Frequency Therapeutics — Hearing Loss Regeneration

This measured approach is clearly much more meaningful and direct than the approach of Hough Ear Institute. It is extremely evident that Frequency Therapeutics wish to do the right thing by consumers and other stakeholders.

 

The milder hearing loss group may see benefit with things like hearing in noise for example. Essentially they are very unlikely to see benefit with word recognition through a normal test though. This is because often they will still fall within the speech ranges and as a result can pick up enough words to get them. Thus this means that there would be little to no benefit on the word recognition aspect and as a result is probably why they were eliminated from the trial.

 

Based on the definition of what constitutes "significant" and "measurable" in a clinical setting, milder cases simply do not have enough room to improve in order to be classified as "significant" or "meaningful". Imagine they are at 90 percent but in order to be "significant", the patients have to have a 20 point increase. Well, anyone starting at better than 80 can't achieve that by definition, even though in reality, they did see benefits, because there isn't room for 20 points to be gained.

 

Apologies if this has been asked already, and I hope this makes sense, but for those with both damaged synapses and hair cells, would it be better to wait for both drugs to be out to get a mixture of the injection?

If I'm following correctly, FX-322 will be out before either Otonomy drugs. I'm wondering if waiting for OTO-413/313 and getting a mixture would be best. Or if it is possible to get FX-322 when it comes out and then do the rest later. Not sure if the process will be a "top up" type thing where you have to redo injections forever or you'll be set once you do the course.

I know it's best not to worry right now, just wondering if there's any speculation on this.

 

I suggest taking whatever comes out first. There's a high likelihood that you'll get some type of relief.

 

@Diesel has already pretty much answered this above but I thought I'd just expand a little bit more on this for what it's worth as I've seen this question come up a lot of times from those who consider themselves more in the "mild" group of hearing loss cases and have concerns as to whether they would benefit from FX-322.

There is a key differentiation here to be made between statistically significant improvement and what one perceives in their own experience as significant improvement. One of the key principles of proving something in science with confidence (or strictly speaking, disproving something with confidence) is to show that an outcome cannot be explained by chance, or at least cannot be explained by chance most or all of the time.

With this in mind, if one were to take a word-in-noise test several times, one would not always necessarily achieve the same score. As an arbitrary example, one with mild hearing loss may take a word-in-noise test several times and on the first occasion they may score 45/50. However, on on the second and third try they may score 42/50 and 48/50 respectively. In other words, scores will vary - perhaps even improve - even in the absence of a treatment. This test variability is what is known in statistics as a "standard deviation". So for one to state confidently that an improvement in a word score is down to treatment and not chance, one would need to see an improvement of at least more than one standard deviation, depending on where one draws the line between chance and real improvement (and this line is usually guided by certain mathematical standards).

Now, in a x/50 word-in-noise test, Frequency Therapeutics considers 3/50 words to be the measurement of one standard deviation. Depending on how confident one wants to be, one may require to see two, three or more standard deviations post-treatment to be able to say "we can say with X amount of confidence that this improvement cannot be explained by chance". Now, I don't remember where Frequency Therapeutics' confidence level was drawn or whether there is a set confidence level for clinical trials, but assuming it was at say 2 standard deviations (6 words), and a patient went from a 45/50 word score to 50/50 (5 words), Frequency Therapeutics would not be able to say they were confident enough that the improvement was not down to chance because 5 words is less than 6 words, and therefore less than two standard deviations. In other words, the "ceiling" for seeing statistically significant improvement in mild hearing loss cases in the phase 1 study was too low, even though there was/may have been (don't remember now) evidence of actual word score improvement.

This is why Frequency Therapeutics are focusing more on the moderate to severe hearing loss groups because they know the ceiling for improvement is much higher in these cohorts and they are likely to achieve much more favourable, statistically significant results - and it's statistical significance that counts when it comes to proving a drug is worthy of going to market.

TL;DR: mild-hearing loss cases should still benefit from FX-322, even if clinical trial results do not show improvement at a clinically/statistically significant level.

 

Thanks for the clarification. Personally, I agree with the premise. I wanted to understand the rationale behind it. I have had three different audiograms and word recognition scores within a month. All were in the normal to mild category; two doctors interpreted the score as normal and one as mild.

