Frequency Therapeutics — Hearing Loss Regeneration

The cochlea is quite a delicate organ! For stapedotomies/stapedectomies a hole is drilled into it to insert the piston, and it is known to be one of the risky parts of this procedure. Mine was done with laser, which is also traumatic, but other methods do include a drill (which makes me queasy just to think about it). I've lost some high frequency sensorineural hearing from that surgery and I can't help but think it could be due to this, since the "drilling" happens "close to the high frequencies".

 

Frequency Therapeutics Presents Results Demonstrating Sustained Improvement in Hearing Loss Patients Treated with FX-322

It looks like even with a single injection it still sustained improvements up to 21 months.

 

This is now giving me more confidence that FX-322 is actually going to be successful.

Seems Frequency Therapeutics has now demonstrated FX-322 has met the three key criteria required for this medicine to be successful, being

- FX-322 can break the barrier in the cochlea

- FX-322 delivers positive treatment results when consumed

- The benefits provided from treatment with FX-322 are maintained a long time after the dosing.

This tells me that the work of Frequency Therapeutics and the creation of FX-322 is not only wonderful, but it is also a mega miracle.

I feel that now FX-322 has achieved the three criteria listed above, it is now just a matter of making the medicine more effective. This does of course rely upon the achievements seen thus far being maintained in future trials .

I hope FX-322 can be made more effective so it provides broader treatment. However, I am fairly confident this can happen. Frequency Therapeutics have shown time and time again that they are keen on doing the work needed to get the best possible treatment that they can and that they are fully focused on achieving this.

I somehow think that this leads me to believe that there will be positive times ahead.

 

So is Frequency Therapeutics allowed to change their formula of FX-322, let‘s say for a Phase 2b, or would this start again at Phase 1/2 if they modified something? Or do they use always the same formula all the way to Phase 3 but with different dosing and concentration?

What are they allowed to change to optimize the treatment?

 

This quote from that statement answers a question I'd had about whether the people who saw the 10 dB improvement were the same that had the WR score improvement:

Although it seems obvious to assume it, it's nice that they spelled it out. I kind of wonder how big an effect the person doing the injection has. I've never had an intratympanic injection, but they can't all be equal, right? It'd be interesting to know if the same person did all of the injections for Phase I.

Also, I wonder if their WR score improvements were due more to the improvements at 8000Hz than the improvements at 8000Hz+.

Lastly, it's nice to see that the pure tone improvements were maintained (and possibly improved? In the announcement they say 10-15dB improvements, but originally they just said there was just a 10dB improvement).

The fact that a 71% increase isn't statistically significant seems really odd to me. How can a 71% increase not be statistically significant? This makes their choice to avoid mild cases from Phase 2a make a lot of sense.

 

If they can optimize the delivery method to target all frequencies in the ear, FX-322 will be a game-changer to all those who have hearing loss in all frequencies.

I do hope by targeting all frequencies can help get rid of tinnitus, pain and loudness hyperacusis.

 

Yes, I was shocked too that they said 71% increase is not statistically significant. 71% is a lot but maybe their terminology of statistically significant for hearing is different to what we think is statistically significant.

 

The CEO of Frequency Therapeutics, David Lucchino, retweeted this on Twitter.

This shows he’s really keen for FX-322 to come out to the market ASAP.

 

They can't change the formulation (e.g. the drug or the vehicle) but they can change the dose.

 

10 dB means it improves hearing two-fold, though mostly the higher frequencies? And they are seeing continued improvement many weeks after delivery?

Sounds too good to be true for my skeptical mind, but I'm down for injection!

 

Good catch. They are confirmed to be the same patients after all.

And 10-15dB improvements does mean that some patients continued to see improvements after the original study completion, which is exciting.

Makes me wonder if the neuro connections are what takes additional time to regenerate after the hair cells have reformed.

 

OK, so in Phase 2A participants are already given 4 shots and Frequency Therapeutics might already know about the improvements.

I hope with 4 doses or more, they can reach deeper areas in the cochlea.

Or how could they optimize it better in this trial if they can't change the vehicle or formulation?

 

Carl LeBel all but said that they wouldn't/couldn't in the recent panel discussion.

A study result is statistically significant if the chances of that result happening by chance are below a pre-defined threshold. 0.05 is a number that is often used. They do some maths, come out with a number which is the probability that their results were due to random chance. If that number is less than 0.05, the results are said to be statistically significant.

 

I am hoping this is something they can look at again perhaps after releasing the first version of FX-322 on the market. Weren't they hiring experts in delivery/vehicle method not long ago though?

