Frequency Therapeutics — Hearing Loss Regeneration

Isn't the benefit of distally injected stem cells from the exosomes providing an anti inflammatory effect and not direct cellular integration? Is there a type of distal stem cell (i.e. not locally delivered into the cochlea) therapy that does lead to cellular integration?
I suppose the UCMSC's that they received could be because of that, but would there be a permanent functional effect from anti-inflammatory actions alone? Also, they now offer IPSC's which are supposed to differentiate into whatever cells are needed, but the question there is 1) when delivered systemically, do they properly target the cochlea; and 2) once in the cochlea, do they appropriately differentiate into the needed cells?

I asked SC21: Is your clinic able to induce IPSC's to differentiate into otic epithelial progenitors? How is it that you intend to fix hearing loss? I don't invest much faith in systemic administration of stem cells to reach the cochlea, where very little blood circulation occurs.

Based on an excerpt from this study, which again bolsters the credibility of FX-322's mechanism of action:

"Human urinary cells isolated from a healthy donor were reprogramed to form iPSCs that were induced to differentiate into OEPs and hair cell-like cells... In vivo, OEPs derived from iPSCs were transplanted into the cochlea of mice by injection through the round window... induced hair cell-like cells displayed typical morphological characteristics and electrophysiological properties specific to inner hair cells. In vitro, OEP-derived hair cell-like cells formed synaptic connections with SGNs in coculture. In vivo, some of the transplanted cellsmigrated to the site of the resident hair cells in the organ of Corti, differentiated into hair cell-like cells, and formed synaptic connections with native SGNs."
 
As I was reading about the Breakthrough Therapy designation. I stumbled upon the 'Regenerative Medicine Advanced Therapy Designation,' or "RMAT."

https://www.fda.gov/vaccines-blood-...erative-medicine-advanced-therapy-designation

Here's a description of the program in detail: https://www.fda.gov/media/120267/download

And products that have received the RMAT designation: https://bioinformant.com/rmat/

It appears that the RMAT designation offers additional expedited benefits beyond the Breakthrough designation. IMHO, based on other products that have received RMAT designation, that FX-322 may be a fit to be accepted.

Questions:
- Does FX-322 fit the RMAT acceptance criteria?
- Why would Frequency indicate they are only seeking a Breakthrough Therapy designation and not RMAT?
What I can find so far is the FDA granted it for a product called jCell made by a company called jCyte. This product involved injecting retinal progenitor cells into the eye.

I realize this is different than treating with progenitor cell activators, instead, but seems similar enough that the FDA could potentially consider RMAT status. What I can't find, though, is if RMAT has to be requested at the time of the IND or not.
 
I asked SC21: Is your clinic able to induce IPSC's to differentiate into otic epithelial progenitors? How is it that you intend to fix hearing loss? I don't invest much faith in systemic administration of stem cells to reach the cochlea, where very little blood circulation occurs.
Did they ever respond?
 
@Diesel, it reading more it looks like it only applies to therapies derived from cells or tissues and one of the original intents may have been to counteract the rise of unregulated stem cell clinics. I'm not sure FX-322 applies if it has to be from biologically derived cells and tissues.
 
What I can find so far is the FDA granted it for a product called jCell made by a company called jCyte. This product involved injecting retinal progenitor cells into the eye.

I realize this is different than treating with progenitor cell activators, instead, but seems similar enough that the FDA could potentially consider RMAT status. What I can't find, though, is if RMAT has to be requested at the time of the IND or not.
If I am understanding the document correctly, it can be added/requested through an amended IND, and needs to be done before the end of Phase 2, similar to the Breakthrough Status.
 
I wonder what order, if any, a person who requires the whole shebang (FX-322 and OTO-413 and/or Pipeline or the Hough pill) would need to take these drugs in order for them to work their, hopefully, magic? Would it make a difference?
Assuming you have hair cell loss, I'm guessing FX-322 first as it seems to be clear there is no risk of it depleting support cells. I'm not clear on how the others will effect support cells. Maybe the others can clarify.
 
Assuming you have hair cell loss, I'm guessing FX-322 first as it seems to be clear there is no risk of it depleting support cells. I'm not clear on how the others will effect support cells. Maybe the others can clarify.
I presume I have hair cell loss as my audiogram showed I have mild hearing loss, and in places even moderate loss. But my auditory nerve may be damaged or/and I may have synaptopathy. My tinnitus was brought about by medication (and possibly worsened by noise) due, I presume, to excitotoxicity and maybe ototoxicity. But it seems difficult to put a finger on it, and I keep getting differing opinions, ie an ENT said I probably didn't have hair cell damage but that I probably have auditory nerve damage.

