Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

Might be, but there's strong evidence of intratympanic delivered drugs barely reaching the apex. I've seen studies where they found out 2.5% of the drugs reached the cochlea.

If they doubled or tripled the dose, more drug should penetrate deeper into the cochlea. My gut tells me they will get reliably to at least 8000 Hz with the higher dose (which is in the functional zone of hearing aids but can't replace them).

I just want the drug approved, even if insurance won't cover it short of a full hearing aid replacement because a) it would likely be cheaper in other countries and b) they can improve delivery with time and those changes won't likely take another prolonged trial.

 

[JohnAdams]

Might be, but there's strong evidence of intratympanic delivered drugs barely reaching the apex.

I thought that the mice tests showed that it reached their apexes more so than the base?

 

[Jurger]

If they doubled or tripled the dose, more drug should penetrate deeper into the cochlea. My gut tells me they will get reliably to at least 8000 Hz with the higher dose (which is in the functional zone of hearing aids but can't replace them).

I just want the drug approved, even if insurance won't cover it short of a full hearing aid replacement because a) it would likely be cheaper in other countries and b) they can improve delivery with time and those changes won't likely take another prolonged trial.

If that's all that happens they can hardly call this a hearing loss drug anymore. Most audiograms measure up to 8000 Hz and between 250-8000 Hz is what most people use on an everyday basis. Most hearing aids don't go any further either. You can also kiss your Breakthrough status goodbye.

I can imagine a scenario where they come out with promising, but not stellar, Phase 2a results. Let's say a 10-30 dB gain in high frequencies, some quieting of tinnitus and perhaps even improved balance (no reason the supporting cells in the vestibular won't react to this drug) in 1/3 patients. They pour some IPO cash into either a licensing agreement with a company that's developing a better delivery method or straight up buy that method and then come out with stronger Phase 2b results.

There's one point I want to make about delivery method before I shut up about this. We know that some people have a round window membrane that provides for great permeability of drugs and some who don't. They've already established that in studies. If you get a bunch of those 'bad permeators' (for lack of a better description) in your study and they don't show a response, you get a bunch of false negatives that can impact your chances of drug approval. What can the FDA/EMA do other then to look at your results? My point is that successful drug delivery is not only important for efficacy once this is approved, but that it's also linked to the chance of this drug being approved in the first place.

 

[Jurger]

I thought that the mice tests showed that it reached their apexes more so than the base?

Maybe the anatomy of the mice is such that that happens, but the high frequency of the area in the cochlea is the first thing an intratympanic delivered drug hits in humans. Can't imagine why the apex would be targeted better. There's no indication supporting cells in the apex respond better then those in the base. A supporting cell is a supporting cell right? That's also why some people think these drugs can be used to improve balance, because of supporting cells in the vestibular organ.

 

[JohnAdams]

Maybe the anatomy of the mice is such that that happens, but the high frequency of the area in the cochlea is the first thing an intratympanic delivered drug hits in humans. Can't imagine why the apex would be targeted better. There's no indication supporting cells in the apex respond better then those in the base. A supporting cell is a supporting cell right? That's also why some people think these drugs can be used to improve balance, because of supporting cells in the vestibular organ.

I think it is because the mouse has a faster heartbeat and thus a faster circulation.

 

[FGG]

If that's all that happens they can hardly call this a hearing loss drug anymore. Most audiograms measure up to 8000 Hz and between 250-8000 Hz is what most people use on an everyday basis. Most hearing aids don't go any further either. You can also kiss your Breakthrough status goodbye.

I can imagine a scenario where they come out with promising, but not stellar, Phase 2a results. Let's say a 10-30 dB gain in high frequencies, some quieting of tinnitus and perhaps even improved balance (no reason the supporting cells in the vestibular won't react to this drug) in 1/3 patients. They pour some IPO cash into either a licensing agreement with a company that's developing a better delivery method or straight up buy that method and then come out with stronger Phase 2b results.