 

I can empathize with your concern and you having asked that question. A "normal" to mild result is what I expect from my evaluations. The chance of not knowing exactly what is the cause of this symptom is debilitating on its own, and it makes you question what value for those without moderate to significant hearing loss there may be with these wonderful cures in the future.

I do understand all of the responses to your original post, though. There is all likelihood that improvements which are important to the patient with "normal" to mild will occur.

I would also think their shifting to focus on those with more damaged hearing is even more hopeful for those milder cases because it almost certifies efficacy of the drug. If something works for a moderate case, it should work for everything up to that point as well. I think others have hinted at or outright said this before.

The main concern on my end is how those with "normal" to mild loss will be able to get their hands (or ears?) on the drug. I worry that insurance, if it does end up covering it, will generally require you have to have at least "moderate" loss, for example. And that's if you can even get an ENT to give it to you.

I know others have said it is far too early to worry about it, and it may be, but this is a concern we shouldn't just ignore.

 

I wouldn’t be concerned at all, for the following reasons:

What is known right now:

1. FX-322 has a favorable safety profile, so the risk of trying it to see if it helps is low from a doctor/patient perspective. For example, right now they’re giving people Prednisone for acute acoustic traumas, which has all kinds of nasty side effects.

Speculation:

1. If FX-322 shows high frequency improvements in the Phase 2A, with normal/mild hearing loss you likely have high frequency hearing loss that FX-322 can be prescribed to treat.

2. ENTs/Audiologists will be aware of what FX-322 can treat and how to assess it by the time it is an approved product.

3. Frequency Therapeutics, like all other drug providers, will offer a list on their website if recommended practices to get their treatment.

4. Insurance will look at quality-of-life (QOL) measures and cost. If QOL increases for people that got the drug in the Phase 2A, it’s more likely to be covered. Cost is unknown, but there have been a few mentions by Frequency Therapeutics that FX-322 won’t be prohibitively expensive.

5. Advertising. This drug will be marketable to pretty much everyone on the planet at some point in their life. Doctors won’t be able to avoid the patients demanding FX-322 because they saw it in an ad on TV.

 

I think you hit the nail on the head. I have mild hearing loss, but still in the normal range (-20 dB) with word recognition 92-96/100. Although this is not drastic, the change in level from 0 dB to -20 dB along with many symptoms has made a significant change in normalcy of life. The emotional impact has been great in the last 3 months.

I'm praying this or any of the currently developing treatments could improve the quality of life across the spectrum for the hearing impaired/tinnitus community.

 

I think your prayers are going to be answered. One dose of FX-322 looked promising in terms of results on a very small sample of patients. Hopefully there are increased improvements across a larger group getting multiple doses.

Based on how Frequency Therapeutics has updated their recent investor presentation, it seems to me that they’re positioning FX-322 to be a “first line of treatment” for hearing loss cases from mild or worse.

So, I would rest assured that the findings from the upcoming trials may help reinforce the drug as a first line treatment for normal hearing + high-frequency loss, tinnitus, age-related loss, etc.

 

Both for tinnitus and for any word recognition score, especially WiN, there surely has to be a massive difference if you test/treat one ear vs. both ears? Two ears are needed for "spatial" hearing, and surely this plays a big roll in how well your brain picks up sound? Just as a very blunt example, I think two "bad" ears would probably have a good chance of scoring better on a WiN test than one "better" ear on its own, no? Surely Frequency must have at least thought about how it may affect scores?

 

Thank you for always doing your best to assuage concerns. With how you reason your responses, it is clear you aren't just telling people what they want to hear, but rather what you have determined to be logically sound based on the facts of the situation. For that, I am very grateful. This extends as well to FGG, tommy, and others who have done the same.

I fully expect it to still take some time for the doubts and uncertainities plaguing my thick skull to diminish, but educated reassurances like this are helpful in keeping me sane. It ensures that the legitimate hope in cures such as FX-322 and OTO-413 remains valid.

 

I think my only slight concern is about how FX-322 will be offered in the UK, i.e. for free on the NHS. My worry is that you'll only be able to access treatment on the NHS if you have measurable hearing loss on a standard audiogram, thus forcing you to go private.

But then, if this drug manages to successfully treat hyperacusis and tinnitus and is marketed as such, then surely you'd be able to get referred to get the injection if you make clear that it's having a significant impact on your quality of life. Like, I don't have measurable hearing loss, was referred to an ENT/consultant audiologist and basically got a diagnosis on my records anyway of acoustic shock/hyperacusis and tinnitus from noise trauma. So it's something that's been acknowledged as substantially impacting my life and hopefully that would be enough even with a 'normal' audiogram.

