Frequency Therapeutics — Hearing Loss Regeneration

[all to gain]

I think that Astellas and Frequency would be happy to save that money and go right to market (they won't turn a profit until then). They need a plan to make it through the full regulatory process, banking on breakthrough status would be poor form.

Plus phase 3 is not like other phases, it is essentially early access. An international phase 3 would be great news for patients imho. Breakthrough status would be even better.

Can you explain phase 3 a bit more? How long does it last and what is it for?

 

[serendipity1996]

Probably next important date is October this year. Then we know if this drug can lower tinnitus. If this turns out to be the case and they have optimised their dosing they may be open up for compassionate use as FGG said. So you may get your shot earlier. What I find a bit unfortunate is that they have not listed hyperacusis as an outcome measure of the trial. But probably out of 96 participants with hearing loss it is quite unlikely that someone has hyperacusis.

Regarding hyperacusis, my guess is that since it's even more of a 'niche' condition than tinnitus that it's entirely plausible that there were no participants with troubling hyperacusis to factor it into the secondary outcomes. So I agree with you. Will be most interesting to see what further trials can tell us!

 

[FGG]

I work in a noisy place where I have to understand sounds that totally overlap or partially overlap, so basically this is like a daily speech in noise test. I have also been submitted to speech in noise tests at several different ENTs. The performance can vary from one day to another for no reason we know. It is just like some days your ears interpret sound better depending on many things, like how you slept, if you are a morning person and the test is in the morning, and many small variables. Sometimes one hears loud but not very clear and suddenly words sound clearer, this just happens for no reason.

Sometimes the input of sound through our ears is exactly the same one day and the next, but what our hearing system do with the input in terms of speech recognition is different and I haven't read why anywhere, so it would be interesting to know the rationale for this. Maybe synapses? Better conduction through the hearing nerve, for some reason? Even cramps in neck area, or areas connected to the ear? I honestly don't know...

I know there are people who are pretty new to hearing problems, but I have been reading about the possibility of hearing loss being reversed and the miracle hearing pill or injection for like 15 years, so sorry I'm skeptical

Sorry, but that's not improbable, it is just the most common thing, and can tell you first hand after 10 years of hearing tests. It happens all the time with audiometric tests, even the ones performed with the same audiometer. There are usually slight differences in hearing performance, and 10 dB is a very small difference, particularly in a high frequency.

Honestly I am hoping for a cure for hearing loss as much as anyone, but in those slides I didn't find much valuable information. The slides are very vague, and the tests and results are derived from a very small sample of people.

They did both speech in noise and, separately, word scores in quiet. I was referring to the raw word scores, which literally doubled. Though speech in noise improved, too, those results weren't nearly as mind-blowing to me.

 

[FGG]

I think that Astellas and Frequency would be happy to save that money and go right to market (they won't turn a profit until then). They need a plan to make it through the full regulatory process, banking on breakthrough status would be poor form.

Plus phase 3 is not like other phases, it is focused of clinical efficacy and has a huge patient base compared to phase 2. An international phase 3 would be great news for patients imho. Breakthrough status would be even better.

Edit: I originally said "essentially early access" but that's too strong wording. It is a very large trial compared to phase 2 though, potentially with thousands of patients. It focuses on clinical use.

If they went straight to market, then they essentially gave Astellas market share without much in return which would be a terrible deal for Frequency, and one that doesn't make financial sense.

Is there a separate clause in the agreement for what would happen if those trials are skipped? Or are those trials just necessary for Europe/Asia approval? I'm really confused by all of this.

 

[Diesel]

A little clarification here: FX-322 has received the Fast Track designation. We are already seeing these benefits in the number of testing locations alone.

The Fast Track designation makes FX-322 eligible for:

Accelerated Approval and/or Priority Review by the FDA.
Benefits here are obvious by the names. Shorter time to get the drug to market, moved up in the review queue.

FX-322 is also eligible to receive the Breakthrough Therapy Status, should Frequency apply.

Basically to get it, FX-322
- Must demonstrate substantial improvement over available therapy
- Show significant improvement in safety or effectiveness over available therapy
- Phase 2A or 2B clinical endpoint "reasonably likely" to predict benefit

If it is granted:
- It receives Accelerated Approval and/or Priority Review
- May be able to begin producing/marketing the drug concurrently with Phase 3 in some locations (probably the US)

 

[Diesel]

If they went straight to market, then they essentially gave Astellas market share without much in return which would be a terrible deal for Frequency, and one that doesn't make financial sense.

