Frequency Therapeutics — Hearing Loss Regeneration

[Zugzug]

Also, I'd like to thank you @FGG and @Diesel for your continued contribution to this thread and Research News. It is both of your posts that I enjoy reading the most. Your posts are read by many and certainly appreciated.

They should write a book about "Inner Ear Regeneration for Dummies." I would buy it.

 

[tommyd87]

When FX-322 regrows hair cells, the new hair cells form new synapses. If just synapses are damaged, a synaptopathy drug is needed.

Here is one for you.

If you had some intact hair cells but damaged synapses around these hair cells as well, you would you need to take a synapse medicine anyway, wouldn't you? Therefore it is going to be likely that there will be the need for most to take both a synapse medicine and also a hair cell medicine.

 

[FGG]

Yeah I just remembered that comment now that you mentioned it.

I'm quite positive @FGG, don't get me wrong, but I was thinking about these possibilities even with the encouraging data early on. You can understand my skepticism. It's been failure after failure when it comes to any potential solution for tinnitus. It's also a fact that most biotechs fail. The odds are against us. There's no denying that. However I am encouraged by these results, however my mind works overtime as I really want FX-322 to work.

Agreed on those points you make and that is what makes me hang on. I go from my own experience though, which is that one audiologist would have diagnosed me with mild hearing loss on a standard audiogram and the next one a couple of weeks later said I was within normal range (on a standard audiogram).

Now if this was done on a larger patient population, I would have been even more convinced (I'll have to wait for the phase 2a) but the sample is so small that I question possibilities of different scenarios.

Can we really say FX-322 definitely does something on such a small sample size?

What about the audiologists saying it's unheard of?

Has there ever been word score tests done in the same time frame as those used in the FX-322 trials, with patients knowing they were on a trial for a hearing restoration drug? What if the placebo effect just coincidentally affected those given FX-322 over the placebo? It was such a small patient population after all.

Also, I'd like to thank you @FGG and @Diesel for your continued contribution to this thread and Research News. It is both of your posts that I enjoy reading the most. Your posts are read by many and certainly appreciated.

Thanks so much .

There was a conversation with Frequency Therapeutics and both an audiologist and an ENT where they went over the findings and both went over how unprecedented the findings were (was it the "Sight and Sound Bites" series from the Eye and Ear Foundation? Someone else remember?).

I realize it's a small sample size (for now) but the degree of improvements they saw without seeing *any* improvements in control ears or placebo subjects would point to the chance of it being coincidence as extraordinarily, astronomically small.

I am very hopeful for phase 2a.

 

[FGG]

Here is one for you.

If you had some intact hair cells but damaged synapses around these hair cells as well, you would you need to take a synapse medicine anyway, wouldn't you? Therefore it is going to be likely that there will be the need for most to take both a synapse medicine and also a hair cell medicine.

Correct. If your hair cells were fine and you only had synapse damage, you would need a synaptopathy drug.

I think a lot of people probably have a mix of both but couldn't even begin to speculate on what the percentages would be.

 

[tommyd87]

I think @Thuan's main issue isn't that synapsing isn't occurring. I think the main question is the following: Say the synaptic direction attempts are totally random (like in the original diagram above). Is the probability of a random synapse occurring high enough to produce all of the results?

The answer is definitely no. There are so many low probability events that have to happen.

1) Frequency Therapeutics has to mess up histology, which is almost unthinkable.
2) The full restoration of hearing in mice has to be totally random.
3) The fact that every single phase 1/2 patient saw clear improvements means that hundreds (thousands?) or hair cells would have to grow in such a way to perfectly synapse.

In my opinion, the probability that some of the hair cells don't synapse correctly is much more plausible than it being totally random.

If you have functional cells and dysfunctional nerve ends/synapses then you could have trouble with getting the sound through correctly too. This makes me wonder whether we will widely see better results if someone simply uses a synapse medicine first then treats themselves with FX-322.