Hence, if I have the whole lot, ie nerve damage, hair cell loss and synaptopathy etc I wondered what order would be best to take these drugs, depending if they work and get to the market of course. But I know little about the science behind all these drugs and the workings of the ear, brain, neurons and so on, hence I'm looking to others more informed. Unfortunately, the doctors I have seen given me little confidence they know what they are taking about.
 
I presume I have hair cell loss as my audiogram showed I have mild hearing loss, and in places even moderate loss. But my auditory nerve may be damaged or/and I may have synaptopathy. My tinnitus was brought about by medication (and possibly worsened by noise) due, I presume, to excitotoxicity and maybe ototoxicity. But it seems difficult to put a finger on it, and I keep getting differing opinions, ie an ENT said I probably didn't have hair cell damage but that I probably have auditory nerve damage.

Hence, if I have the whole lot, ie nerve damage, hair cell loss and synaptopathy etc I wondered what order would be best to take these drugs, depending if they work and get to the market of course. But I know little about the science behind all these drugs and the workings of the ear, brain, neurons and so on, hence I'm looking to others more informed. Unfortunately, the doctors I have seen given me little confidence they know what they are taking about.
None of the synaptopathy drugs will likely come out around the time of FX-322 with the exception of OTO-413 possibly. OTO-413 is just injectable BDNF. I can't imagine it would be harmful to receive that particular injection first or after other treatments.

Audion/Regain depletes support cells and perhaps it would be better to avoid that one if you have had ototoxicity (speculation). FX-322 does the same thing without depleting support cells and if Lucchino is to be believed, does it better, anyway. Apart from that, you are looking at a longer time frame unless you plan on being part of a trial.
 
None of the synaptopathy drugs will likely come out around the time of FX-322 with the exception of OTO-413 possibly. OTO-413 is just injectable BDNF. I can't imagine it would be harmful to receive that particular injection first or after other treatments.

Audion/Regain depletes support cells and perhaps it would be better to avoid that one if you have had ototoxicity (speculation). FX-322 does the same thing without depleting support cells and if Lucchino is to be believed, does it better, anyway. Apart from that, you are looking at a longer time frame unless you plan on being part of a trial.
Thanks for the reply. Ok, so I should just try FX-322 as soon as it is, hopefully, available? For some reason i've been thinking that if I have auditory nerve damage that I would need to deal with that first.

I am looking at a longer time frame anyway.

Off topic, I want to very slowly get off the AD over the next 2 years and then have a year where no drugs of any type are put in my body to let my body recover a little, if that makes sense. Then just see where these hearing/tinnitus drugs are at. Until then I can do loads to improve my overall health though; lose 50lbs, start regular exercise and get on an anti-inflammatory diet. That should help naturally with BDNF levels. Also I need to start trying some supplements, but I don't know where to start. What top three supplements do you suggest for someone who has tinnitus due to medication? I tried curcumin, but it spiked me. In Russia it has been suggested I take Milgamma, which is a B1, B6, B12 + Lidocaine vitamin/drug combination for 10 days via injection, as well as Beteserc for 30 days and others.

I wish now I had studied sciences:(:LOL:
 
Thanks for the reply. Ok, so I should just try FX-322 as soon as it is, hopefully, available? For some reason i've been thinking that if I have auditory nerve damage that I would need to deal with that first.

I am looking at a longer time frame anyway.

Off topic, I want to very slowly get off the AD over the next 2 years and then have a year where no drugs of any type are put in my body to let my body recover a little, if that makes sense. Then just see where these hearing/tinnitus drugs are at. Until then I can do loads to improve my overall health though; lose 50lbs, start regular exercise and get on an anti-inflammatory diet. That should help naturally with BDNF levels. Also I need to start trying some supplements, but I don't know where to start. What top three supplements do you suggest for someone who has tinnitus due to medication? I tried curcumin, but it spiked me. In Russia it has been suggested I take Milgamma, which is a B1, B6, B12 + Lidocaine vitamin/drug combination for 10 days via injection, as well as Beteserc for 30 days and others.

