Frequency Therapeutics — Hearing Loss Regeneration

[patorjk]

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The market is crazy right now. I'd buy more but I've already purchased an amount within my comfort zone.

Assuming FREQ has good results, it'll be interesting to see how it moves in this market.

 

[patorjk]

Profit taking going on. Investors/speculators getting cold feet.

This is something different. It's a market-wide shift. We're seeing hedge funds and large investors move out of growth stocks and into value stocks. It's driven by increasing bond yields and the anticipation of the economy getting back to normal. It's why you're seeing companies like Tesla and Square tanking right now, while companies like AT&T are doing fine. FREQ will probably remain volatile until this correction passes - and for better or worse we'll most likely get the results of Phase 2a before the market correction is done.

 

[scotty03874]

Profit taking going on. Investors/speculators getting cold feet.

The whole biotech sector is way down. It doesn't mean insider news of Phase 2A are bad.

 

[Mica Rambin]

They're going to make us all wait for the whole month, aren't they?

 

[Tezcatlipoca]

They're going to make us all wait for the whole month, aren't they?

Of course they are.

 

[Diesel]

Of course they are.

I'm hopeful it'll be by mid-month.

 

[FGG]

They're going to make us all wait for the whole month, aren't they?

From a strategic point of view, it would be a bad time to release news while the market is down. Even worse for good news even.

 

[Tezcatlipoca]

I'm hopeful it'll be by mid-month.

Yeah that's definitely the date but I can't understand why they won't release them ASAP.

I made a post earlier where I speculated the 17th of March at the latest because of a conference they have.

 

[Aaron91]

The whole biotech sector is way down. It doesn't mean insider news of Phase 2A are bad.

I think what was meant was that day-traders and/or outside investors bought in to make profits on the speculation wave post Phase-1 but are now cashing out their margin before Phase 2 results are announced in the event of bad news. These would be investors who probably don't know much about FX-322 in the first place, other than the fact that they're releasing results soon.

 

[grate_biff]

That Toby guy was spot on about how the stock would plummet. I hope he is not right about the drug. I can't help but worry, it's down 20% in two days.

What the hell is going on? He obviously knows the stock market. But hopefully he is dead wrong about FX-322.

But I'm starting to think about what he said about the Twitter message and everything.

Please bring some good news soon.

I'm counting every minute of the day...

 

[GBB]

That Toby guy was spot on about how the stock would plummet. I hope he is not right about the drug. I can't help but worry, it's down 20% in two days.

What the hell is going on? He obviously knows the stock market. But hopefully he is dead wrong about FX-322.

But I'm starting to think about what he said about the Twitter message and everything.

Please bring some good news soon.

I'm counting every minute of the day...

The whole market is down dude, chill. Tinnitus is hell but no reason to catastrophize re stock valuations.

 

[Greg Sacramento]

Use timing. I had explained how to value FREQ short and longer term on the FREQ stock thread (for Tinnitus Talk Benefactors) a short time ago. This model has always been 99% accurate.

Frequency Therapeutics (FREQ)

Earlier today near the open, I posted on the above FREQ stock thread with concern. Notice that market recovery did not help price other than a spike. It went down like stairs for the rest of the day. Most other biotechs, techs and everything else had recovery for the day. I haven't viewed closing charting, so I don't know if a cushion is present.

 

[patorjk]

That Toby guy was spot on about how the stock would plummet. I hope he is not right about the drug. I can't help but worry, it's down 20% in two days.

What the hell is going on? He obviously knows the stock market. But hopefully he is dead wrong about FX-322.

But I'm starting to think about what he said about the Twitter message and everything.

Please bring some good news soon.

I'm counting every minute of the day...

The growth market is going through a correction right now. To ease your fears a little, Google the following tickers and look at how they've done the past month:

$TSLA (Tesla)
$SQ (Square)
$ROKU (Roku)
$ARKK (an innovation ETF - hell, look at any of ARK's funds)

What do these stocks have in common? They're all high growth stocks. If you look at a news source like the Wall Street Journal, it'll tell you that this is due to bond yields and large investment companies moving their money into value stocks.

