Frequency Therapeutics — Hearing Loss Regeneration
- Thread starter RB2014
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MemberThis share sell off is pretty standard stuff and is part of Frequency Therapeutics' Form 10b5-1 trading agreement. As a result this sell off is nothing really concerning or surprising.
Pero1234
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- Mar 15, 2018
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- home theatre system + high pressure washer
You got my heart racing there for a minute. He still owns a lot more though!
David L. Lucchino, Frequency Therapeutics, Inc.'s President and CEO and a director of the company, recently disposed of 15,716 shares of the company. The disposals took place at prices ranging from $18.87 to $19.71 per share, on October 01, 2020. Lucchino still owns 355,228 shares of the company.
No need to panic, I guess. I may set that stoploss though.
Otonomy had a maximum share price of $29.43, but fell to $1.71 in 2017.
Now it's $4.69.
What will happen to Frequency Therapeutics?
Does the sale of the CEO's holdings have any positive implications, such as raising funds for headhunting?
https://www.nasdaq.com/market-activity/stocks/freq/insider-activity
Now it's $4.69.
What will happen to Frequency Therapeutics?
Does the sale of the CEO's holdings have any positive implications, such as raising funds for headhunting?
https://www.nasdaq.com/market-activity/stocks/freq/insider-activity
- May 16, 2017
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They are both jointly responsible. Dilution of shares will happen, but that is only a concern for investors. Hedge funds that have both financial and medical analysts are not yet invested. One reason is insider selling of shares.
There is definitely zero connection between the FX-322 clinical trials and the selling of shares under this agreement.
Actually I am also very certain that this cycle will repeat itself again sometime soon with David Lucchino getting the next payment (shares) and again selling some set portion of these off in order to get money.
Answered in the Otonomy thread.
Not to mention that these type of hedge funds are actually often the last to invest in pharmaceutical companies until they have demonstrated more concrete results in their treatment's performance. They definitely are not as willing to take the very big risks that some firms are by investing when the treatment is still somewhat unknown. But they will invest at a point where they know that there is a reasonably good chance that the product will be successful and that they will get value for money with their purchase.
The insider selling of shares is somewhat of a smokescreen I think for these medically orientated investment firms. Fair enough that they have their concerns about this, though really it is not that unusual or even troubling.
Probably worth noting too that these investment firms with medical experts on them are actually also the type who will hold onto their shares to get the dividend benefit rather than actually looking to make speedy money by buying and selling shares for a profit. Hence they don't care if they pay a bit more for the shares initially either.
Thuan
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- Jul 5, 2020
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- 05/2018
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- Ear infection right ear 2018. Sound trauma left ear 2020.
I think there's some misconceptions that everyone who hasn't carefully read their actual animal studies here:
Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells
First, their animal studies directly and surgically removed inner ear rather than working with it live. They used in vitro and explants to study cochlear hair cell regeneration. In layman's terms, think of in vitro as growing cells in a test tube. The explants are transferring live cells, from a surgically removed cochlea, to another artificial medium. Both were done to confirm hair cell regeneration markers.
However, their methods of introducing the drug to the ear is completely different from the hydrogel delivery that they are doing for humans. They did confirm the drug crossed the cochlea via the hydrogel in cochlear implant patients but keep in mind these are different conditions than the animal studies.
Second, they animal studies confirmed that new hair cells did regenerate. However, they did not confirm if these hair cells are actually carrying neurological signals back to the brain. They did not measure the animals' brain activity after hair cell regeneration because they can't. They surgically removed the cochlea from the animals.
The purpose of Frequency Therapeutics' research paper was to confirm hair regeneration and neuronal structures because that is a huge discovery that has never been done before. But, they did NOT CONFIRM if these new hair cells and neuronal structures resulted in improved hearing or improved auditory signals. They should have done this. They should have measured the animals' brain activity, destroy their hair cells, measure the brain activity again to confirm hearing loss, intratympanically inject the drug to their cochlea, let them heal, and then measured their brain activity to confirm hearing restoration.
The assumption is that the newly regenerated hair cells are neurologically active. Who knows if new hair cells have working neurological connectivity because they did not test this.
Tldr; Frequency Therapeutics' animal studies confirmed cochlear hair cell regeneration but did not confirm if these regenerated hair cells are neurologically active nor that it leads to restoration of hearing.
With that said, I'm eagerly awaiting and hoping for good results from their live phase 2a clinical studies...
Over and out.
They actually did restore all frequencies in vivo in a adult deafened mice (https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1):
Also there is already statistical significant clinical data in humans for restored hearing functionality with FX-322.