I wish now I had studied sciences:(:LOL:
I can't answer your supplement question because it seems highly variable but I personally take Astaxanthin, NAD+ and a multi-vitamin.

Some people have luck with Ginkgo but others do not. Same with Turmeric and the same with any of the supplements I'm taking.

Be careful with too much B6, though, because it can actually damage nerves (in excess quantities).

I am not familiar enough with the use of either Lidocaine injections or Betaserc (other than it is often used in Meniere's cases). Maybe others can weigh in.
 
I can't answer your supplement question because it seems highly variable but I personally take Astaxanthin, NAD+ and a multi-vitamin.

Some people have luck with Ginkgo but others do not. Same with Turmeric and the same with any of the supplements I'm taking.

Be careful with too much B6, though, because it can actually damage nerves (in excess quantities).

I am not familiar enough with the use of either Lidocaine injections or Betaserc (other than it is often used in Meniere's cases). Maybe others can weigh in.
Lidocaine has a possible side effect of tinnitus, which isn't very ensuring. I think I will not try it or Betaserc. Will just start on NAD+ and NAC.
 
Thanks for the reply. Ok, so I should just try FX-322 as soon as it is, hopefully, available? For some reason i've been thinking that if I have auditory nerve damage that I would need to deal with that first.

I am looking at a longer time frame anyway.

Off topic, I want to very slowly get off the AD over the next 2 years and then have a year where no drugs of any type are put in my body to let my body recover a little, if that makes sense. Then just see where these hearing/tinnitus drugs are at. Until then I can do loads to improve my overall health though; lose 50lbs, start regular exercise and get on an anti-inflammatory diet. That should help naturally with BDNF levels. Also I need to start trying some supplements, but I don't know where to start. What top three supplements do you suggest for someone who has tinnitus due to medication? I tried curcumin, but it spiked me. In Russia it has been suggested I take Milgamma, which is a B1, B6, B12 + Lidocaine vitamin/drug combination for 10 days via injection, as well as Beteserc for 30 days and others.

I wish now I had studied sciences:(:LOL:
I was taking 25mg Amitriptyline but kicked it out of fear of ototoxicity. Also paranoid of it potentially doing anything to my support cells. Want to preserve my ears to respond as best they can to these future treatments. Plus I've had great results with Valerian and Melatonin for sleeping so the AD wasn't necessary.

I've also just started taking NAD+ and Astaxanthin, only a few days in so it's too early to tell but I woke up this morning with the tinnitus slightly softer (probably just jinxed myself). Been taking Magnesium, B12, Zinc, and Curcumin for weeks but haven't noticed any effect from them. I even tried the @JohnAdams high Curcumin dosage of like 3grams but all it did was make my head feel tight.
 
Just to stir up conversation in lieu of any information forthcoming for the foreseeable future: how many people with unilateral tinnitus plan on getting this in both ears?

I've been flipping back and forth on this. I am 99.9% certain that I have singular, left-sided tinnitus. It's the same ear I had horrific hyperacusis in following my car accident and my right ear never reacts to sound. My right ear WILL get fleeting tinnitus for 5 seconds once every four months or so, so I can distinctly tell when the sound in the right completely dissolves to nothingness.

I have no detectable hearing loss, even at UHF, although there is a 25 dB difference (-10 dB right ear, 15 dB left ear) between ears @16 kHz. I'd hate to get the procedure done, wait out however long it takes to heal and then take effect, and find out my right ear was somehow contributing to the phantom sound.

I'm also curious about the prospect of repeating the injections. At this time it doesn't seem like if the procedure were to fail at first there would be any reason to repeat it in hopes for different results.

I'm curious what your guys' approaches are going to be.
 
Just to stir up conversation in lieu of any information forthcoming for the foreseeable future: how many people with unilateral tinnitus plan on getting this in both ears?

I've been flipping back and forth on this. I am 99.9% certain that I have singular, left-sided tinnitus. It's the same ear I had horrific hyperacusis in following my car accident and my right ear never reacts to sound. My right ear WILL get fleeting tinnitus for 5 seconds once every four months or so, so I can distinctly tell when the sound in the right completely dissolves to nothingness.

I have no detectable hearing loss, even at UHF, although there is a 25 dB difference (-10 dB right ear, 15 dB left ear) between ears @16 kHz. I'd hate to get the procedure done, wait out however long it takes to heal and then take effect, and find out my right ear was somehow contributing to the phantom sound.