Also, just seen they stated this in their latest press release:

If that's the case then I will probably be taking a break from reading about this until summer 2021. Although I respect all of you for continuing to discuss and raise good questions, valid points and meaningful discourse, I find that the hypothesizing and uncertainty doesn't do my mental health any good. Sometimes perhaps as much (or more so) than tinnitus and hearing loss itself.

 

Unrelated but - he responded to me the other day, which surprised me. It's good that he's seeing what this means to the patient community.

 

Is there compelling evidence that if you fix the ear the tinnitus will just go away, as opposed to being internalized by the brain? This has always been my big worry with regenerative treatments. I feel like in the absence of Frequency Therapeutics giving detailed feedback on tinnitus decreases in their trials, we are all banking on a big assumption.

 

Were the 4 documented patients given just one injection? If so, that makes me very hopeful. Imagine how much more it could achieve with 3-4 spaced out injections.

 

Frequency Therapeutics will document the effects after this trial as tinnitus has been added to their experimental end points after receiving testimonials that it did lower tinnitus in phase 1.

I would listen to the Tinnitus Talk Podcast interview with Frequency Therapeutics if you haven't already.

Other evidence is the fact that cochlear implant studies have shown a reduction in tinnitus and hearing from CIs is extremely crude compared to regenerated natural hearing.

In addition to that, when you can treat the underlying cause, the tinnitus responds. Sound Pharmaceuticals found a reduction in tinnitus with their Meniere's treatment because they were treating the cochlear cause (hydrops) which means it's not "stuck in the brain." Other treatable causes of tinnitus (e.g., ETD, TMJ) similarly respond.

And understanding neuroplasticity, it's not a switch that gets stuck in one direction because that would imply the brain has a preference for tinnitus (and it doesn't, brains are dumb in that sense and just respond to the input they are given).

 

I gotta hand it to you. I would not have personally messaged the CEO on Facebook but props to you for doing that.

 

I thought it wouldn't hurt to try, certainly better than moaning at them. The more they see what this means to us the more they can hopefully keep pushing forward with intent.

 

True, they are probably sick and tired of us moaning but we are just glad that so far Frequency Therapeutics have been getting positive results in their current clinical trials for FX-322.

 

I totally agree. At the risk of advancing to an optimistic plateau on the thought of FX-322 being the potential cure, yes cure, I believe we have finally reached 'the light at the end of the tunnel' whereas through modifications along the way we may be witnessing the beginning of the end of sensorineural hearing loss and associated tinnitus.

The signal that Frequency Therapeutics has reached is quite phenomenal. The needed capital investment is not only there but this company's primary sole existence is for this shining moment to occur. Remember, Carl came out of retirement with a true belief that this is within reach. One day within sight this medical procedure from an ENT physician will become routine.

It's worth noting that a stock purchase in FREQ would probably pay for the treatment. Again, I am being optimistic but for good reason.

 

I agree with you about improving and optimising the delivery method. What we have seen to date with the results doesn't necessarily tell us the full picture. Although FX-322 has delivered improvements to date, I think that we have only seen a small improvement due to the small size of the dose used in the inaugural trial.

Frequency Therapeutics have discovered in the lab that their treatment works throughout the whole ear. Therefore we now know that FX-322 isn't the problem, but rather the reason we haven't seen more extensive growth in ears is to do with the dosing factors.

Therefore I think that there are three things that should be noted about the dosing of FX-322:

1. We have only seen the benefits of one dose of FX-322 in people. The results from this one dose have been nothing short of remarkable, especially with the gains seen in all patients (both those deemed to be statistically insignificant and those deemed statistically significant).

2. If the evidence and research is true which suggests doing multiple doses, spread out a week apart to achieve better results, I think there will be better outcomes. This could include not only a larger improvement in decibels but also increased word recognition scores too.

My hypothesis (I could be completely wrong) is that those who had worse improvement in the inaugural trial (ie: those with statistically insignificant improvement) were the people with the worse hearing losses. Therefore I believe that based off of how FX-322 operates (by targeting the stuffed cells till it has been all used), more of the medicine would have had to get used in the very high frequencies with the higher hearing losses. This in turn has led to the lower word recognition improvement and the no measured decibel improvement, because their gain was not widespread enough to demonstrate benefit.

Therefore I think that more dosing does seem like a highly likely method to improve the outcomes from treatment with FX-322. This is because the methodology does indicate that this will lead to a better outcome.

3. Frequency Therapeutics needs to redesign the dose in order to deliver FX-322 to all areas of the cochlear. It is already known that Frequency Therapeutics is redesigning the delivery method and/or reformulating the dose of FX-322 in order to make it work better.