Thuan
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- Jul 5, 2020
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- 05/2018
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- Ear infection right ear 2018. Sound trauma left ear 2020.
You are confusing the Frequency Therapeutics' investor slides with research studies. Those investor slide claims it restores hearing in all frequencies (based on the assumption that newly restored hair cells are neurologically active for the animal studies and improved word scores for the human clinical data). For the animal studies, they definitely did not test for frequencies restoration. For the human clinical phase 1 data shows and confirm that there is improvement in word scores for 3 or 4 out of some 15 or 20-ish patients? Improving word some word scores is not conclusive evidence that it restores a broad spectrum of frequencies.
If you read their actual scientific studies on "Experimental Procedures here, then it should be clear they did not measure restoration of auditory frequencies in their animal studies. The experimental procedures measured the concentration of new hair cell markers. Thus, the scientific studies confirmed restoring hair cells.
Restoring hair cells alone is not confirmation that it restores frequencies because obviously you also need to restore the neuronal connection from the hair cells to the actual cochlear nerve. If you have all these newly restored hair cells but they don't connect to anywhere, they're completely useless. In an analogous example, it's like getting a new limb without the nerve connecting and so that limb is dead weight.
This is the misconception that I so often see in this thread... The point is that all these speculations on dosage and etc. is based on the fact that the new hair cells work, which it might not. I HOPE it works.
EDIT:
The more I think about the majority that did not improve in phase 1 makes me conclude there is more to it than just restoring new hair cells, i.e. cochlear synaptopathy.
The Cell study was an in vitro study on cell cultures, so of course it didn't measure auditory function. Unless I'm missing your point?
The claim Frequency Therapeutics made was that they grew hair cells in all frequencies (which they can easily assess on necropsy after in vivo dosing and they aren't required to publish this in Cell or anywhere else, but I'd believe them if they published it in a presentation since they are publically traded and would be liable for that kind of false information). In the Tinnitus Talk Podcast, Carl LeBel confirmed that these hair cells form synapses. These synapses are the neuronal connections. So they are not dead hair cells that don't work. And if they were, they certainly wouldn't have gotten the word score results they did.
Do you have an alternate explanation as to why some patients doubled word scores if they formed "dead weight" hair cells without a connection? Because none of the control ears (in the same patient even) had these improvements.
I understand some people are married to audiogram data but we should have that with phase 2a data soon. I think there is plenty of evidence that it doesn't regrow non-connected hair cells though but the extended audiogram should make a lot of people much more confident IMO because even though you can't fake those kind of word score improvements, audiogram data seems to mean more to people.
But I can completely discount the "maybe they are dead weight hair cells" theory because that would have absolutely been tested before human trials with multi species necropsy and histology (to confirm the morphology and synapse connections). That would be literally the first thing any researcher would do and LeBel confirmed this as well even if he didn't use the words "necropsy" or "histology".
The company, Frequency Therapeutics, did their own preclinical testing and evaluations separate from what's published on that paper. That paper was not published by Frequency Therapeutics, and was submitted by scientist independently from the company.
The company cannot "claim" false information to investors as that would be illegal, nor can they do so in their preclinical data that they submit to the FDA to start initial human testing.
"FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer), having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans." - FDA
Their testing included treating a living, deafened mouse with FX-322 to gather data on the drugs effects. In turn, they discovered it did restore hearing across all frequencies. I've also read that they tested on primates but I can't find the source. All data is submitted to the FDA, to initially start human trials.
Also to explain the the "inconclusive evidence", while it isn't data that shows to restore broad spectrum hearing (in humans, with a inferior delivery method), it does show that it is a clinically meaningful improvement in hearing, which is conclusive evidence of hearing functionality being restored.
Of the 23 patients, 14 has mild hearing loss, thus none of them has any clinically meaningful word recognition improvements as they were already scoring 45+ words out of 50, also called the ceiling effect. Of those, 9 had moderate to moderately severe hearing loss, 3 of which were given placebos. Of the 6 of those, 4 showed clinically significant results that can be without a reasonable doubt attributed to FX-322. Of those 4, 3 has a 10-15 decibel improvement at 8 kHz.
This tends to be why it will be a matter of dosing due to the issues in a human ear essentially being different to those of a rat. I really reckon that the top sign that this is possible in a human is that the ears of rats and us are apparently actually very similar.
So it seems that what you are saying is that we know FX-322 can completely cause hair cell regrowth but basically it might not cause nerve reconnection.