I'm probably worrying too much - any other UK folks here?

 

I believe it was Dr. Cliff (The YouTube Audiologist) that discussed the notable improvements between WR and WIN when testing each ear independently vs. both ears. He showed an example where a patient had a word score of like 25/50 words in the left, and like 22/50 in right. But when testing both ears at once, they scored something like 35/50 words correct.

I assume the same is going to be correct for WIN, possibly even more-so. When filtering out spatial noise when focusing on a conversation, for example, both ears enable the listener to focus on sound directly in-front of them while filtering out the ambient noise. Now that I think about it, a WIN improvement of 20% from a single injection testing only one ear is actually impressive, considering the brain is "centrally handicapped" to using only 1 ear to do the sound processing.

As far as the 2 bad ears vs. 1 good ear for WIN go, it would depend on the damage of the bad ears in question.

For spatial/directional hearing; I am speculating on total opinion but - 2 bad ears would be better than a deaf ear and a good ear. But in terms of FX-322 treatment, if you do not have a bad ear and a treated/good ear, one might hypothesize that the added information would make spatial hearing better as one ear is providing more signal to that side and to the "central" channel synthesized by the brain.

There is no doubt that Frequency Therapeutics is aware of all of this. Which, in my opinion, makes the gains that we're seeing from just one treated ear even more impressive for WR and WIN score improvements. Since they only inject and test in the treated ear, the brain is working with like a -2 handicap (no other ear, no central hearing), to receive word recognition and word-in-noise signal.

 

I imagine there is going to be a subset of people for whom FX-322 will work to restore hearing. There will then be another subset, of that original subset, for whom the brain actually adapts and eliminates the tinnitus signal once hearing is restored.

Let's say the drug does its job, but can only properly diffuse in 80% of people's ears (or whatever other physiological stumbling block you want to make up). Then, of those 80%, 75% get some reduction in their tinnitus. That's an effective rate or 60%. Maybe of that 60%, half get a real cure, meaning silence, while another half get a reduction. So we could be looking at an incredible drug that does everything it promises, but gives 30% of people silence.

People need to keep in mind this is a complex situation, and I would be willing to bet lots of money that as we achieve new successes, we will also encounter hitherto unknown challenges and complexities unique to each of our pathologies. Those challenges will then take further iteration in order to overcome, where they can be actioned at all.

 

To put the advertising situation into perspective, we already get this repeatedly with LASIK treatment advertising on the TV and radio now.

There is no guarantee that there will be a mixture of both medicine types either, especially since currently the only company who we will potentially see do a synapse and a hair cell medicine is Otonomy. One cannot assume that a mixed medicine might even be possible either at this stage, since there is no evidence or data to positively demonstrate that combining these would work.

What I would say is take whatever comes first since I cannot see any negative and/or adverse outcomes coming from taking a synapse medicine first and then a hair cell medicine later or vice versa. Especially when both treat totally independent things.

 

My fear as well, but if it does end up getting rid of both hyperacusis and tinnitus then as long as FX-322 is stated to treat these conditions, the ENTs can’t deny us for wanting to get treated with FX-322.

 

Good point but just regarding the diffusion point, they have already demonstrated that the drug successfully diffuses into people's ears based on their Germany perilymph analysis from last year. They stated that the presence of anatomical factors such as round window membrane mucosal folds in certain subjects did not hinder the drug's ability to diffuse into the cochlea.

 

You should start saving up. It will take many years for the NHS to offer this.

Just go private and be done with it. Socialized health systems suck anyway.

 

It's the same with vision. They are tested individually and then together, since vision works in unison with both eyes. It's very interesting.

 

I mean the NHS isn't perfect and I do wonder how quick (or not) it will adopt FX-322 so going private is probably ideal in this situation but universal healthcare has saved my life and probably tens of thousands in medical bills and prescriptions so I wouldn't say they suck lol.

 

Ya, I'm just thinking there will be different responses to the drug, whatever the physiological cause may be. There is always variance for one reason or another. I'm being speculative but I don't think I'm being unrealistic or cynical.

 

Everyone would prefer for that 30% to be 100%, there's no doubt about that, but even something along that line is much better than the zero products that are available right now in the market.

