebo. So, there's no reason for them to post TFI scores, since they were secondary outcomes.

By the way, do you own some FREQ shorts that are at-risk now that the stock is rebounding? Because your arguments are severely one-sided and rather tone-deaf with other members as well.

This will be my last engagement with you, I don't think this dialogue is helpful for the readers here that actually want to learn about the research going on with this firm.

 

Aren't the positive effects from Trobalt anecdotal too? I'd love to see a source claiming otherwise.

 

Separate to the prior arguments on here, no one knows if FX-322 / FX-345 will treat tinnitus. I admire the work Frequency Therapeutics are doing and I am excited by FX-345.

As I have repeated many times, Bob Langer does not fail. To be the most cited engineer in history is some accomplishment.

I believe that Frequency Therapeutics will get there and produce an efficacious treatment for hearing loss but a lot is unknown about the durability and function of regenerated hair cells, plus their ability to form connections to the synapses. Will these 'new hair cells' be as good as the original. It is all unknown and is very interesting.

I am however worried about funding. They need good news fast.

I recently spoke with a Professor who has connections with Bob Langer and he was not all that enthused with PCA, but is focusing on gene therapy.

Progenitor cell activation would be amazing if it works.

I will keep a head in here and not post further as people need hope, as I do very much every day, to keep me going. I do feel as a 'tinnitus' treatment it should not be the hot topic it is.

That is my opinion and hey, I'm only one person, but facts are facts and at this present time there is no evidence that it will help tinnitus. No evidence apart from company reported 'anecdotes'.

I hope it will treat tinnitus. It would be amazing.