Right now I reckon that this is why a synapse treatment can be quite important. I think that the regrowing of the nerve ends and the synapses simply reforms the connections that then in turn assist with hairncell growth. I know Frequency Therapeutics said that they think that FX-322 helps with this synapse and nerve growth, however I think that it is not nearly as beneficial as the outcomes attained with a specific synapse treatment.
The video created by Frequency Therapeutics shows how nerves grow and connect to regenerated hair cells.
Is this an unfounded optimistic imagination?
Did they just imagine when they had no evidence?
It is very hard for me to fathom Frequency Therapeutics falsely representing what FX-322 does and/or how it works considering their consistent approach towards providing reasonable, transparent and accurate details about it. Therefore I feel that your point is very valid and I don't see how Frequency Therapeutics could have given us inaccurate facts on this.
What I have been thinking about recently is that would it still be possible for FX-322 to regrow synapses even if there was no hair cell loss? Even if they say synapses only regrow where there is hair cell loss?
- May 27, 2020
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Don't biotech companies have to be very, very careful with their claims though, as this could upset the FDA and jeopardise the whole operation?
As for only 3 or 4 patients having "improvement", it is important to remember that Frequency Therapeutics are talking about statistically significant improvement here. I think it's also very important to remember that 9 out of the 15 patients already had 45+ (out of 50) word scores before treatment, so the threshold for measuring statistically significant improvement in these patients was already extremely high because the headroom for improvement was already extremely low to begin with. I think this was a bit of hiccup on Frequency's part, but as this was primarily a safety study and not an efficacy one, I don't think this was at the forefront of their minds, nor should one aim criticism at them for it.
I haven't seen Frequency Therapeutics present any data on these 9 patients (if they have, I'd be interested to see it), but that may be exactly because they can't make any claims with regards to their outcomes exactly because their outcomes were not statistically significant, even if the patients themselves "felt" and subsequently reported to Frequency Therapeutics some kind of improvement in their quality of hearing. Although I have no background in biology, I have done a module at MSc level in statistics and I can that I, personally, am not overly concerned by the fact that these 9 patients did not present statistically significant outcomes for the reasons I have explained above, but I would be interested to have seen their before and after UHF audiograms (not that Frequency Therapeutics measured these, but they will be in Phase 2). Also, didn't half of the 15 patients get a "low dose"?
With regards to @Thuan's point, can someone who understands the biology of the cochlea a bit better shed some light on how one can determine whether these cells reconnect to the auditory nerve and whether this is something Frequency Therapeutics have glanced over because it's self explanatory, or are they too in the dark as to what is actually happening once the hair cells have been regenerated?
If synapses only grow when there is hair cell loss, and the thought was that there was synapse benefit obtained in the first FX-322 trial, then this leads me to believe that there would also have been hair cell growth in the very high frequencies.
I also reckon that one of the benefits of a synapse only medicine is that this would regrow only the synapses and obviously overcome any of the problems that FX-322 may face when trying to regrow synapses.
Really.
Well then I pray that Frequency Therapeutics + Astellas and their competitor Otonomy + Kyorin will both succeed, and that the effects of both drugs will produce a good synergistic effect. For example, if no problem occurs, administration of both at the same time will reach the lower frequencies, and hair cell regeneration and nerve healing will occur more effectively.
There are economic benefits to both sides, and the benefits to the patient also increase.
It may be an impossible dream, but...
- Feb 14, 2020
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Are we still wondering if FX-322 really does anything?
Come on, just read the investor presentation on their website.
https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1
Page 23.
The patients in the Phase 1/2 that received FX-322 (15 drug / 8 placebo)... ALL 15 averaged a 30% increase in word score after 90 days. With a P-val = 0.010; it's 99% likely that the drug input resulted in improved hearing.
It works.
Come on, just read the investor presentation on their website.
https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1
Page 23.
The patients in the Phase 1/2 that received FX-322 (15 drug / 8 placebo)... ALL 15 averaged a 30% increase in word score after 90 days. With a P-val = 0.010; it's 99% likely that the drug input resulted in improved hearing.
It works.
Thuan
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- Jul 5, 2020
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- 05/2018
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- Ear infection right ear 2018. Sound trauma left ear 2020.
That is my point, which they obviously of course can not test auditory function based on their experimental procedures. Scientifically, if there isn't hard evidence to establish renewed cochlear hair cells are fully functional, i.e. that the synaptic structures connect or connect correctly back to the cochlear nerve, then it's an assumption to say that renewed hair cells mean restoration of frequencies.
I've been a month away from Tinnitus Talk and the FX-322 hype and it's given a clear head to think about their animal studies.
