Frequency Therapeutics — Hearing Loss Regeneration

Based on my own observations here on this forum, earbuds / headphone use is certainly a common complaint for new users first discovering their tinnitus. Considering the recent growth in popularity of wireless earbuds like AirPods, and that usage of headphones has occurred at a younger age for the more recent generation, this isn't a surprise.

 

I can imagine constant AirPod/earphone usage due to working from home/Zoom classes and meetings can't be great for people's ears.

 

How can I buy some FREQ stock? I'm from France and can't seem to find any websites to buy from.

Thanks.

 

That's pretty amazing. You must have normal hearing above 8 kHz then. Have you ever had an extended audiogram?

 

You too??

 

Looking online, it looks like you should be able to just open a brokerage account with a company like eTrade, Robinhood, Webull, etc, and then just buy the stock like a US citizen would.

 

Same with me. -65 dB at 3 kHz & 4 kHz, yet have a 100% word recognition score. I still can hear pretty well with the speech in noise. I have only been tested up to 8 kHz, but I know I can't hear past 12 kHz in both ears.

Must be a collaborative effort then

 

What caused your hearing loss?

 

Acoustic Neuroma on left 8th cranial nerve. Having consulted with various specialists, the sudden loss that I experienced last October could be from nerve damage, toxic secretions from tumor or compromised blood flow. I'm not sure myself but holding out hope that since it was sudden, that it may have been toxic secretions affecting the cochlea.

It may be a long shot but perhaps FX-322 can aid in restoring some lost hair cells and improve hearing/lower tinnitus. Might be wishful thinking but I'm remaining optimistic.

 

Where have they said this? My understanding is that they consider test variability between re-taking WR/WIN tests as 3 words*. See bottom right of slide below.



In other words, if your score improves by 3 words, this still falls within the parameters of chance, not meaningful improvement.

*For the record, there is actually a lot of debate in the field as to what one should consider as the threshold for test variability. Thornton and Raffin, who Frequency Therapeutics have made previous reference to when describing their results, attempted to answer this question some years ago. For those who may be interested, check this link out and scroll down to the subheading "When is a difference really a difference?"

 

It says it right there in the slide.

 

The graph is entitled as clinically meaningful improvement. The sidenote about test variability on the bottom right doesn't mean clinically meaningful improvement = test variability (i.e. 3 words). The purpose of that is to show transparency in their methodology and how one standard deviation translates in real terms as a reference point.

If clinically meaningful improvement = 3 words, why have they only shown patients with improvements of 20, 9, 19, 21 and 9 words? That would suggest that the other 10 patients saw improvements of less than 3 words.

 

Exactly. Those that had clinically meaningful improvements scored beyond a single standard deviation (6+ words would be 2 standard deviations). Confirming the improvement wasn’t variability.

This is why they excluded the mild group that had a word score above 40. There isn’t enough headroom for clinically meaningful improvements, but there is enough for statistical significance of measured as a percent of improvement.

 

The average person also thinks that loudness hyperacusis is just the volume being turned up. It's so much more -- the brain completely rejects sound like an allergy.

 

I also want to add something regarding the definition of clinically meaningful.

There are many drugs that go through clinical trials that show a statistically significant difference between placebo, but the actual difference between the two groups can be very small (say 5% or 10%). What's important to note here is that the word "significant" should not be taken to mean "important". As long as the groups are large enough and the methodology is strong, the investigators can state that there is a statistically significant difference between the treatment and placebo groups, even if in real terms the improvement acquired from the drug is small/hardly noticeable.

This is where the term "clinically meaningful" is useful, because the term suggests that the patient sees/experiences a real and tangible difference to their condition and daily experience. That is why the scores on that slide are labelled as clinically meaningful, because we are seeing in some of those patients an almost doubling of word scores - hence the so-called "hearing signal". It is unlikely that an improvement of 3 words could be described as "clinically meaningful" regardless of where someone's baseline is on an x/50 WR test. A score of 11/50 is 4 words better than 7/50, but in real terms it's still a crap score from a patient who still has terrible hearing post-treatment, even if the improvement is measurable and indeed statistically significant. The same would also apply to someone who goes from 41/50 to 45/50 - that kind of improvement would not be noticeable to a patient, hence why it also would not be regarded as clinically meaningful.

