Frequency Therapeutics — FX-345

Hmm... Maybe.

But then why doesn't it do that for all people with tinnitus and hearing loss?

Dirk De Ridder said only 1 out of 5 gets their tinnitus alleviated from wearing a hearing aid.

Maybe because the tinnitus frequencies doesn't match the hearing loss the hearing aid is boosting?

Sure are more things to find out about all this.

 

Yeah, the brain isn’t damaged due to noise-induced or sudden sensorineural hearing loss and therefore doesn’t need restored.

 

A hum in a mixer/sound system can be caused by many things, but if it's caused by a faulty microphone cable, and you replace the cable, the hum won't be "stuck in the mixer", it will stop.

 

I like the analogies, but they are of course naive and inaccurate. The brain is arguebly one of the most complex things in the universe. The understanding of tinnitus is mostly based around theories, so only the future will tell what actually happens when you restore hearing.

 

IMO tinnitus doesn’t damage the brain. The ear damage makes the brain do weird things to get a signal.

 

You're right, the comparison is ridiculous, the brain is not a microphone. If it were that simple, Alzheimer's would have been cured for centuries.

 

I'm not sure you understood the analogy. Mic/cable = ear/auditory nerve. Mixer = brain.

 

Although it’s a good analogy, you can’t compare tinnitus to a microphone cable and a mixer, lol. That’s far too simplistic and shortsighted. Are mixers capable of processing emotions, intellectual thought, or are they self-aware? Do they get depressed, anxious, or obsessed?

Treating hearing loss may or may not fix/improve tinnitus for a subset of people. Fact is, it’s unknown what will happen until we achieve it, so all we have for now are opinions on the matter, and this includes all those from academia.

 

The problem with analogies is sometimes people draw the wrong conclusions. Anyone who's ever disconnected a guitar from the cable without turning the volume down on the amplifier first has heard that distinct buzzing sound. It could very well be that the nerves (cable) have been disconnected from the cochlear (guitar) therefore producing tinnitus due to the nerves propagating stray signals. A damaged guitar (cochlear) will also produce buzzing for the same underlying reason - lack of connection to, or damaged pickups (stereocilia). Until there is solid proof otherwise I believe this is plausible reasoning.

 

I'm not sure how emotions got mixed into this? A cochlea is typically damaged by noise, aging, infection, medication. This is reinforced in academics and commercially. Reversing the damage in this peripheral sensory organ is what FX-345 and many of the other locally administered drugs are designed to do.

If it were all up to the brain, and its emotions, wouldn't there be more cases of patients "stressing themselves to deafness." I can't find too much to support that case. There's also not much work going on to restore hearing by messing with the brain.

There is recent research / academic presentation, discussed on this very site, pointing to tinnitus commonly being the brain's response to missing signal from the cochlea. It seems to be also the case from a few trials (FX-322, OTO-413), that restoring parts of the peripheral organ results in improvement in hearing by the patient. Therefore, isn't it reasonable to say that the restoration (mic/cable) led to the brain (mixer) receiving better/more signal? Wouldn't it also be a reasonable stretch to postulate that if enough restoration in the peripheral organ took place, long-term symptoms like tinnitus would be partially or completely resolved?

Most patients get tinnitus as a result of losing hearing (aging, noise, infection, medication) at the peripheral organ (cochlea), there are statistics to support it. I just don't see how toying with the brain does enough to reverse a symptom without addressing the root cause.

 

Because our emotions directly affect so many biological processes in our body, from our endocrine system, brain chemistry, limbic system, etc. This all has an impact on how our brains react to various stimuli because our bodies are always attempting to return to a state of homeostasis.

I would argue that this is an extremely simplified reasoning that only looks at one subset of sufferers, and even then, it doesn’t completely explain what is happening. There are too many unexplained variables and not enough evidence, either way, to make any meaningful conclusions (at this point). Let me be clear here, I’m not saying that by resolving hearing loss we couldn’t expect to see tinnitus abate in various individuals. It absolutely could, and there are reasons to believe this would be the case. Would this work for everyone? I’d say not, and I’d go further and say that it would likely only work on a subset of those who have tinnitus caused by sensorineural hearing loss.

That’s my opinion, at least.

This does happen. High levels of cortisol that are sustained can wreak havoc on the body, and this includes the auditory system. It can affect blood flow into the inner ear by restricting the tiny capillaries, which in turn can restrict oxygen to the cells. It can affect glutamate transmission, and it can even shrink one’s brain. Stress is often seen as a precursor to tinnitus; it’s so common that it’s become a highly studied area. Anecdotally, you hear so many stories about people experiencing the onset of their tinnitus during stressful events, such as during pregnancy, with burnout syndrome, depression, anxiety, etc. The idea that it’s just because of a faulty cable, in all cases, seems highly suspect to me. That’s just my opinion, though.

