Frequency Therapeutics — Hearing Loss Regeneration

Did Frequency Therapeutics release the results of their most recent clinical trial? Seems like this went from hopeful to sour and I don't know why.

 

But the agreement only applies to FX-322. Astellas only benefits if FX-322 specifically goes to market. The agreement was for the licensing of that one product. Not for stock options not for future progenitor cell applications Frequency Therapeutics may have.

 

This is the agreement Astellas made with Frequency Therapeutics:

https://www.astellas.com/en/news/14841

The 80 million may be small potatoes but they won't see a dime of it back if FX-322 doesn't show efficacy for hearing loss and go to market (they don't benefit from any other source of Frequency Therapeutics' income whether it be stock options, government grants or future progenitor cell drugs). I don't think established pharmaceutical companies would throw money away on a drug that clearly showed it didn't work, even if it's "just" 80 million.

 

Although there is some debate between clinicians’ experience, both older and newer research suggests that testing frequencies beyond 10kHz may obtain useful information for tinnitus patients who report higher frequency pitches, difficulties with speech in noise, and may be able to reduce the rates of "idiopathic" diagnoses.


"Best-Practices" Flowchart of Tinnitus Diagnosis and Management:
https://www.tinnitusresearch.net/index.php/for-clinicians/diagnostic-flowchart

Contains comprehensive recommendations for treatments organized in a flowchart with evidence levels and further details. See attached sample at the end of these links.


Importance of Extended High Frequency Testing:
https://journals.lww.com/thehearing...Extended_High_Frequency_Audiometry_for.8.aspx

Contains research links to address concerns such as:

-Is signal energy above 8kHz important and useful for tinnitus and hidden hearing loss?
-Reliability of EHF thresholds
-Equipment limitations
-Clinic testing times
-Treatment and management strategies


Tinnitus and Range of Frequency Loss:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438350/

Although the conclusion of this particular research project said that the exact (or close approximation) frequency of tinnitus wasn't significantly correlated with the edge of the high-frequency loss, it was reported that patients had tinnitus frequencies that were higher than the edge of the hearing loss on the audiograms. This may suggest that we can at least get some useful information through extended high-frequency audiometry. Newer research is expanding upon these findings mentioned below."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307623/

"The findings revealed more decreased hearing sensitivity at UHFs and higher prevalence of TEOAE abnormalities in normal hearing individuals with tinnitus compared to the control group. Moreover, stronger correlation was observed between increasing UHFs hearing threshold and decreasing SNRs of TEOAEs in tinnitus group compared with the controls. Tinnitus severity was not related to UHF hearing thresholds or SNRs at all investigated frequencies. Further research is needed to understand the value of measuring OAEs and UHF hearing sensitivity in normal hearing individuals with tinnitus, and their potential advantages on clinical outcome of these patients. Furthermore, the combined use of different tests investigating cochlear function can help comprehend the role of cochlea and hair cells in tinnitus generation better."


Ultra-High Frequency Sudden Sensorineural Hearing Loss:
https://journals.lww.com/thehearing...Frequency_Sudden_Sensorineural_Hearing.9.aspx

“Tinnitus matching is typically measured at or below 8,000 Hz, particularly for tinnitus caused by noise-induced hearing loss, although tinnitus may occur above this range

Ultra-high frequency testing may provide a wider range of understanding of patient complaints in the absence of hearing loss using standard audiometry.

Audiometric testing regularly measures frequencies between 125 Hz and 8,000 Hz. Typically, most of the hearing changes occur in this range, as does tinnitus. However, a case of unilateral ultra-high frequency SSHL suggests that a near normal or normal audiogram does not always mean a lack of significant hearing loss, and extended range testing may reveal valuable information.”


Hidden Hearing Loss:
http://canadianaudiologist.ca/issue/volume-5-issue-2-2018/hidden-versus-not-so-hidden-hearing-loss/

The above article suggests that "speech-in-noise" tests are more useful than typical pure-tone audiometry (only going up to 8kHz) for diagnosing problems of hearing in noisier, social environments. "Threshold assessment at high frequencies (from 10k - 20 kHz) should be considered for inclusion in test batteries when patients report difficulties understanding speech-in-noise despite audiometrically normal thresholds up to 8 kHz. Although there are no clear causal relationships between high frequency hearing and speech-in-noise test performance, high-frequency hearing loss in relatively more noise-exposed participants has been reported by multiple teams (citations 33,36,37) and may be one of the first changes among long-time users of personal audio systems.(75)... Empirical data are needed to assess this specific suggestion, and determine the strength of any potential relationships between high-frequency hearing and speech-in-noise performance. Regardless, documentation of deficits to the high frequency regions of the cochlea will provide a tool for counseling patients on the importance of protecting their ears from loud sound to reduce the risk of further damage.