I'm also curious about the prospect of repeating the injections. At this time it doesn't seem like if the procedure were to fail at first there would be any reason to repeat it in hopes for different results.

I'm curious what your guys' approaches are going to be.
I'd shoot them both up if I were you. Every trace of this thing must be annihilated. Plus, won't the drug presumably restore the top end frequencies we've lost with age? Why not touch them up in both ears I say.
 
I was taking 25mg Amitriptyline but kicked it out of fear of ototoxicity. Also paranoid of it potentially doing anything to my support cells. Want to preserve my ears to respond as best they can to these future treatments. Plus I've had great results with Valerian and Melatonin for sleeping so the AD wasn't necessary.

I've also just started taking NAD+ and Astaxanthin, only a few days in so it's too early to tell but I woke up this morning with the tinnitus slightly softer (probably just jinxed myself). Been taking Magnesium, B12, Zinc, and Curcumin for weeks but haven't noticed any effect from them. I even tried the @JohnAdams high Curcumin dosage of like 3grams but all it did was make my head feel tight.
Yeah, that's how I'm looking at it: I don't want other drugs getting in the way of any potential benefits the upcoming treatments may have.

I will start by getting on a proper diet and exercise programme and add vitamins one at a time. I think I will start with NAD+, but boy is it expensive (a 90 day container of Tru Niagen costs the equivalent of 250 dollars where I am).
 
Just to stir up conversation in lieu of any information forthcoming for the foreseeable future: how many people with unilateral tinnitus plan on getting this in both ears?

I've been flipping back and forth on this. I am 99.9% certain that I have singular, left-sided tinnitus. It's the same ear I had horrific hyperacusis in following my car accident and my right ear never reacts to sound. My right ear WILL get fleeting tinnitus for 5 seconds once every four months or so, so I can distinctly tell when the sound in the right completely dissolves to nothingness.

I have no detectable hearing loss, even at UHF, although there is a 25 dB difference (-10 dB right ear, 15 dB left ear) between ears @16 kHz. I'd hate to get the procedure done, wait out however long it takes to heal and then take effect, and find out my right ear was somehow contributing to the phantom sound.

I'm also curious about the prospect of repeating the injections. At this time it doesn't seem like if the procedure were to fail at first there would be any reason to repeat it in hopes for different results.

I'm curious what your guys' approaches are going to be.
There are so many ifs and buts. That's why I asked about what would be the best order to take the upcoming treatments, i.e. maybe if I took FX-322 first and then OTO-413 neither would work, but maybe the other way around they would. But I know so little about the science behind all of this.

It's interesting that you have no detectable hearing loss. What do you put your tinnitus down to? My hearing has been badly hit by the medication I took, and I really don't know how much they upcoming treatments will be able to help me.

Whatever, I'm going to get this stuff in my ears as soon as possible, pending data that it has a decent chance of working, but a lot of it comes down to cost in my case. In your case I would definitely get it in both ears. Mine started in one ear and moved around until I had it permanently in both ears. This thing is too unpredictable to just do one ear.
 
There are so many ifs and buts. That's why I asked about what would be the best order to take the upcoming treatments, i.e. maybe if I took FX-322 first and then OTO-413 neither would work, but maybe the other way around they would. But I know so little about the science behind all of this.

It's interesting that you have no detectable hearing loss. What do you put your tinnitus down to? My hearing has been badly hit by the medication I took, and I really don't know how much they upcoming treatments will be able to help me.

Whatever, I'm going to get this stuff in my ears as soon as possible, pending data that it has a decent chance of working, but a lot of it comes down to cost in my case. In your case I would definitely get it in both ears. Mine started in one ear and moved around until I had it permanently in both ears. This thing is too unpredictable to just do one ear.
But really, what would be the harm in waiting a month or two between ears?
 
Just to stir up conversation in lieu of any information forthcoming for the foreseeable future: how many people with unilateral tinnitus plan on getting this in both ears?

I've been flipping back and forth on this. I am 99.9% certain that I have singular, left-sided tinnitus. It's the same ear I had horrific hyperacusis in following my car accident and my right ear never reacts to sound. My right ear WILL get fleeting tinnitus for 5 seconds once every four months or so, so I can distinctly tell when the sound in the right completely dissolves to nothingness.