With this in mind, it's unlikely Frequency Therapeutics are interpreting 3 word improvements as clinically meaningful, but I'm happy to stand corrected on this.

 

Would this suggest that the hair cells die off again as time goes by?

No never, only up to 8000 Hz.

 

Same here.

 

Yes, even the new hair cells will continue to wear and die over time.

 

Agreed. If this drug can't show improvements on the audiogram, they are screwed.
People can disagree all they want , but its the truth.

 

I do like the fact that they are promoting on Twitter improvement with background noise speech interpretation, because in small loud restaurants I struggle bad. Have to read lips even. Sucks...

 

So far it has been proven that FX-322 works and show word score improvements on the audiogram.

Now we wait to see if additional doses of FX-322 allow it to go deeper in the round window for additional word score improvements on the audiogram.

Praying that additional doses of FX-322 help.

 

They showed small improvements in Phase I/II at 8 kHz. I think there will be better improvements at the 12 kHz and 16 kHz bands, and I also think we'll see a bigger improvement at 8 kHz for the multiple doses.

However, I am curious what will be deemed a success in this area, and what the threshold will be for statistical significance. It'd also be nice to see improvement in the lower bands, but due to where they've shown the drug gets concentrated (most likely due to not being able to get deep enough), I'm not getting my hopes up. Though it would be a nice surprise if multiple doses helped in this area.

 

It’s good to Google some brokers based in France.

Most likely they will report the necessary information to the government for taxes.

Go for an international one like Robinhood and you will have to manage that yourself.

Compare fees and reviews. Some brokers are a lot more expensive than others.

 

I would think it's more due to older hair cells dying off that were still there at the time of the injections? New hair cells will wear for sure, but I'd expect it to take more time.

 

This comment is really important, and why their Twitter feed and messaging tends to focus on the hearing loss challenges of the patient. The typical person doesn’t go through their day “gee, I think I’m deficient at 4 kHz on the audiogram”... they say, “I can’t hear while in noisy restaurants” or “I don’t understand conversations as well.”

With just one dose of FX-322 in the Phase 1/2, the early data has demonstrated that it likely can address these everyday concerns. So, it seems as though their public-facing marketing strategy will continue this theme.

While I also would like to see improvements on the audiogram, as others have mentioned, I tend to think that showing continued gains in the word score at or above the Phase 1/2 alone makes FX-322 a marketable product.

 

I feel like anything on the extended audiogram is not going to be considered important. You have to remember doctors at the FDA are going to scrutinize the shit outta this. They are going to say frequencies outside of speech range don't matter. Remember you have idiots like Julian Cowan Hill who want this to fail so he and his cronies can keep screwing the system.

They need gains in the normal audiogram. If the extended audiogram shows improvement that's a huge bonus, I guess if the super high frequencies recover a lot, it may help with tinnitus, but it will be considered a failure if it does not help with the lower frequencies.

Just my 2 cents. Not trying to be negative but I'm being realistic. I truly hope this works and works well but I'm skeptical.

 

If they successfully make the case that the higher frequencies make a difference in word scores and co-relate the two, I'm confident the drug would still be released. It might just have less of a market share.

I expect multiple doses to reach lower frequencies though.

Also, there is no way they are having people like Julian Cowan Hill contributing to the AdCom meeting either.

 

From what I’m understanding, you’re essentially getting the same hardware that you got in the womb. So, yeah it’s going to take a while for the new hair cells to noticeably wear from a performance perspective, but they aren’t any more durable than the original equipment you got at birth.

 

Not saying they're more durable, but if a hair cell can take, say, 40 years of a certain amount of "abuse," then assuming that person isn't subjecting their ears to anything worse, the shiny new hair cells should have more life on them than the older ones. Like mileage on a car.