Also again if any of the three points you raised above happened, then there would be no way where FX-322 and Frequency Therapeutics would get away with this and actually we would have probably seen them get blasted by the FDA for making unproven and/or false claims about the medicine's performance too. This tends to indicate that there is no way Frequency Therapeutics muddle histology and no way the other two didn't happen

 

[Thuan]

Who says there is no molecular guide? This was from @Killer's post above.

Per a conversation with Dr. McLean (a founder):

"In development it is the hair cells and supporting cells that release the proteins to attract neurons (NT3, BDNF). Their research shows that regenerated hair cells make the synapse components to communicate with neurons, even if neurons are not present."

This means the newly formed hair cells (e.g., regenerated hair cells) produce the molecular "signal" you are looking for, hence the doubling of word scores, etc.

As an aside, large quantities of BDNF are what OTO-413 is but it seems from Frequency Therapeutics' results that the quantity produced by regeneration is enough to form connections with the new hair cells.

Which actually makes me wonder if enough hair cell regeneration in the more moderate to severe cases will also confer an additional synaptopathy benefit from the extra NT3 and BDNF (which wouldn't help the mild cases as much but is still exciting).

Anyway, there is no evidence that neurite outgrowth to the cell is random or haphazard and non functional, just the opposite.

I realize you won't be happy with word scores and the assumption Frequency Therapeutics did the bare minimum and need audiogram changes but luckily we will have extended audiogram findings soon and it will hopefully allay your fears.

That is good evidence. I like this support to the arguments. I'm glad this is true.

 

[Gb3]

@Thuan coming in hot.

 

[tommyd87]

Correct. If your hair cells were fine and you only had synapse damage, you would need a synaptopathy drug.

I think a lot of people probably have a mix of both but couldn't even begin to speculate on what the percentages would be.

No no I think you're misunderstanding what I have written.

If you have intact hair cells in some parts but do have damaged synapses connected with these intact hair cells

and

Then you have other parts which are completely damaged.

In this case, wouldn't you need a synapse medicine on its own anyway first before taking FX-322 because the intact hair cells cannot currently attach to the synapses simply by taking only FX-322?

Or doesn't it work like that?

 

[FGG]

They should write a book about "Inner Ear Regeneration for Dummies." I would buy it.

I would leave that up to @Diesel and @Killer .

The stuff I write (or used to) is ridiculous (the last thing I wrote before losing hearing was a short story about what would happen if Santa had to IPO his toy factory).

 

[FGG]

@Killer's post referencing an early Dr. McLean interview got me thinking about something:

When Carl LeBel said in the JP Morgan interview that FX-322 was also a synaptopathy drug only when hair cells are restored, he may not have meant *only* for those hair cells.

Perhaps, he could have also meant the endogenous BDNF and NT3 production produced in this process (because McLean indicated that both are produced with regeneration just as they are embryologically during development) could be in enough excess to effect the synapses of neighboring cells.

So, if this were true, if you had no hair cell loss, this drug wouldn't treat synapses or if you had minimal hair cell loss but widespread synaptopathy it wouldn't do much either *but* if you had mild synapse and hair cell loss in the same area or moderate hair cell loss, perhaps FX-322 could treat both.

Thoughts?

 

[100Hz]

@Thuan I understand what you're saying about the possibility that a percentage of new hair cells don't synapse. To take your mic analogy one step further I imagine a 16 channel mixer with no mics plugged in (deaf), then you get 16 new mics and plug in 5 of them randomly leaving 9 still unplugged. I'm glass half full about this scenario because it's still potentially a vast improvement even if not perfect, although I'm happy to believe that it does synapse all new hair cells otherwise I think this possibility would have been raised already.

And as per @Zugzug comment below,

Is your fear that we take the drug prematurely, obtain useless healthy hair cells, only to find that in a few years, better synapsing (such as OTO-413) capabilities don't work because the body is fooled into thinking everything is okay?

The way I understand synapse drugs to potentially work is that they do re-synapse healthy hair cells where only synaptopathy has occurred (not hair cell death). I would hazard a guess that synapse drugs wouldn't differentiate between an original disconnected hair cell and a newly grown one that didn't synapse especially if a proportion of them did randomly synapse correctly (suggesting they are no different to original hair cells).