When Toby made his post 2 days ago, this correction had already begun. In my reply I even stated that we may very well see FREQ hit the lows that he's talking about by the 11th, but it's NOT because of the reasons he gave. He was scare-mongering about the 4 individuals in Phase I possibly being frauds and about Frequency Therapeutics pumping their stock so that they could cash out. It's important to note that most of the insiders haven't sold any stock. We've only seen 3 of them sell, and all of those 3 have been on predictable selling schedules. Also, if they were to pump and dump before the results, knowing that they were going to be bad, that would be illegal. It's one of the reasons the chairman of Otonomy's board of directors waited until after the failed Otividex results to sell his shares. Had he done so before the results, there would probably have been lawsuits.

We will most likely continue to see a lot of volatility in FREQ, it may go down further or it may jump 10% on Monday. Until the correction is over, volatility will be high.

 

[FGG]

That Toby guy was spot on about how the stock would plummet. I hope he is not right about the drug. I can't help but worry, it's down 20% in two days.

What the hell is going on? He obviously knows the stock market. But hopefully he is dead wrong about FX-322.

But I'm starting to think about what he said about the Twitter message and everything.

Please bring some good news soon.

I'm counting every minute of the day...

Toby flat out admitted he didn't understand the recruitment and testing process but said there was "definitely" fraud. I mean, c'mon...

Also, the Twitter messaging has been the same for months and Frequency Therapeutics has even said in interviews that an important part of their product launch is going to be patient education because the patients themselves are going to have to educate the doctors some on this. There is a very positive way to look at this too and that is that they are starting that process now.

 

[AfroSnowman]

Of course the stock drop is a little disconcerting, but I imagine that two major things are happening.

1) Buy the rumor, sell the news, the run up was/is based upon a real excitement for what the drug might be and promising early results now with the news imminent folks are taking their money off the table and clearly there is a bit of momentum selling at the moment.

2) The rising bond market that has a particularly negative impact on businesses that rely on borrowing.

Or maybe someone knows something that we don't.

 

[john paul]

The stock will be down because of the overall correction in the stock market and because of nervous investors. They would rather sit out and wait for the results than have their pants pulled down. The run up to now was based on nothing but speculation and a general flow of money into stocks. Money is being pulled out because trading stocks is risk management and right now there is a lot of risk in holding FREQ shares.

 

[Aaron91]

How to derail a 486-page scientific research thread: post your gain/loss porn, throw in some false collusion/security fraud allegations, detract from company and science fundamentals, shatter everyone's hopes and claim the company is a dead duck.

For everyone's peace of mind, I know that for every member who's well-read on this company and who has sold their position, there are another 10 I can show you who are long and holding. There are some incredibly bright minds here who think differently from Toby guy and I'm inclined to agree with them.

 

[Diesel]

Of course the stock drop is a little disconcerting, but I imagine that two major things are happening.

1) Buy the rumor, sell the news, the run up was/is based upon a real excitement for what the drug might be and promising early results now with the news imminent folks are taking their money off the table and clearly there is a bit of momentum selling at the moment.

2) The rising bond market that has a particularly negative impact on businesses that rely on borrowing.

Or maybe someone knows something that we don't.

Over the past year, there's been a lot of "overspeculation" (myself included) on how the stock price change somehow relates directly to what is expected from the FX-322 Phase 2A trial. The stock goes up, the drug must be tits. The stock goes down... omg we're all screwed.

I think the fact that most can't point to anything that proves their case relating to the stock without backing it up shows it's nothing to be too concerned about.

In the meantime, I find the on-going assessment of the science / research released by the firm as actually valuable and insightful. Nowhere else on the 'net is anyone going into this much detail on the research behind FX-322, which many appreciate.

After all, we all want the drug to work, and understand how it can help us. The profits are secondary imo.

 

[Aaron91]

I hope peeps don't mind if I bring the conversation back to fundamentals.

There was a really interesting debate going on about the pharmacokinetics/dynamics behind FX-322 and specifically the notable difference between how deep the two molecules, VPA and CHIR, reach into the cochlea and how quickly they are absorbed. It started to become obvious to many of us here that this is something Frequency Therapeutics must have known about prior to Phase 2 from both their guinea pig models and human cochlea samples, and some of us wondered whether this was something that could have potentially been remedied by changing the volume and/or timing of dosages. Given that Frequency Therapeutics didn't do this, the question became: why not?