There's one point I want to make about delivery method before I shut up about this. We know that some people have a round window membrane that provides for great permeability of drugs and some who don't. They've already established that in studies. If you get a bunch of those 'bad permeators' (for lack of a better description) in your study and they don't show a response, you get a bunch of false negatives that can impact your chances of drug approval. What can the FDA/EMA do other then to look at your results? My point is that successful drug delivery is not only important for efficacy once this is approved, but that it's also linked to the chance of this drug being approved in the first place.

To get Breakthrough status you just need a "clinically significant endpoint" it doesn't have to be standard 250-8000 Hz audiogram, if they can get a consistent word score improvement in those with moderate to severe hearing loss, they've achieved that.

People said the same thing about Sarepta and their DMD drug, Eteplirsen. It didn't increase much in the way of dystrophin production but it did increase the 5 minute walk test significantly. People tried to argue bias and placebo effect but the results were so dramatic (and so different from the natural course of the disease), it was approved.

I believe with increased dosing especially, Frequency will have enough for approval.

 

[Philip83]

Yes, it's in their very large IPO announcement file.

That's amazing!

 

[Mr Mister]

I am surprised that so little has been commented here about the valuation. IPO valuation reflects what the founders, investors and advisors (Goldman, JP Morgan, etc) believe is the current status, upside and risks of development of FX-322 and also the rest of the pipeline.

According to the source below the fully diluted market value is 526 MUSD and my understanding is that pro forma post-IPO net cash is 273 MUSD. I have not focussed on this too much but if it's right then net cash consists of 30 MUSD cash in hand as of June 31 2019 plus 62 MUSD to be received from financing round C plus 80 MUSD to be received from Astellas plus 101 MUSD from IPO proceeds. With a net cash of 273 MUSD they are certainly going to be very well financed going forward.

https://www.nasdaq.com/articles/deg...apeutics-sets-terms-for-$101-million-ipo-2019

That would mean an enterprise value of 253 MUSD. What is the view, is it cheap or expensive? Would you buy Frequency Therapeutics shares in the IPO?

 

[ChrisBoyMonkey]

That's bad ass.

That is the dumbest idea I have ever seen. For that to work then the drug would have to be mixed with ferrous nano particles. Do we really want nano sized pieces of metal in our cochlea? Also, if you watch the video, they clearly have no idea how magnets work. You cannot just make a magnetic field to hold stuff in space a certain distance from the magnet, magnets attract. The only way to do that is by using super conductors and cryogenics.

I know this is going way back now, but just wanted to add that magnets don't attract if they are the same polarity, they repel, most likely how this is working.

I've seen some pretty cool stuff based off of this, like floating death star speakers and the sort.

 

[d'Wooluf]

they repel, most likely how this is working.

That's exactly how it works. Better that than using a magnet strong enough to pull particles through the width of your head.

 

[Jurger]

I know this is going way back now, but just wanted to add that magnets don't attract if they are the same polarity, they repel, most likely how this is working.

I've seen some pretty cool stuff based off of this, like floating death star speakers and the sort.

Yeah, I have pretty high hopes for this delivery method. In pre-clinical work they established the following in comparison with intratympanic injections:

"We observed that magnetic delivery improved both the amount (by a factor of ten) and the uniformity of drug (a factor of three increase in apical-to-basal concentration) delivered to the cochlea."

https://www.entandaudiologynews.com...-delivery-of-therapy-to-middle-and-inner-ears

What's not to like?

 

[d'Wooluf]

So what changes can they make to the drug itself or the delivery method without having to go back to square 1? Anyone out there with an informed opinion?

 

[JohnAdams]

I know this is going way back now, but just wanted to add that magnets don't attract if they are the same polarity, they repel, most likely how this is working.

The nano particles are not magnets, they are just ferrous. Magnets do not repel non magnetically polarized metals. Only attract. Also, even if the nano particles were magnetically polarized, there would be nothing to hold them in an orientation where they would be in a repulsive state. If you take two magnets and set them on the table with two same poles facing each other and start moving one towards the other, then one sitting there will start to move a little and then quickly flip around and be facing the opposite pole and become attractive.

 

[Jurger]

So what changes can they make to the drug itself or the delivery method without having to go back to square 1? Anyone out there with an informed opinion?