Its an interesting point though and it makes me wonder something else, If say worst case scenario FX-322 did not synapse all new hair cells. Could that potentially (at the very least) still stop ATP release from support cells of the dead OHC's being replaced (effectively creating correctly terminated although non functioning hair cells that move and respond to sound stimuli as normal but transmit nothing)? (This is based on the theory that ATP is released from supporting cells post OHC death/damage.

@FGG I know you recently mentioned a different spin on this about ATP maybe being released from GAP junctions. I'm reading and trying to understand this now.)

 

[Billy_Shears]

See, the point that I was trying to make is not to say "this doesn't work" but to give a plausible explanation that's different from just a dosage issue for the phase 1 results. It's quite reasonable not to discount actual possibilities that can seriously affect the success of Frequency Therapeutics' product, both in terms of potential patients as ourselves and more importantly, for actual investors of Frequency Therapeutics. People should understand that they definitely did NOT confirm functional hair cells in their animal studies. They did confirm that it grew new hair cells. Those are not mutually exclusive. The phase 2 clinical trial is definitely going to prove this. And because I think there's such a large ambiguity on the point I'm making that investors here should clearly understand the risk I'm pointing out.

Your argument is plausible in a theoretical sense of why the FDA requires clinical trials and why they take so long - because there are questions out there such as yours and rightfully so. You mentioned that Frequency Therapeutics have based their findings on assumptions rather than evidence and that the functionality of new hair cells have yet to be outright proven.

Progenitor cells are, in fact, pre-programmed stem cells that are designed to function in the same manner as in the womb and this science has been proven in recent years. The animal studies in mice were conclusive in regenerating auditory hair cells and the early Phase 1 clinical trial, albeit a small sample, revealed clinically significant improvements in the higher frequencies with the unknown so far being the result beyond 8 kHz.

Of course, not any of us on this forum want to hear the contrary to what has been provided thus far - hope is of the essence. But you address valid concerns to think about and I think that is a good thing while we all wait for 2Q/2021 - sort of like keeping our checks and balances thought process intact.

It must be reiterated that Frequency Therapeutics has a strong code of conduct and business ethics in their corporate structure and that investors have pounded the table given the evidence provided so far and have delivered financially for all of Phase 3. Of course, there are many answers we are waiting on but sometimes you get that intuitive feeling that a concept is right, that it is correct and so far I have that feeling that what is now known about FX-322 will eventually become the real deal when all configurations are complete.

 

[d'Wooluf]

There was a conversation with Frequency Therapeutics and both an audiologist and an ENT where they went over the findings and both went over how unprecedented the findings were (was it the "Sight and Sound Bites" series from the Eye and Ear Foundation? Someone else remember?).

It was the AHAA (or HLAA or... something) panel discussion. The audiologist and the ENT were associated with Frequency Therapeutics' clinical trials.

 

[Jurger]

It was the AHAA (or HLAA or... something) panel discussion. The audiologist and the ENT were associated with Frequency Therapeutics' clinical trials.

There's a tendency in this thread for both the people who are more bullish and bearish about this drug to kind of cognitively block information that doesn't support their view. It's a shame really, because it doesn't make a discussion easier.

 

[FGG]

It was the AHAA (or HLAA or... something) panel discussion. The audiologist and the ENT were associated with Frequency Therapeutics' clinical trials.

Thanks.

As I recall, they were part of the ENT group contracted for the first wave of clinical trials. They are independent of Frequency Therapeutics but yes in that sense they are "associated" with them.

 

[tommyd87]

No no I think you're misunderstanding what I have written.

If you have intact hair cells in some parts but do have damaged synapses connected with these intact hair cells

and

Then you have other parts which are completely damaged.

In this case, wouldn't you need a synapse medicine on its own anyway first before taking FX-322 because the intact hair cells cannot currently attach to the synapses simply by taking only FX-322?

Or doesn't it work like that?

@FGG not sure if you missed the above, or didn't answer this, or maybe you just don't know?