I hadn't planned on even attempting to answer this question, but for those of you who may have missed it, there's been an interesting conversation going on over at the Pipeline Therapeutics thread. Inadvertently, I may have stumbled across the answer to this question in some of my analysis over there, but as always I wanted to see what the hive mind thinks and peeps agreed that I should cross-post here. I know @FGG and @Diesel are already mulling over it.

To keep things simple, I'm just going to copy paste my two original posts below. The first post explains a bit more about the differences in drug philosophy between PIPE and FX-322 and why the difference is important to optimising regeneration. The second post goes into the implications regarding pharmacokinetics/dynamics and speculates why we may be seeing the differences in diffusion and absorption between the two molecules.

Original post:

"So with FX-322 news imminent, I thought I'd go down the rabbithole a bit with this question [of whether support cell depletion is minimal because of minimal OHC regeneration] in the event Frequency Therapeutics do drop a bombshell on us.

I think most are already aware of this, but PIPE have a transdifferentiation approach when it comes to regenerating hair cells:

To put it simply, FX-322 causes asymmetric division where you end up with a hair cell and a new progenitor, whereas with PIPE the progenitor turns into a hair cell and the progenitor is depleted. Of course people are confused because PIPE are saying they are not seeing much depletion of the support cells, but as @FGG has pointed out this could be down to the fact that they're not getting much regeneration in the first place.

So I did a bit more digging, and found an interesting slide from one of Frequency Therapeutics' presentations. Before I get to that though, here's just a reminder of what Carl LeBel had to say on this:

"What those [transdifferentation] programmes have tried to do is take a progenitor cell and – it's a process we call transdifferentiation – you're taking a supporting cell, a progenitor cell, and turning it into a hair cell, you're making it want to become a hair cell. The problem is, it can't be a fully functional hair cell, because you haven't turned the right genes on. And the other problem is, you have now exhausted now your progenitor pool".

PIPE use one small molecule, whereas Frequency Therapeutics use two. Again, this is what Carl LeBel had to say:

"The other molecule is a proprietary molecule, and this is a molecule that goes after a specific pathway, and as I said earlier, it's the combination of these two agents that we think is important"

So far, I don't think I've said anything new, but I just wanted to bring people up to speed in any case. But now, here's the slide from Frequency Therapeutics that I think is interesting and backs up the above:

So what we are looking at here are the differences in cell proliferation when using the two Frequency Therapeutics molecules individually and then together. As I don't have a medical background, the first thing I was interested to know was whether valproic acid (sodium valproate), as a HDAC Inhibitor, is comparable to other notch inhibitor approaches companies such as PIPE have. After a bit of research I came across this paper, which looks at transdifferentiation of pancreatic cells using HDAC. Indeed, it seems to confirm (in paraphrasing another paper) that "HDAC1 regulates retinal neurogenesis by suppressing Wnt and Notch signalling pathways". Obviously we are talking about ears and not eyes or the pancreas here, but I'm assuming the science remains largely relevant.

So one could argue that what we are looking at in the 3rd graph is something close to what one might see when using PIPE's drug, as that too is a notch inhibitor. If anything, it may be even worse in reality, because HDAC seems to also have Wnt inhibition properties as well. What's interesting about the last graph though is that although the red area is more than double, if you look at the x-axis, which indicates the number of green-fluorescent progenitors observed, the numbers are logarithmic. Using Frequency Therapeutics' approach, we are seeing 10x more progenitors compared to single-molecule approaches.

I can only then infer that the reason why there isn't much cell support depletion observed is because there probably isn't much regeneration going on in the first place, at least compared to that observed when using a drug like FX-322."

And here's the follow up to my own post:

"I've had a few more thoughts.

There's been a lot of discussion recently on the FX-322 thread about the pharmacokinetics/dynamics of the two small molecules. Specifically, there has been some concern about VPA, the HDAC inhibitor, being depleted a lot more quickly compared to CHIR99021 in that it does not go as deep into the cochlea, the implication being some regeneration potential goes to waste because Frequency have "undershot" the amount of VPA required. See graph below:

I'm now wondering whether this is actually somewhat intentional.