It is inevitable that this will happen, as from what we know Frequency Therapeutics was hiring someone to work through this. Furthermore we know that the issue is not with FX-322 but rather it is with getting the medicine to all parts in the ear. We have seen FX-322 provide complete regrowth in a lab setting and as a result there is no real reason why this cannot be replicated in an ear. Therefore I reckon that this is an excellent area to focus on in order to get improved benefit from FX-322 in terms of treatment.

I asked someone I know well who works as a data analyst why there could be a large percentage increase (like the one you referred to) and he indicated that there tends to be a number of mathematical rules around this that he said can be complicated. He said that there was no real point in going into the nuts and bolts of it all. Basically he said that the reason it wasn't classified as statistically significant is probably solely due to a technical reason, like complying with the rules of statistics.

He thinks Frequency Therapeutics has probably been mandated to report results in this way. If Frequency Therapeutics doesn't comply with these rules, it could lead to them getting in trouble for delivering misleading and wrong info.

He suggested to look at the data from a real world perspective and interpret it accordingly. As a result he hinted that if you see something which looks like it is a good gain or good improvement for what it is then treat it as such and actually ignore what was reported.

So I agree with you that 71% is a large improvement, significant and also a good result.

 

I think I am like you. I am optimistic, however I won't be fully satisfied until the day this medicine is completed and usable LOL.

I think that your analysis that we may be reaching the "end of the tunnel" is accurate, as I think that FX-322 has achieved the titanic breakthrough needed to get treatment that works in the ear. Even if FX-322 isn't the best treatment over time (I think it will possibly be), the amount of unbelievable work Frequency Therapeutics has completed has set the foundation for the future of ear medicine up wonderfully well.

I think that Frequency Therapeutics certainly reflect the quality of the people who are working to develop both FX-322 and the company. Carl LeBel appears to be a very decent operator. He has been very direct in his comments and he has not done anything that could jeopardise Frequency Therapeutics or FX-322. I believe the fact that Carl had faith in this for the reasons you stated, is an excellent sign too.

While it isn't finished yet, I have a feeling FX-322 will provide quite positive benefit to a number of people.

 

So with Frequency Therapeutics' recent press release, this related article popped up in my news feed:

https://www.wbur.org/commonhealth/2020/09/13/frequency-therapeutics-regenerate-hearing-drug

And from the article's quotes regarding pure tone testing:

An improvement of 10 decibels at 8000 hertz is also almost a negligible gain, adds University of Iowa's Gantz, "within test, retest variability of an audiogram," he says.​

I do agree that current equipment to test hearing is not great but is 10 dB really so small that it can be attributed to testing variability? Decibels are measured in logarithmic terms so anyone going from 10 dB to 20 dB hearing loss is ten times less sensitive to sounds, not just two times less sensitive (correct me if I'm wrong).

 

I get the impression that most of the ENTs interviewed haven't read much beyond a few press releases. The reason I say that is this quote:

"But Dr. Alan Cheng, an otolaryngologist at Stanford University who did not work on the study, says there isn't enough evidence to show the drug is truly regenerating sensory hair cells. While Frequency scientists have shown that FX-322 can regenerate sensory hair cells in mice and in the lab, he says there’s still a long road ahead to demonstrate it works in living human beings."

And maybe he means the human cochlear explants are considered "in a lab" vs living human beings but when you consider that they *did* grow hair cells in intact human cochleas removed before nearby tumor removal surgery and then also showed in their German perilymph study, that the drug could reach their target in "living human beings" it seems misinformed and it's likely due to the fact that Frequency Therapeutics didn't release many press releases on the perilymph studies and most ENTs don't have incentive to keep up with the progress of the drug until phase 3.

It's an easy way to avoid having to take time to discuss it with patients before they can offer the drug commercially.

 

10 dB is definitely significant for anyone who has hearing loss and tinnitus. I had a sudden drop of 15 dB which caused tinnitus and diplacusis. And my ENT essentially said it wasn’t statistically significant. Not enough to cause concern to do anything.

Without real life experience I just don’t think ENTs or other physicians really comprehend how much “just” 10 dB can mean when it comes to the difference in real life to people and ear function.

 

Particularly for those of us with 'normal audiograms' yet who have developed tinnitus and hyperacusis, it shows that you probably don't necessarily need a significant degree of hearing loss to induce maladaptive plasticity.

 

Agreed. My hearing is trending towards moderately severe in the highest frequencies and a 10 dB improvement would bring it to moderate. Even taking into account variability, there would be an improvement regardless.

 

Well, to be fair, dexamethasone or methylprednisolone in the inner ear is kind of a crapshoot. For sudden hearing loss anyway, for which I believe it’s most commonly used. I don’t believe there’s any hard evidence to support its efficacy. The drug not getting where it’s supposed to might be the reason for it. People who get it do improve sometimes, but sudden hearing loss is known for its substantial number of spontaneous recoveries.