I have no problem with the idea that the brain is plastic enough to remodel itself and reverse the tinnitus based upon the root cause being fixed. I’m saying there are too many root causes and likely complex interactions within the brain that span beyond the initial cause in many individuals. We need to better understand the heterogeneity of this condition.

 

I'm not sure you understand what I meant and also what @dbeats says, but you address me anyway.

If you think that I have not understood the analogy - it must be intelligent and meaningful - you must come down from your pedestal and be much more humble.

It makes no sense to compare a material object with something biological, what do you not understand? It has nothing to do with it, and as I said before, if the brain, or the ear if you prefer, were as simple as a microphone (material object, without a nervous system, cells, bone, muscle, etc.), all diseases would have already been resolved.

 

I agree with @Ed209. If this does work for tinnitus, I assume it will only work for people with tinnitus from sensorineural hearing loss.

 

Praying they move faster with these new trials lol.

 

That’s who it is intended for to begin with. The scope of the drug is hearing loss that is sensorineural, which also makes up a vast majority of hearing loss. We can reference tinnitus edge cases all day, but that’s not who this drug is for.

 

They won't. The first one won't be for another year, in late 2022. It will probably take almost another year to run the trial and release the results, sometime in late 2023.

 

And yet when we dream we don’t have tinnitus. Even though our ears are still damaged when we are dreaming. I’ve always been fascinated by that. There exists some state in which altering the brain stops tinnitus.

Even in lucid dreams where I’m aware that I’m dreaming and can manipulate the dream any way I want, I still don’t have tinnitus. Why?

If only we could replicate whatever is happening in that state.

 

Even for people with sensorineural hearing loss, the aetiology of their tinnitus is likely to be varied. The pathophysiological mechanisms are still not fully understood, but we know that it is a very heterogeneous condition, so it’s a bit of a minefield. It’s likely that fixing one’s hearing loss will only work for a subset of people, and that’s if it works at all. I think there’s also an argument to be made about the period of time that one has had chronic tinnitus and what can be expected as an outcome.

It will be interesting to see what the data on this drug looks like (when it comes to tinnitus suppression) if it proves to be successful.

 

I've said it before and I've said it again. Put in some tight earplugs or earmuffs and go do something around the house. Dishes, yardwork, gardening whatever. If you're like me, your tinnitus will be a lot louder but as soon as you take out the earplugs or earmuffs, it's quieter in an instant. Because you're letting more sound in. I don't buy the "it's in the brain" debate.

That being said, when I get extra stressed, yes, it's worse. I'm not sure why that is. But the fluctuation is way higher with earplugs.

I'm confident if you fix the ear, the rest will follow.

 

There is recent research / academic presentation, discussed on this very site, pointing to tinnitus commonly being the brain's response to missing signal from the cochlea. It seems to be also the case from a few trials (FX-322, OTO-413), that restoring parts of the peripheral organ results in improvement in hearing by the patient.

Hello, @Diesel! Whose research is the drug development based on? And has there been enough research done and by whom? As far as I know, Frequency Therapeutics cooperates with the Mass Eye and Ear but there there were no tests on pigs, only on rats and their research is now abandoned.

 

When you block your ears you should expect your tinnitus to become louder, though. That is just common sense. You are effectively lowering your signal-to-noise ratio, and when you take them out you are increasing it again. This is a poor way of demonstrating that “it’s not in the brain.” Everything we experience is in the brain.

This is something else that cannot be explained by hearing loss alone. Many people have tinnitus that fluctuates quite considerably based upon their emotional state, sleep hygiene, jaw tension, neck tension, etc. You also have to remember that hearing loss doesn’t always lead to tinnitus, so the faulty cable to the mixer analogy is flawed in this regard as it’s a bit too selective and convenient, in my opinion. What we have to ask ourselves is what’s different about the brains where tinnitus emerges as a symptom and the ones where it doesn’t.

You could be absolutely spot on with your assertion. All I’m saying is that there isn't much to go by in order to predict what would happen with any kind of certainty, and we haven't regenerated anyone’s hearing yet, so our current knowledge base is limited.

Let’s be patient and see what develops before we all smack ourselves on the backs.

 

Frequency Therapeutics cites the research/publications behind PCA (Progenitor Cell Activation) and FX-322 on their website:

https://www.frequencytx.com/science/publications/

Not as much more is known about FX-345 specifically other than what was disclosed at R&D Day, and in the Investor Deck. It appears the reformulation uses a higher concentration of small molecules, and perhaps one different small molecule than FX-322 to reach more deeply into the cochlea.

 

My belief is that it's pretty much always a matter of hearing loss, but many different types of events can cause the brain to latch onto it and generate tinnitus, be it a quick loss of hearing during an acoustic trauma, a long term loss of hearing while working in a factory, stress, a hit to the head, medication, infection, whatever.

That doesn't necessarily make it a non-brain problem. I think, what we call, the "hyperactive neurons" definitely reside in the brain, so the tinnitus is really a brain problem - but at the same time, I think hearing loss is a kinda prerequisite for the neurons to go bonkers.