Is there a separate clause in the agreement for what would happen if those trials are skipped? Or are those trials just necessary for Europe/Asia approval? I'm really confused by all of this.

Frequency is retaining the rights to market the drug in the US. Astellas gets the rest of the world to market the drug, but has to pay Frequency a royalty in doing so. So, there is no direct competition in this partnership.

It may be possible for Frequency to begin marketing the drug in the US before Astellas can throughout the world. It's also possible that Astellas may be able to market the drug in some countries before Frequency can in the US. Either way, Frequency makes money.

 

[MrCrybaby]

If they went straight to market, then they essentially gave Astellas market share without much in return which would be a terrible deal for Frequency, and one that doesn't make financial sense.

Is there a separate clause in the agreement for what would happen if those trials are skipped? Or are those trials just necessary for Europe/Asia approval? I'm really confused by all of this.

I imagine they have a plan, seeing as Frequency themselves mentioned breakthrough status. The funding of studies is not profit, it just gets burnt up. The meat and potatoes of the agreement is that Frequency manufactures and distributes in the US and Astellas handles international distribution (including additional trials and international manufacturing) and gives Frequency generous royalties. Any trials that have to happen are being funded by Astellas either way from my understanding of the agreement?

I'm sure it's WAY more complicated than that but I trust that they have a plan for any outcome. Even they won't know what's up until after 2a is done, so planning for more trials is sensible.

 

[FGG]

A little clarification here: FX-322 has received the Fast Track designation. We are already seeing these benefits in the number of testing locations alone.

The Fast Track designation makes FX-322 eligible for:

Accelerated Approval and/or Priority Review by the FDA.
Benefits here are obvious by the names. Shorter time to get the drug to market, moved up in the review queue.

FX-322 is also eligible to receive the Breakthrough Therapy Status, should Frequency apply.

Basically to get it, FX-322
- Must demonstrate substantial improvement over available therapy
- Show significant improvement in safety or effectiveness over available therapy
- Phase 2A or 2B clinical endpoint "reasonably likely" to predict benefit

If it is granted:
- It receives Accelerated Approval and/or Priority Review
- May be able to begin producing/marketing the drug concurrently with Phase 3 in some locations (probably the US)

Intuitively, it makes the most sense that they would work out the dosing in phase 2a, then show efficacy with even more robust data with the final dosing protocol for a phase 2b and then hopefully have a limited US release while collecting phase 3 data. I can't see them "skipping" at least 2b though, the more I think about this. Would be nice though.

You also made a good point about marketing costs overseas (vs just clinical trial costs). Even though the product would "sell itself" to patients, there would be a lot of physician education and marketing that goes into it.

 

[Lucifer]

A little clarification here: FX-322 has received the Fast Track designation. We are already seeing these benefits in the number of testing locations alone.

The Fast Track designation makes FX-322 eligible for:

Accelerated Approval and/or Priority Review by the FDA.
Benefits here are obvious by the names. Shorter time to get the drug to market, moved up in the review queue.

FX-322 is also eligible to receive the Breakthrough Therapy Status, should Frequency apply.

Basically to get it, FX-322
- Must demonstrate substantial improvement over available therapy
- Show significant improvement in safety or effectiveness over available therapy
- Phase 2A or 2B clinical endpoint "reasonably likely" to predict benefit

If it is granted:
- It receives Accelerated Approval and/or Priority Review
- May be able to begin producing/marketing the drug concurrently with Phase 3 in some locations (probably the US)

I hope Frequency Therapeutics get both accelerated approval and breakthrough therapy status which will help speed up the process.

 

[Bobbette]

Something like 70% of new drugs fail in phase 2. And 35% of those that reach phase 3 will fail. And those were drugs that were successful enough to get into phase 3 but still failed.

There's no guarantee FX-322 will ever make it to market.

 

[Lucifer]

Something like 70% of new drugs fail in phase 2. And 35% of those that reach phase 3 will fail. And those were drugs that were successful enough to get into phase 3 but still failed.

There's no guarantee FX-322 will ever make it to market.

I don't think it will fail though. How did they even get a big company like Astellas to fund their clinical trials without seeing proof. It's very rare to have a well known company like Astellas to fund a small biotech company like Frequency Therapeutics. I think Frequency Therapeutics have a winner in FX-322.

 

[FGG]

Something like 70% of new drugs fail in phase 2. And 35% of those that reach phase 3 will fail. And those were drugs that were successful enough to get into phase 3 but still failed.

There's no guarantee FX-322 will ever make it to market.