FX-322 is also addressing one specific part of the problem in terms of hair cell damage or hearing loss. OTO-413 is going to have its own separate value of full recovery, and I think it's logical to assume both taken together will have an even higher figure. There's also a chance that the drugs are so effective at reducing tinnitus and the figures are even better than expected. It's hard to know at this point, but it is good to ensure expectations don't lie on either side of the extremes.

And while total silence would be great, as that is the ultimate goal, noticeable reductions are still excellent to have. These reductions could at the very least tide one over until more comprehensive and robust treatments are developed.

You are entirely correct in the sense that this condition is very complex and very subjective person-to-person. Optimistically, however, you can consider that learning the further challenges and complexities will enrich research, so scientists are therefore able to iterate upon designs as you said.

FX-322 1.0 is most likely not going to be the final solution for hearing loss, but if it is successful and does what it claims to do, that's an extremely good head start. Revolutionary. Literally the first of its kind. Dare I say, it might even be a breakthrough therapy. There is no reason to think it wont inspire others to follow in its footsteps. Something like this might be what the medical industry needs to kickstart itself into a new era of development.

In essence, I definitely understand where you're coming from, but I think there's a good case for the results being very promising.

 

Cool, I hadn't heard about this.

My thoughts exactly!

 

This is very likely to be the case, but as the field progresses there will be more and better treatments. I'd happily take 30% reduction in say 1 year, another 30% reduction in 5 years and maybe silence within 10 years.

 

From what we know so far, three factors play a role in how effective FX-322 will be treating the individual's condition:

- Depth of damage in the cochlea that FX-322 can treat. Right now, it seems to be anything above 8 kHz on the audiogram. This may change with multiple doses, but it still probably won't reach the lowest frequencies from the Phase 2A results.

- Extent of damage in the cochlea. So far, we know that FX-322 can treat moderately severe cases, but it is unknown whether areas of severe or profound losses can be regenerated.

- Type of damage. Hair cell loss or synaptopathy. FX-322 will treat those damaged hair cells, but not those that are healthy but with broken synapses.

Expectations should be that most probably have some degree of wear/damage at all three bullets above. One or all of these conditions may be a factor contributing to their tinnitus.

In terms of outcomes, I don't think anyone should think that FX-322 will alone bring them back to complete silence in a quiet room wearing earplugs. It can't go deep enough, and treat all conditions of wear/tear to be a 'cure' back to a day-zero cochlea.

However, it's likely that FX-322 will give patients much needed relief, even if partial.

Assuming most patients have a combination of the above bullet points, let's say distributed equally between all 3. FX-322 should help restore their frequencies at the higher ranges where hair cells are missing, they should recover some level of hearing bringing them up at least 10 dB. It cannot treat synaptopathy where the hair cells are 'healthy', but likely repair adjacent hair cells that have acquired damage.

So, in this case, and for many of our cases, maybe it won't eliminate the tinnitus and fully restore hearing, but it'll be the first treatment to begin the reversal process.

As it relates to tinnitus, I would imagine many on here would be thrilled if FX-322 perhaps did even one of the following:

- Reduced 1 or more tones / static / hissing / clicking / popping / humming, but left some remaining
- Reduced the overall loudness of all the tinnitus by 25%, 30%, 50%
- Made the tinnitus less annoying on a daily basis, i.e. made it softer
- Reduced reactivity of their tinnitus

 

I couldn't imagine being stuck waiting for care if it's urgent and could actually help. Thousands of people from Canada come to Detroit all the time for care. I have talked to people waiting over a year to see a neurologist.

Our medical system in the U.S is fucked up and expensive but at least you can see a doctor if you need to.

 

I think that there could be treatment offered for ear related medicines through government funded medical systems in countries like the UK, Sweden and Australia actually a lot sooner than that, provided that the medicines get demonstrated to provide better benefits than current options such as hearing aids provide. Presently most governments which offer health care options cover cochlear implants or hearing aids and as a result are likely to cover substitute treatments for these.

 

Sorry to focus on this point, as the rest of the post is great, but wasn't the delivery method already confirmed to sufficiently travel the cochlea? Or is this still an ongoing problem?

Were you talking specifically about a single initial dose? I thought the general idea was that multiple doses would indeed allow the depths of the cochlea to be reached. Perhaps that number may even be x4 as that's the maximum doses being tested in the current trial.