 

Currently, the FDA has granted the drug the Fast Track Status, which based on the Phase 1 and 1/2 data, they have indicated that FX-322 meets ONE or MORE of the following criteria:

• Shows superior effectiveness, effect on serious outcomes or improved effect on serious outcomes
• Avoiding serious side effects of an available therapy
• Improving the diagnosis of a serious condition where early diagnosis results in an improved outcome
• Decreasing a clinical significant toxicity of an available therapy that is common and causes discontinuation of treatment
• Ability to address emerging or anticipated public health need

At the END-OF-PHASE 2 Meeting, FDA will directly consider the data from the Phase 2A and both Phase 1Bs based on the FX-322 dosages outlined in the specific trials. Note, the Fast Track Status offers that the FDA can review data prior to the End-Of-Phase 2 meeting, and make suggestions for future trial design, or assist in expediting future trials, among other things.

The Primary Outcome data to be assessed will be:

1. Speech Intelligibility
   Assessment of speech intelligibility using the Word Recognition in Quiet test measured with Consonant-Nucleus-Consonant (CNC) word lists.
   
   
2. Speech Intelligibility
   Speech intelligibility using the Words-in-Noise test measured with Consonant-Nucleus-Consonant (CNC) word lists
   
   
3. Standard Pure Tone Audiometry
   Standard pure tone audiometry will be measured to determine a subject's threshold for hearing at standard frequencies (Hz)
   
   
4. Systemic Safety: Number of patients with treatment-related adverse events
   Number of patients with treatment-related adverse events assessed by CTCAE v5.0
   
   
5. Local Safety: Number of patients with abnormal changes from baseline in otoscopic examinations
   Microscopic otoscopy will be included to specifically record any abnormalities of the external ear canal, tympanic membrane and middle ear.
   
   
6. Local Safety: The number of patients with abnormal changes from baseline in tympanometry
   Tympanometry tests the integrity of the tympanic membrane by varying air pressure in the ear canal. Middle ear compliance (mL), peak pressure (daPa), and ear canal volume (mL) will be recorded.
   
   
7. Columbia-Suicide Severity Rating Scale (C-SSRS)
   Risk assessment through a series of simple, plain-language questions

The Experimental Outcome data to be assessed will be:

1. Extended High Frequency Pure Tone Audiometry
   Pure tone audiometry will be measured to determine a subject's threshold for hearing at extended high range frequencies (Hz)
   
   
2. Tinnitus Assessment
   Measured by the Tinnitus Functional Index (TFI), with a scale ranging from 0 to 100 that defines severity categories based on 25 self-reported answers.
   
   
3. Hearing Handicap Inventory
   The Hearing Handicap Inventory for Adults (HHIA), is a 25-item self-assessment scale composed of two subscales (emotional and social/situational). The subject will self-report one of the following answers for each item on the scale: Yes, Sometimes, No.
   
   
4. Hearing Screening Inventory
   The Hearing Screening Inventory (HSI) is a 12 item self report inventory to assess hearing impairment. The subject will self report one of the following answers, for each question from 1 to 8: Never, Seldom, Occasionally, Frequently, Always, and for each question from 9 to 12: Good, Average, Slightly below average, Poor, Very Poor. The HSI is designed to assess subjective change during the study.

Based on the significance of the Primary Outcomes (Safety + Efficacy) from both a statistical and clinical standpoint will determine if the drug is assigned the Breakthrough Therapy Status, AND/OR if FX-322 is approved for a pivotal trial. Usually at this point the FDA will also provide comments to Frequency Therapeutics for future trial design.

So yes, there will be a lot of doctors + experts scrutinizing the data; and they have already done so for the Phase 1 + 1/2 which has led to the Fast Track Designation. Indicating that the FDA already sees the drug as promising. This is what we want to see. Experts reviewing the data and moving the process forward, or suggesting that Frequency Therapeutics make changes to a future trial to more clearly answer ambiguous results.

I do not see in any of my research on the clinical trial process the FDA bringing in outside influences (Like Julian Cowan Hill, the ATA, hearing aid manufacturers) to weigh in on decisions that are data specific. The sponsor can provide peer-reviewed research to reinforce the data found from specific primary outcomes, which I expect Frequency Therapeutics to do; for example: the recent data on hearing loss being the largest modifiable risk to developing depression / dementia, and that age-related hearing loss is largely just hair cell loss. The FDA does accept petitions in the case of some drugs in clinical trials, but they do so in a way that weighs those petitions FOR and AGAINST.