Given my post yesterday, we can infer that VPA alone, given its inhibition properties, causes progenitors to transduce into hair cells, not divide asymmetrically. The paper I posted yesterday, in paraphrasing another paper, supports this:

"A study recently reported the usefulness of VPA in transdifferentiation of BMSSCs into hepatocytes in vitro."

So it would appear this is why the two-molecule approach is key, because it is the presence of CHIR99021, the proprietary molecule, that ensures we have asymmetric division and not transdifferentiation, although it's unclear whether the prevention of transdifferentiation is synergetic i.e. either drug alone causes transdifferentiation but together we have asymmetric division.

My point though is this: assuming transdifferentiation is limited to VPA, I'm wondering whether Frequency Therapeutics have purposefully "capped" the amount of VPA relative to CHIR in order to prevent a case of transdifferentiation in places where there is not enough CHIR, as an excess of VPA could lead to FX-322 causing unintended support cell depletion."

Thoughts?

 

[AfroSnowman]

After all, we all want the drug to work, and understand how it can help us. The profits are secondary imo.

That's the entirety of the game for me. I put some money in a while ago with the thought in mind that if it works I'd use my gains to pay for it.

I presume for most of us here the endless speculation and dissection of the science and the stock is a coping mechanism. Something pleasant to distract us while we deal with another day with this condition. Fantasizing of getting rich while getting well is all the more fun. In the end the only thing of any real importance to me is that there may be a treatment in the near horizon, the rest is just killing time. I check my stock ticker to see if it is jumping not really to count my pennies but to find out if they have released the results.

I agree with you looking at the stock nothing has changed from two weeks ago, no negative hints, no announced delays, no problems discovered in the underlying science in their peer reviewed paper. This is a speculative stock and people are going to speculate. The unfounded exuberance that kept pushing this higher has now been met with equally unfounded dismay that is leading this sell off. People didn't want to miss out on a shooting star and now folks don't want to catch a falling knife. All this is is a gamble, an educated gamble but a gamble all the same. Spin the wheel, maybe it lands on red, maybe black or maybe, just maybe we hit on red 23. The announced results will determine if we have hope and money or a lot less of both.

 

[Guywithapug]

After all, we all want the drug to work, and understand how it can help us. The profits are secondary imo.

I honestly don't care about a profit and would give everything I have to be healed. I would happily start again from scratch.

 

[GBB]

Of course the stock drop is a little disconcerting, but I imagine that two major things are happening.

1) Buy the rumor, sell the news, the run up was/is based upon a real excitement for what the drug might be and promising early results now with the news imminent folks are taking their money off the table and clearly there is a bit of momentum selling at the moment.

2) The rising bond market that has a particularly negative impact on businesses that rely on borrowing.

Or maybe someone knows something that we don't.

There's a general rotation out of volatility at the moment. It will be temporary. If FX-322 blows up, obviously it's not coming back with the tide, but all else being equal in the future, this price decline is more a macro issue, in my opinion.

 

[Koz]

I think you are referring to this report described by a surgeon:

Cochlear nerve section for intractable tinnitus

Since I think my etiology may be related to the cochlear nerve, I read the paper in entirety. Very interesting stuff. The author indicates that the group helped by this has cochlear or cochlear nerve issues, hence relevant to many people. The reason why Translabyrinthine VIII Nerve Sections are avoided is because they (obviously) cause total deafness on the side that is sectioned.

The case report is nuts. The guy had tinnitus so bad that he told the surgeon he would kill himself if it wasn't relieved. He ended up getting the surgery, deafening the bad ear, and saw a near total relief.

My suspicion is that it works because the brain stops being "teased" by a hearing signal. It's just gone, completely and moves on. Also, this is an interesting piece of evidence that tinnitus is not stuck in the brain. If it was, we wouldn't see a 2/3 success rate by sectioning the cochlear nerve.

My right ear is normal but my left ear is in the severe/profound range. This is really interesting.