While this is true, that's across the whole industry and is not evenly distributed. For instance, almost 100% of Alzheimer's drugs fail to reach the market.

Hearing regeneration is brand new and you can't use stats on unrelated drugs to speculate on it.

Also, with some drugs you get a *very* strong, very early indicator it will work. With Sarepta's DMD drug, for instance, you had effected boys skiing (his mom posted a video on Twitter) in an age bracket where he shouldn't even be walking and another, different patient who didn't lose mobility after breaking a leg (both unheard of with the particular gene they had). The drug is approved now.

With Frequency, it has been shown to work. It regrows hair cells in an ex planted human cochlea and word scores have doubled using the small phase 1 safety dose.

The only thing that would stop it would be a completely unforeseen safety issue at a higher dose but I don't see that as very likely because the pharmacokinetics in phase 1 showed extremely small absorption systemically.

 

[Diesel]

How did they even get a big company like Astellas to fund their clinical trials without seeing proof.

Astellas has seen more than enough proof, we (the public) just haven't seen behind the curtain. As I've said before here, business activity can be very telling.

Here's how:

First, and most importantly: Significant data that the public hasn't seen, but the investors have:
I believe it was during the JP Morgan conference — it was mentioned that Frequency had been developing FX-322 by testing it on hundreds of donated human cochlea. Consider the data that Frequency has shared with investors about FX-322 that is not publicly known. The know it works on human cochleas in-vitro, and they have data to prove it. That would certainly open some wallets.

Second, 2018 - Department of Defense awarding a $2M grant in 2018 to continue developing FX-322. Hearing loss/tinnitus is the most common military service-connected disability according to the CDC. Consider the value of having the DoD as a backer; and the US Military and VA as a consumer of a product.

Third, 2019 - Statistically/clinically significant results from the Phase 1/2. AND, likely some anecdotal data that isn't publicly known, but Astellas has seen it.

Since then:

2019 - C-Round of financing, without a marketable product or income stream. Usually C-Rounds take place after a company has demonstrated some market success but needs to expand production, distribution, product-line. Frequency still has nothing.

2019 - IPO. Same reasons as C-Round, generally.

 

[serendipity1996]

The thing about Frequency's approach too which makes it stand out is that they are using progenitor cell activation to induce hair cell regeneration, so it's basically a brand new technique.

E.g. here it talks a little bit about it:
https://www.liebertpub.com/doi/abs/10.1089/gen.38.11.04?journalCode=gen

 

[xyz]

With Frequency, it has been shown to work. It regrows hair cells in an ex planted human cochlea and word scores have doubled using the small phase 1 safety dose.

How is this actually possible to regrow hair cells in ex planted human cochlea? Doesn't it mean these are dead cochlea? And when is it possible? Shouldn't it then not also be possible to optimise dosing just based on explanted human cochlea because there one can probably count how many hair cells have regrown based on how many mg of FX-322 was used. And then it should also be possible to check if FX-322 heals what is known as this "cochlear synaptopathy".

 

[FrontRoomFanatic]

Is there any issues with how FX-322 treatment would work if I've taken prednisone or prednisolone before? I read in another thread that it is ototoxic and wondered if there would be an issue there?

 

[Diesel]

How is this actually possible to regrow hair cells in ex planted human cochlea? Doesn't it mean these are dead cochlea? And when is it possible? Shouldn't it then not also be possible to optimise dosing just based on explanted human cochlea because there one can probably count how many hair cells have regrown based on how many mg of FX-322 was used. And then it should also be possible to check if FX-322 heals what is known as this "cochlear synaptopathy".

I am not a scientist.

I understand that tissue/organs can be kept in a state of "inactivity" where testing can be performed. I also understand that depending on the organ or tissue, this inactivity window can be maintained for days and up to years. So, it stands to reason the cochlea doesn't "die" immediately either during removal from a surgery, or in the passing of the donor. As a result it can be harvested, placed into an "inactive" state and supplied to labs like frequency for research/testing during an inactivity window.

 

[FGG]

How is this actually possible to regrow hair cells in ex planted human cochlea? Doesn't it mean these are dead cochlea? And when is it possible? Shouldn't it then not also be possible to optimise dosing just based on explanted human cochlea because there one can probably count how many hair cells have regrown based on how many mg of FX-322 was used. And then it should also be possible to check if FX-322 heals what is known as this "cochlear synaptopathy".

These are cochlea that were removed from living humans due to nearby tumors. And then immediately treated.

They have said in their JP Morgan Q and A that it is not a cochlear synaptopathy drug except where the hair cell regenerated. So it seems they already know it's not a synaptopathy drug.