 

[tommyd87]

@Killer's post referencing an early Dr. McLean interview got me thinking about something:

When Carl LeBel said in the JP Morgan interview that FX-322 was also a synaptopathy drug only when hair cells are restored, he may not have meant *only* for those hair cells.

Perhaps, he could have also meant the endogenous BDNF and NT3 production produced in this process (because McLean indicated that both are produced with regeneration just as they are embryologically during development) could be in enough excess to effect the synapses of neighboring cells.

So, if this were true, if you had no hair cell loss, this drug wouldn't treat synapses or if you had minimal hair cell loss but widespread synaptopathy it wouldn't do much either *but* if you had mild synapse and hair cell loss in the same area or moderate hair cell loss, perhaps FX-322 could treat both.

Thoughts?

I think that this theory is incredibly plausible, however I actually reckon that the issue is somewhat different and could be treated in a different way.

Treating synapses first with OTO-413, get everything reconnected, and then treat with FX-322 or similar hair cell medicine. That way you would have all synapses available and also connected prior to the treatment with FX-322 and you therefore wouldn't have to worry about issues of synaptopathy when you tried to regrow hair cells. That is because theoretically the cells can already connect to functioning synapses when they are triggered for regrowth meaning that the connection should be much more straightforward.

 

[FGG]

I think that this theory is incredibly plausible, however I actually reckon that the issue is somewhat different and could be treated in a different way.

Treating synapses first with OTO-413, get everything reconnected, and then treat with FX-322 or similar hair cell medicine. That way you would have all synapses available and also connected prior to the treatment with FX-322 and you therefore wouldn't have to worry about issues of synaptopathy when you tried to regrow hair cells. That is because theoretically the cells can already connect to functioning synapses when they are triggered for regrowth meaning that the connection should be much more straightforward.

I don't think order matters. But you can't "pre-grow" synapses without something to synapse (in the case of missing hair cells) to if that's what you are thinking.

 

[tommyd87]

I don't think order matters. But you can't "pre-grow" synapses without something to synapse (in the case of missing hair cells) to if that's what you are thinking.

So this is what I am trying to work out. Would you be better off taking OTO-413 first, or would you be better off taking FX-322 first?

It sounds like you would need to regrow the hair cells with FX-322 first and then use OTO-413 or similar to reconnect the missing synapses etc after you have finished FX-322 treatment.

I was widely interested in the theory that you cannot pre-grow synapses, isn't this what has been done in lab trials with OTO-413 and also again with the Hough Ear Institute Pill?

 

[GBB]

I don't think order matters. But you can't "pre-grow" synapses without something to synapse (in the case of missing hair cells) to if that's what you are thinking.

The only determinant I could think of if you truly don't know what kind of hearing loss you may have is price / insurance coverage. I imagine most people will try the more accessible solution first. Side effects may also be a point of consideration, but hopefully with both these they will be minimal.

 

[FGG]

So this is what I am trying to work out. Would you be better off taking OTO-413 first, or would you be better off taking FX-322 first?

It sounds like you would need to regrow the hair cells with FX-322 first and then use OTO-413 or similar to reconnect the missing synapses etc after you have finished FX-322 treatment.

I was widely interested in the theory that you cannot pre-grow synapses, isn't this what has been done in lab trials with OTO-413 and also again with the Hough Ear Institute Pill?

Hough Ear Institute were growing synapses that attached to intact hair cells.

This may help: the synapses in "synaptopathy" are between the IHC and the SGNs.

A synapse is a neural "bridge" connecting neural structures. Each hair cell has multiple synapses and "synaptopathy" occurs when you have a reduction.

Hough Ear Institute was forming synapses with intact hair cells. All synaptopathy drugs are attempting to do this. No one is growing a "bridge to no where."

This is why the order doesn't matter: if you have intact hair cells, but missing synapses then you have no missing hair cells to regrow with a hair cell drug. If you regrow missing hair cells however, they will reform these connections on regrowth.

For the people that have both, they need both treatments but order should not matter because a synaptopathy drug fixes the problem in *intact* cells only and hair cell drugs regrow hairs where they are absent.