Still not something I would consider doing because surely doing so would mean any chance of potential treatments coming in the next years are going to be ineffective for me as a result?

My ideal scenario is FX-322 working on the severe range (mostly where I'm at) and for the frequencies at profound (for me only 2) I would leave them for when something for that comes out.

Also, as mad as it sounds, hearing loss is a bigger issue for me than tinnitus and yes my tinnitus is super loud, constantly present and cannot be masked by anything.

 

[RichieTheKid]

Toby flat out admitted he didn't understand the recruitment and testing process but said there was "definitely" fraud. I mean, c'mon...

Also, the Twitter messaging has been the same for months and Frequency Therapeutics has even said in interviews that an important part of their product launch is going to be patient education because the patients themselves are going to have to educate the doctors some on this. There is a very positive way to look at this too and that is that they are starting that process now.

Educating doctors eh? I somehow get the feeling doctors that I have interacted with so far wouldn't like me doing that. Maybe it's just my personality though.

 

[L34]

Thoughts?

I am nowhere near capable of having any smart thoughts about this subject, but I am very impressed about your knowledge and your ability to explain.

Thank you very much for this

 

[FGG]

Not sure how relevant this is, and maybe I'm overthinking this but VPA can reactivate viruses in the herpes family that can effect the ear and maybe that implies some caution on the part of Frequency Therapeutics in their dosing of it at the moment (since viral infections are a cause of SSNHL).

In fact, it's being studied for use with anti virals to make the virus reactivate / come out of latency to kill it effectively:

Cytolytic virus activation therapy and treatment monitoring for Epstein-Barr virus associated nasopharyngeal carcinoma in a mouse tumor model

Since I have had severe vertigo related to EBV in the past, I would plan to take anti virals during treatment, personally.

 

[FGG]

Educating doctors eh? I somehow get the feeling doctors that I have interacted with so far wouldn't like me doing that. Maybe it's just my personality though.

I don't think they mean showing up to your ENTs with copies of journal articles and PowerPoint presentations (even if some of us would want to ), I think they mean asking for extending audiograms and explaining why, etc.

 

[spacehunter]

Not sure how relevant this is, and maybe I'm overthinking this but VPA can reactivate viruses in the herpes family that can effect the ear and maybe that implies some caution on the part of Frequency Therapeutics in their dosing of it at the moment (since viral infections are a cause of SSNHL).

In fact, it's being studied for use with anti virals to make the virus reactivate / come out of latency to kill it effectively:

Cytolytic virus activation therapy and treatment monitoring for Epstein-Barr virus associated nasopharyngeal carcinoma in a mouse tumor model

Since I have had severe vertigo related to EBV in the past, I would plan to take anti virals during treatment, personally.

Another reason might be that VPA alone could also deplete support cells (see @Aaron91's post in the Pipeline Therapeutics thread). So maybe it is even on purpose that the VPA concentration drops faster as to make sure that VPA cannot reach cells without CHIR99021.

 

[Keith Handy]

I don't think they mean showing up to your ENTs with copies of journal articles and PowerPoint presentations (even if some of us would want to ), I think they mean asking for extending audiograms and explaining why, etc.

Heck with that, I'm doing a PowerPoint and an interpretative dance and I expect several of you to be there with me in costumes representing the middle ear, inner ear, and brain.

 

[FGG]

Another reason might be that VPA alone could also deplete support cells (see @Aaron91's post in the Pipeline Therapeutics thread). So maybe it is even on purpose that the VPA concentration drops faster as to make sure that VPA cannot reach cells without CHIR99021.

Yep, there is an ongoing discussion there but I think there is a key difference between hepatocytes and their associated stem cells and cochlear hair cells and their progenitors and that is that hepatocytes do not have their regenerative capacity switched off. The liver has extraordinary regenerative capacity after injury, in fact.

So it seems that HDACs (like VPA), might permit hepatocyte formation because they are stimulating notch (but inhibiting part of the pathway so that lateral inhibition of neighboring cells does not limit the regeneration).

With the cochlea, I'm not sure that's enough because you can stop lateral inhibition woth VPA but you'd still need to switch back on the wnt pathway where you don't need to do that with liver cells.

@Aaron91, thoughts?