So numerous different events can make the neurons go bonkers, but what ultimately allows the neurons to go bonkers is some kind of hearing loss.

But I could be wrong of course.

 

That is, do I understand correctly that Frequency Therapeutics conducted the testing themselves, and summed up the results and results themselves? Do you trust this company? Why can we trust that their goals are honest? What is your position on this issue? It is very likely that their goal is to make money not so much by creating a medicine as by deceiving the trust of investors.

 

The early published work was conducted by the founders prior to forming the company, under a lab operated by the highly-respected Robert Langer (also, the founder of Moderna, and others). Langer is also a co-founder.

Published work is peer-reviewed by entities that do not have a conflict of interest, and must meet certain scientific / academic standards. So, it's not the company making stuff up for its own gain / interests.

Frequency Therapeutics is publicly-traded. It is regulated by the US Securities and Exchange Commission (SEC). As an SEC Regulated firm, it is required to be fairly transparent with stockholders and the public in regards to its financial health, operations, and communication, among other things. Communications include investor presentations, marketing, etc, are fairly well regulated and the rules concerning them are clearly defined by the SEC.

Frequency Therapeutics as a drug developer, is also regulated by the FDA when it conducts clinical trials on its treatments. The FDA requires that drugs in clinical trials are tested by independent, FDA sponsored testing sites, and are placebo controlled. The FDA has essentially 100% say on what the firm can and cannot do with regards to patient inclusion/exclusion on the trials, number of test sites, etc. So, the firm doesn't have much ability to influence the outcomes of their trials in their favor.

Diesel's Personal Thoughts on Trusting the Science and the Firm:

- Progenitor Cell Activation (PCA) looks to be promising from an academic standpoint, FX-322 seems to have an effect on specific patients. It's likely to see a commercial outcome.

- The firm is highly regulated by two federal bodies: The SEC and FDA. They're not big enough or have deep enough pockets to pull a "fast one" on investors without severe penalties from either. So, they're incentives to be honest.

- Bob Langer, the PCA advisory board, the board, and most of the leadership at the company have a LONG career history in therapeutic development, hearing, and academic research/science. I find it hard to believe that all would want to tarnish their careers by running a scam. Also, many of the on-camera interviews seem to have genuine, honest interactions about the future of PCA/hearing regen and the learnings from failures.

- FX-345 and FX-322 existing in the trial pipeline concurrently is a signal of the firm's commitment to continue to improve its hearing treatment product. In my opinion, it adds legitimacy to the science. Drug development is highly expensive, and these types of small firms operate at high risk with one drug alone. One mistake can bankrupt. Having two in the pipeline shows they are committing to continuing the first-gen product (FX-322), while developing a second-gen product (FX-345). A company seeking to mislead investors wouldn't continue to sink money into the first-gen, they'd just switch to the "newest thing" and move on.

I have spoken.

 

...and probably almost all people devolop (more or less serious) hearing loss during their life span (mostly, at older age, but with a generation growing up with AirPods in their ears more and more), but still the question is why in some people the neurons go bonkers and other just get worse hearing but no tinnitus. Not that I understand it, but comparing these group might be an interesting approach to understand tinnitus:

Is the posterior cingulate cortex an on-off switch for tinnitus?: A comparison between hearing loss subjects with and without tinnitus

 

I personally suspect that genetics are what causes that discrepancy. Maybe some people's brains are "wired"/predisposed through genetics to develop tinnitus while others are not. I'll just say that my case is clearly noise induced, and tinnitus is present 3 generations back on my mother's side, while my father can seemingly hunt repeatedly without hearing protection and not get tinnitus. In my case, I've clearly inherited the predisposition to develop tinnitus.

 

Thank you very much for the detailed answer. Very encouraging.

It's great that Frequency Therapeutics does not give up and announces the development of a new generation drug FX-345. This cannot but rejoice us.

What are the medical achievements of Frequency Therapeutics? Didn't the second phase of trials of the previous generation drug FX-322 fail? FX-345 is its continuation and inherits the technology. Investors now want to file a class action lawsuit against the Frequency Therapeutics director.

Sincerely,
Artem

 

To my knowledge, Frequency Therapeutics is the first clinical stage biotech company to activate progenitor cells in the body using small molecules. FX-322 is their first attempt at a drug that causes temporary progenitor activation.

The FX-322 Phase 2A failed due to poor control on establishing reliable patient baselines, not the drug itself. They made it too easy for participants to "fake" their word scores below a predetermined threshold. This caused unexpected errors in both drug and placebo groups, which made the trial outcomes unusable. If you review their R&D Day videos/presentation, they've taken steps to mitigate it in the Phase 2B, which is on-going. These same steps will probably apply to FX-345 as well.

 

I am certainly not a bioengineer and very far from science. But why not use the subjects' audiogram as a control, if there really is an interest in the objectivity of the results?

Sincerely,
Artem