 

[FGG]

Is there any issues with how FX-322 treatment would work if I've taken prednisone or prednisolone before? I read in another thread that it is ototoxic and wondered if there would be an issue there?

Steroids are usually given as a treatment for ototoxicity. I read the same thread you are refering to and apparently it can worsen body remodeling in otosclerosis. FX-322 should have no effect either way on the middle ear or otoscleorosis since it treats SSHL in the inner ear.

 

[Mr.tdog15]

Hi, I'm new to Tinnitus Talk and this is my first post.

I got my tinnitus from Cipro and I just want to know if RX-322 would be of any benefit to me?

Please someone tell me some future treatments will benefit me. Just really stressing that I won't ever get fixed.

 

[FGG]

Hi, I'm new to Tinnitus Talk and this is my first post.

I got my tinnitus from Cipro and I just want to know if RX-322 would be of any benefit to me?

Please someone tell me some future treatments will benefit me. Just really stressing that I won't ever get fixed.

Do you know the method of Cipro's ototoxicity? I can't seem to find that information.

 

[Mistertdog15]

Yeah I don't know about the effects of ciprofloxacin on the hair cells.

Do you think I can benefit from Hough Ear Institute's Pill or FX-322? Any info would greatly be appreciated. I'm stressing out.

 

[FGG]

Yeah I don't know about the effects of ciprofloxacin on the hair cells.

Do you think I can benefit from Hough Ear Institute's Pill or FX-322? Any info would greatly be appreciated. I'm stressing out.

Have you had an extended audiogram? That might give you some information.

 

[Diesel]

Yeah I don't know about the effects of ciprofloxacin on the hair cells.

Do you think I can benefit from Hough Ear Institute's Pill or FX-322? Any info would greatly be appreciated. I'm stressing out.

It's possible. It will take some patience. We are all here talking about these novel therapies in clinical trials because we all want to know. The good news is that there are a number of products in the R&D/clinical pipeline that show promise to help us one day.

Think positive. Hang in there!

 

[GregCA]

I read the same thread you are refering to and apparently it can worsen body remodeling in otosclerosis.

Could you please point me to that thread?

 

[FGG]

Could you please point me to that thread?

It was the thread you commented on. I re-read and it otosclerosis was suggested, not confirmed. Sorry. I think I read it too quickly the first time.

But steroids definitely cause bony remodeling throughout the joints in the body so this makes the most sense to me. I never saw any studies linking steroids to SSHL and in fact it is used as a first line treatment.

 

[GregCA]

It was the thread you commented on. I re-read and it otosclerosis was suggested, not confirmed. Sorry. I think I read it too quickly the first time.

Oh ok, no problem.

But steroids definitely cause bony remodeling throughout the joints in the body so this makes the most sense to me.

Are you sure about that? My understanding is that it decreases bone formation and increases bone resorption.

In otosclerosis, you have bone remodeling that is happening where it shouldn't (near the cochlea). My fluoride treatment is supposed to help prevent that, and it looks like steroids may have a similar effect, rather than be a remodeling stimulant.

This is important to know, because loss of hearing symptoms often trigger a steroid treatment. If it turns out it could aggravate otosclerosis, then there should be disambiguation before this treatment is offered.

 

[FGG]

Oh ok, no problem.

Are you sure about that? My understanding is that it decreases bone formation and increases bone resorption.

In otosclerosis, you have bone remodeling that is happening where it shouldn't (near the cochlea). My fluoride treatment is supposed to help prevent that, and it looks like steroids may have a similar effect, rather than be a remodeling stimulant.

This is important to know, because loss of hearing symptoms often trigger a steroid treatment. If it turns out it could aggravate otosclerosis, then there should be disambiguation before this treatment is offered.

I meant to say cause abnormal bone remodeling. But really the way you worded it is more descriptively correct. It is inhibitory/thinning.

This obviously seems like a problem with chronic use in normal bones but if it's used to prevent overgrowth, I could see the value it. I know so little about the middle ear tbh.

 

[Mistertdog15]

How do we know if we have nerve damage or hair cell damage? if we have nerve damage what drugs are in the pipeline that will benefit us?

This is so confusing. Sorry for being a noob. I'm just really interested in getting my silence back

 

[ThomasRobert]

How do we know if we have nerve damage or hair cell damage? if we have nerve damage what drugs are in the pipeline that will benefit us?

This is so confusing. Sorry for being a noob. I'm just really interested in getting my silence back

I'm in the same spot like you... I keep updating the attached sheet... I'll share with you...