They don't have to change the drug fundamentally to fit a certain delivery method. It's like dexamethasone or prednisolone. The drug is already here, now they're using it in certain types of gels, nanoparticles or direct injection in the cochlea (intracochlear). Most of it still in (pre-)clinical work though. I do believe Otonomy is gonna get their dexamethasone gel approved for Meniere's disease shortly.

 

[Jurger]

The nano particles are not magnets, they are just ferrous. Magnets do not repel non magnetically polarized metals. Only attract. Also, even if the nano particles were magnetically polarized, there would be nothing to hold them in an orientation where they would be in a repulsive state. If you take two magnets and set them on the table with two same poles facing each other and start moving one towards the other, then one sitting there will start to move a little and then quickly flip around and be facing the opposite pole and become attractive.

I think Otomagnetics is too far along for this being a sci-fi concept. They already tested it on rats, multiple times and with drugs attached to it. They're looking at 2021 to release it.

 

[Reinier]

Making a small hole in the cochlea with a laser is what is done in the CGF-166 trial. Perhaps they not yet have confidence in other delivery methods.

 

[JohnAdams]

So what changes can they make to the drug itself or the delivery method without having to go back to square 1? Anyone out there with an informed opinion?

Add a solution to the compound that will transiently increase the permeability of the RWM without affecting the function or concentration of the drug. The other way into the cochlea is through the blood labyrinth barrier (BLB) from the systemic blood supply. It has been shown that a compound called manitol transiently increases the permeability the BLB so maybe if applied locally to the RWM it would increase the permeability of that as well. Or instead of adding the manitol to the gel containing the drug they could give you an injection of that first and then let it flush out before giving the injection of the drug.

Update:
Benzyl Alcohol

"High osmolarity solution increased RWM permeability by a factor of 2 to 3, benzyl alcohol (a preservative used in some drug formulations) increased permeability by a factor of 3 to 5, and suctioning near the RWM increased permeability by a factor of 10 to 15."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596477/

Also, I think perhaps you could also apply bone conduction headphones to the patient to vibrate the middle ear which would probably work more of the solution into the RWM. That is an idea I got from the great doctor from South Korea.

 

[JohnAdams]

I think Otomagnetics is too far along for this being a sci-fi concept. They already tested it on rats, multiple times and with drugs attached to it. They're looking at 2021 to release it.

Right, I was talking about the magnetic force field crap they showed in their video. There is just no way to suspend things in space with a magnetic field like how they showed.

 

[JohnAdams]

Making a small hole in the cochlea with a laser is what is done in the CGF-166 trial. Perhaps they not yet have confidence in other delivery methods.

I think they do that because they don't want the viral vectors to go anywhere except the cochlea. What would be the consequence of have live viruses injecting AToH1 into epithelium of the middle ear, eustachian tubes, and throat? Probably cancer.

 

[85dB T]

Also, I think perhaps you could also apply bone conduction headphones to the patient to vibrate the middle ear which would probably work more of the solution into the RWM. That is an idea I got from the great doctor from South Korea.

Since I swim a lot, I've noticed how intense the vibrations can be while being underwater, exhaling and vocally humming simultaneously.

I've tried different frequencies thirty minutes at a time during continuous swimming in hopes of having some effect on tinnitus.

* Totally unrelated here, but this has an effect on tinnitus which is written about involving bone conduction sounds over extended time. What happens is the brain normalizes the "not normal" higher volume sounds of bone conduction and when they cease we percieve tinnitus as being quieter. How long this effect lasts varies from person to person, but not very long. If I swim an hour with this noise vibration, I will enjoy some relief for a while. Not sure exactly how long but I'll take whatever relief I can get.

 

[JohnAdams]

Since I swim a lot, I've noticed how intense the vibrations can be while being underwater, exhaling and vocally humming simultaneously.

I've tried different frequencies thirty minutes at a time during continuous swimming in hopes of having some effect on tinnitus.

* Totally unrelated here, but this has an effect on tinnitus which is written about involving bone conduction sounds over extended time. What happens is the brain normalizes the "not normal" higher volume sounds of bone conduction and when they cease we percieve tinnitus as being quieter. How long this effect lasts varies from person to person, but not very long. If I swim an hour with this noise vibration, I will enjoy some relief for a while. Not sure exactly how long but I'll take whatever relief I can get.