We know that from the cochlear implant patients have confirmed therapeutic concentration of the delivered drug to the cochlea. So it isn't a matter of patients not receiving a good concentration of the drugs. So theoretically, most of the mild and moderate hearing loss group, who has hair cell damage damage, should improve as much as the severe hearing loss group.
But obviously the severe hearing loss group showed statistically minor improvements while mild and moderate showed no improvements. And I'm thinking why this is occuring when they have established concentrated drug delivery in the cochlear implant patients, and what I realized is that in their original animal studies we are assuming that new hair cells are neurological and fully functional. And this assumption was not proven with their animal studies. That study only proved the presence of a lot of new hair cell growth. The question is, does that directly correlate with auditory function in the brain?
@FGG when you said "Podcast, Carl LeBel confirmed that these hair cells form synapses", can you please cite exactly, in their preclinical studies which I have linked above, where they proved these synaptic structures are connected to the cochlear nerve? They showed that the synaptic markers are there with the new hair cells, but where exactly, as in their experimental procedures, that support these synaptic structures lead back to the cochlear nerve?
It's a great discovery to be able to induce regrowth on a once believed impossible situation. Now the question is, are these regenerated cochlear hair cells fully and neurological functional. I think the clinical phase 2 trials will confirm this.
I don't think it's impossible at all, but likely that a lot of hearing loss patients will need multiple treatments to get the best results.
It would be an easy thing to confirm. You give multiple species the drug, euthanize them and then examine the cochlea histopathologically.
If the new hair cells didn't synapse with the nerve, this would have been apparent during pre-clinical trials (because you can see this on histology, the same way makers of synapse drugs know their drug restores synapses). And there is no way they would invest in a drug without checking this first. Literally none.
And LeBel has specifically said the new hair cells do synapse with the nerve.
Thuan
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- Jul 5, 2020
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- 05/2018
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- Ear infection right ear 2018. Sound trauma left ear 2020.
So the basis for my concern is that the new hair cells and the spiral ganglions are not connected to the receiving end of the cochlear nerve. The spiral ganglions need a signal to know the direction to grow toward the cochlear nerve. The issue is that we currently do not know if these drugs provide such signal for the ganglions to grow in the direction of the nerve. My guess is that the some cochlear hair cells are able to grow the spiral ganglions to the correct direction by random chance. And, the majority of the new hair cells are growing the spiral ganglions in the wrong direction or places.
So if it's by random chance, then by simple math, the more regenerated hair cells you have the higher the chances of renew hair cells being randomly connected correctly. We know from Carl LeBel that overpopulation is not an issue, which means there is a population saturation where new hair cells stop growth. Because the severe hearing loss group has more spaces to grow the new hair cells, then it makes sense for them to have more random correctly connected hair cells. Hence, only the severe hearing loss group had minor improvements. It's a hypothesis on why the majority did not show improvements. And I think this is a legitimate concern.
For a quick and dirty illustration:
I'm not blindly taking his words for it if it doesn't show in the research paper. Like you said, if would be easy to confirm this so it would be trivial to include this in the research paper but they did not include this in the research paper. Please quote me the exact section that shows this in the research paper. I'm very happy to be proven wrong because I want this to work too.
Edit: The thing is a lot of people are just focusing on the fact that all we need is new hair cells. There's also the aspect if these hair cells are formed correctly because these are delicate structures in terms of mechanical transductions of signals to the spiral ganglions and to the correct connection from the spiral ganglion to the nerve.
Edit 2: Btw, they did an immunohistochemistry (showing the presence of protein structures), not a histology exam of microscopically looking at the spiral ganglion.
The Cell study was in vitro. You can't test hearing function on cells in a lab.
Most of the time the full extent of pre-clinical histology is not posted somewhere I can link you (this is true for biotech in general, Sarepta, who had a DMD drug, didn't post their full pre-clinical muscle histology) but I can say Carl LeBel would not have said they connected if they didn't. And this goes all the way back to the JP Morgan presentation.
And it's way too obvious of a thing to have checked before starting trials. There is no way they didn't do full histopathology.
- Jan 16, 2020
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- noise? infection? negative stress? other?
Whether you are right or wrong, or to what percentage you are right or wrong -- I'm talking about both sides of the argument, it is a fantastic piece of dialogue getting right down to the heart of the matter.
...there is the tiny side-issue question, word-recognition and decibel improvements aside:
Will this magic mixture tackle tinnitus?
Roll on May-June 2021. I've had it since 1992. Like only yesterday
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