 

[tommyd87]

Hough Ear Institute were growing synapses that attached to intact hair cells.

This may help: the synapses in "synaptopathy" are between the IHC and the SGNs.

A synapse is a neural "bridge" connecting neural structures. Each hair cell has multiple synapses and "synaptopathy" occurs when you have a reduction.

Hough Ear Institute was forming synapses with intact hair
cells. All synaptopathy drugs are attempting to do this. No one is growing a "bridge to no where."

This is why the order doesn't matter: if you have intact hair cells, but missing synapses then you have no missing hair cells to regrow with a hair cell drug. If you regrow missing hair cells however, they will reform these connections on regrowth.

For the people that have both, they need both treatments but order should not matter because a synaptopathy drug fixes the problem in *intact* cells only and hair cell drugs regrow hairs where they are absent.

This is now making much more sense, thanks. This also clarifies that it is OK to use OTO-413 or some synapse treatment first before being treated with a hair cell component like FX-322 and vice versa.

So basically a hair cell treatment works to build new hearing function from scratch and is like you are building a new car from the base up because basically you are regrowing everything. While a synapse treatment is like you are actually just repairing a component of the car which does not function correctly like the engine and fixing that makes things theoretically work correctly once again.

 

[Ken219]

Guys may we get off the 'price', 'investment return' until there is a viable product?

 

[tommyd87]

Guys may we get off the 'price', 'investment return' until there is a viable product?

The discussion relating to pricing came about because Frequency Therapeutics made (cryptic) comments that indicated the types of things that would be relevant and/or considered when it comes to pricing FX-322. Furthermore, from what I have seen, the pricing for FX-322 wouldn't probably be commented on by Frequency Therapeutics if they didn't feel that they had a viable treatment. Also return on investment became relevant because it was directly relevant to the discussion around the information put out about the research work by Frequency Therapeutics.

Thus this is why both the issues of pricing and return on investment have been bought up and I actually believe that both of these issues are relevant to the discussion that we have had too.

 

[NewLionel]

Guys may we get off the 'price', 'investment return' until there is a viable product?

It's quite encouraging that people are confident enough in FX-322 to discuss these issues It's a big leap from a year ago.

 

[tommyd87]

It's quite encouraging that people are confident enough in FX-322 to discuss these issues It's a big leap from a year ago.

It is also somewhat encouraging that Frequency Therapeutics would actually be willing to discuss price at this point.

 

[weab00]

It's quite encouraging that people are confident enough in FX-322 to discuss these issues It's a big leap from a year ago.

I'm excited to see where we'll be in a year from now. Progress is exponentially increasing.

 

[tommyd87]

I'm excited to see where we'll be in a year from now. Progress is exponentially increasing.

It won't stop I think. The mere fact that they are on the verge of a breakthrough and actually about to be able to deal with these ear issues says to me that they will be going full pelt at resolving it until they can get it to do exactly what they want it to do. I am actually quite excited at this prospect.

 

[Paulmanlike]

Guys may we get off the 'price', 'investment return' until there is a viable product?

No.

A few Tinnitus Talk members investing in Frequency Therapeutics should be able to discuss it here. Agreed it's not an investment forum, but those of us who have been cursed with this dreadful condition, should be allowed to ask for others' opinions on this. I have wasted lots of money on snake oil over the years. I want to be part of Frequency Therapeutics. I want to be part of the discussions on Tinnitus Talk. And I want to be a patient of my own company. As long as it's not thread after thread, what's the problem?

Besides, it's nice to know that there are members with enough confidence to take a chance.

 

[Billy_Shears]

Trading vibes on investments in Frequency Therapeutics may be boring to some but in all practicality it has everything to do with the health of the company. A viable product will only come about through investments in on-going research including the payroll of those doing the research. It is a barometer of potential success or failure.

If investors begin to waiver on Frequency Therapeutics it will likely be the result of flawed research and development and we who suffer daily from tinnitus and/or hearing loss and look to this forum for support will be quite disheartened if this should occur. Investment news relating to anything resourceful toward Frequency Therapeutics is highly relevant.