The best thing to do would be to determine the ranges of resonance for the RWM and or the drug itself and use those.

 

[d'Wooluf]

What's not to like?

The extra step in the process I guess. Intratympanic injection plus the magnetic push. Also the 5-10 years of further development and clinical studies. I agree it sounds pretty nifty. I noticed that it got partial funding from Action on Hearing Loss in the UK.

 

[Jurger]

The extra step in the process I guess. Intratympanic injection plus the magnetic push. Also the 5-10 years of further development and clinical studies. I agree it sounds pretty nifty. I noticed that it got partial funding from Action on Hearing Loss in the UK.

I don't think FX-322 in combination with magnetic delivery needs a separate approval. Frequency needs to get the drug approved and Otomagnetics needs to get the delivery method approved. Those are stand alone tracks.

 

[d'Wooluf]

Also the 5-10 years of further development and clinical studies

Ok, I looked back at the article Jurger linked to, and it was published in 2014. So we're at the more optimistic end of that range now. Any link for the 2021 prediction?

 

[d'Wooluf]

They're looking at 2021 to release it.

I think the 2021 release was contingent on them receiving orphan status for an otoprotective treatment to protect the hearing of children receiving chemotherapy. I couldn't find if they received a favourable ruling on that.

 

[Coleoptere]

I think they do that because they don't want the viral vectors to go anywhere except the cochlea. What would be the consequence of have live viruses injecting AToH1 into epithelium of the middle ear, eustachian tubes, and throat? Probably cancer.

We will not come to know that very easily. Novartis is now in Phase 2C testing to be completed Oct 9th this year. As for results & information sharing:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

They could have supportive information for the method of delivery but I do not think they will share that with Frequency Therapeutics. The good thing is that they still continue with their trials so very curious what has been achieved.

 

[Jurger]

I think the 2021 release was contingent on them receiving orphan status for an otoprotective treatment to protect the hearing of children receiving chemotherapy. I couldn't find if they received a favourable ruling on that.

I tried the Orphan Drug register of the EMA; no luck. I'm Dutch so I'm more focused on what's going on over here than at the FDA. The EMA website also said you can apply with pre-clinical work so I take it they won't have to go through a clinical trial first. They have done some pre-clinical work already, some of which I quoted here.

By the way, I wonder when Frequency will publish that article with Phase 1/2 results. Press announcement at the time mentioned that. Might give us some more insight than the prospectus.

 

[JohnAdams]

I am surprised that so little has been commented here about the valuation. IPO valuation reflects what the founders, investors and advisors (Goldman, JP Morgan, etc) believe is the current status, upside and risks of development of FX-322 and also the rest of the pipeline.

According to the source below the fully diluted market value is 526 MUSD and my understanding is that pro forma post-IPO net cash is 273 MUSD. I have not focussed on this too much but if it's right then net cash consists of 30 MUSD cash in hand as of June 31 2019 plus 62 MUSD to be received from financing round C plus 80 MUSD to be received from Astellas plus 101 MUSD from IPO proceeds. With a net cash of 273 MUSD they are certainly going to be very well financed going forward.

https://www.nasdaq.com/articles/degenerative-disease-biotech-frequency-therapeutics-sets-terms-for-$101-million-ipo-2019

That would mean an enterprise value of 253 MUSD. What is the view, is it cheap or expensive? Would you buy Frequency Therapeutics shares in the IPO?

And remember, they have other drugs in their pipeline including a treatment for MS and hair loss.

 

[Jurger]

IPO-day tomorrow right? Wonder what they will be valued at. I read somewhere that none of their investors has indicated they will buy stock, which is supposed to be kind of an odd/negative signal.

 

[Daniel Lion]

IPO-day tomorrow right? Wonder what they will be valued at. I read somewhere that none of their investors has indicated they will buy stock, which is supposed to be kind of an odd/negative signal.

Is it?
I know nothing about stocks etc... you would think they had sunk in enough money already, hope you are wrong about that being a negative signal...