I have no detectable hearing loss, even at UHF, although there is a 25 dB difference (-10 dB right ear, 15 dB left ear) between ears @16 kHz. I'd hate to get the procedure done, wait out however long it takes to heal and then take effect, and find out my right ear was somehow contributing to the phantom sound.

I'm also curious about the prospect of repeating the injections. At this time it doesn't seem like if the procedure were to fail at first there would be any reason to repeat it in hopes for different results.

I'm curious what your guys' approaches are going to be.
Right now we're really just shooting in the dark.

Data from their trials should show, if successful, recommendations for dosage, frequency, etc. Perhaps you'd need multiple doses, or maintenance doses. Intratympanic steroid injections, for example, can require multiple injections to be effective. Or perhaps once is all it takes. Or perhaps there's an adverse reaction or risk yet to be reported that influences those other variables. Or... who knows?

After promising Phase II trials, AM-101 advanced to Phase III trials before they determined, mid-trial, it was ineffective and pulled the plug. These circumstances seem far more promising, but for all we know FX-322 will flame out and FX-323 is the moonshot.

That said, if it works, I'll jam it into both ears with a turkey baster if I have to. :cool:
 
But really, what would be the harm in waiting a month or two between ears?
I have no idea, I don't know the science behind all of this, but if he's had tinnitus present in both ears, even if for only a short while, I wouldn't want to take the chance of. But you know much more about this stuff:)
 
There are so many ifs and buts. That's why I asked about what would be the best order to take the upcoming treatments, i.e. maybe if I took FX-322 first and then OTO-413 neither would work, but maybe the other way around they would. But I know so little about the science behind all of this.

It's interesting that you have no detectable hearing loss. What do you put your tinnitus down to? My hearing has been badly hit by the medication I took, and I really don't know how much they upcoming treatments will be able to help me.

Whatever, I'm going to get this stuff in my ears as soon as possible, pending data that it has a decent chance of working, but a lot of it comes down to cost in my case. In your case I would definitely get it in both ears. Mine started in one ear and moved around until I had it permanently in both ears. This thing is too unpredictable to just do one ear.
Yeah it's dumb as hell considering I'd rather be stone-cold deaf but have objectively great hearing. I put it to the difference between ears (25 dB is a large difference) at 16 kHz. I believe the many untested notches (e.g, 13,233 Hz, 14,424 Hz) can contain OHC damage as well. Just because I performed well at select data points doesn't not mean my hearing is uniformly great among the untested notches. I think it's actually the biggest reason why people have difficulty selecting the specific pitch of their tinnitus, because their tinnitus is a composite of so many damaged hair cells' corresponding frequencies.

I'd like to say that maintenance dosing is almost certainly not going to be an issue. Hair cells either grow, or they don't.

Repeat dosing for NHPN-1010 might be plausible though, especially with new acoustic traumas.
 
Thank fucking Christ the first avenue they explored after the intestines, was the cochlea. Seriously, thank God.
As thankful as I am as well, it actually makes great business sense. Huge potential market, literally everyone can be a potential client, or anyone at any time may have a need. And there is not a lot of active competition in the space. This makes it ripe for a disruption, and establishing a new cash cow.
 
Thank fucking Christ the first avenue they explored after the intestines, was the cochlea. Seriously, thank God.
I know, right?

The first time I heard that, during the research, they happen to discover that the signaling was extremely similar in the cochlea, that's as close to believing in an actual miracle as I ever came (still on the fence :) ).
 
As thankful as I am as well, it actually makes great business sense. Huge potential market, literally everyone can be a potential client, or anyone at any time may have a need. And there is not a lot of active competition in the space. This makes it ripe for a disruption, and establishing a new cash cow.
And from a humanitarian perspective, I think it's about freakin time. This should've been a priority long ago.
 
I know, right?

The first time I heard that, during the research, they happen to discover that the signaling was extremely similar in the cochlea, that's as close to believing in an actual miracle as I ever came (still on the fence :) ).
I don't want to get ahead of myself, but I can't stop dreaming of the day this drug finds its way into countless sufferers' ears, and I want to cry imagining the wave of relief that washes over people's faces when they find that their years of torture are finally over.

It is just a dream. For now. Until then, I will wish and pray it into existence.
 
I wonder if people will start having FX-322 parties, the way they have botox parties?

You know, invite some people over.

Have a few drinks.

Administer intratympanic injections of hydrogel-suspended FX-322 into everyone's ears and call it a night. :dunno:
 

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