Addressing Concerns of Standing Waves and Reliability Obstacles (More info found in the Hearing Journal linked above):
https://www.ncbi.nlm.nih.gov/pubmed/7642821

"Abstract: Standing waves, in the ear canal are created by the interference of two plane waves of the same frequency traveling in opposite directions. One manifestation of this phenomena is that any lateral motion of the transducer produces a change in the length of the canal and therefore, in general, a change in the sound level at the eardrum. Because of the smaller wavelength at the higher frequencies, the changes produced by movement of the transducer will be larger for the higher frequencies than for the lower frequencies. Thus, when the transducer is removed and replaced between successive threshold estimates, it is expected, from physical principles alone, that the intrasubject reliability of the estimates should be better at the lower frequencies. Previous studies, however, have shown that the intrasubject reliability of threshold estimates is nearly the same at both the low (0-8 kHz) and the high (8-16 kHz) frequency regions. A possible explanation for these anomalous results is proposed. While it is found that transducer placement increases the variability of threshold estimates more at the higher frequencies, it has also been found that conventional headphones reduce the size of the standing wave ratios compared with a hard wall termination. An additional factor is the steeper slope of the psychometric function at the higher frequencies. The combination of these factors produces a standard deviation for threshold estimates that is only about 1 dB larger at the high than at the low frequency region."

https://hal.univ-brest.fr/hal-00742225/document

"1.5. Variability of hearing thresholds:
For most audiological applications, hearing thresholds are obtained with 5-dB resolution in the 125Hz to 8kHz range. Many studies have shown good reliability of repeated threshold measurements in this conventional range[8,9]. The use of 5-dB step sizes was adopted for the majority of these reliability studies, and the variability of hearing thresholds is therefore considered to be approximately 5 dB[10].

However, studies showed that self-recording audiometry (using 1-dB step sizes) resulted in slightly more sensitive thresholds than manual audiometry (sensitivity improved of 1–2 dB) [11]. Finally, investigators have compared threshold reliability between conventional and high-frequency ranges (above 8kHz) and have reported that reliability is equally good in both ranges [12]."


Audiometry Headphones Suggested for Reliability and Repeatability:
https://en-de.sennheiser.com/audiom...-testing-closed-dynamic-ear-protector-hda-300


Extended High Frequency Reliability Across Populations:
https://www.tandfonline.com/doi/abs/10.3109/14992027.2014.893375?src=recsys&journalCode=iija20

"Objective: The aim of the present study was to study patterns in the extended spectrum of the human hearing (0.125 to 20 kHz) in order to obtain reference thresholds. Then, we compare our values with existing results at extended high-frequencies (8 to 20 kHz) in an attempt to establish new standards for potential international adoption. Design: A prospective study in a group of otologically healthy subjects. Study sample: A total of 645 subjects aged between 5 and 90 years were recruited. Pure-tone thresholds were determined for conventional and extended high-frequencies. Results: There was an increase in the hearing thresholds as a function of frequency and age. For the 20 to 69 years old group, thresholds were lower in females than in males, especially at 12.5 and 16 kHz. Our threshold values are comparable to those presented in previous studies that used different instrumentation and populations. Conclusions: When comparing different studies the hearing thresholds were found to be similar. Therefore, it would be possible to establish international standard thresholds."

 

Trust me, we don't want GCF-166.

 

No shit...

 

Forgot to add that Astellas also agreed to fully front the cost of European trials and bringing the drug to the non-US market. Again with no expectation of payment other than royalties on future sales of FX-322 for hearing regeneration only. This is a lot more than an 80 million dollar speculation.

 

For what it's worth, I just called Frequency Therapeutics and was greeted by a nice gentleman who answered the phone, although I believe he was just a third party hired out to manage incoming calls. I was asked name and email, reason for inquiring and told that they would get back to me through email. He had no knowledge of FX-322 himself.

So, they have received my question which is "when are you planning to publish the results of your most recent trial for FX-322?".

I'll certainly keep you all updated the moment I hear back.

 

No doubt, I've been trying to read back and figure that out too? They administered a single dose in a safety study, and people are thinking it's a failure because hearing wasn't restored? I could pop a single aspirin for a brutal hangover too, and it would do nothing, nor would it make me even more sick. Does that mean aspirin doesn't work for a hangover?? Then there's Astellas' investment deal. What am I missing here?

 

A good hedge: if FX-322 works you improve your hearing and tinnitus, and the put expires worthless. If it fails, at least you become rich with the put payoff.

 

I was thinking of Audion and wondering why it is mentioned much less than FX-322. Research is taking place here in London at UCL.

 

Audion is sponsored and financially secured by Eli-Lilly so there is no need to be forthcoming to get the Euros/Dollars in place. Frequency Therapeutics is another story. That's a start-up which needs the dollars and has to go the market place to get it. That's why.

FX-322 does not deplete the supporting cells which the Audion method might. So FX-322 is a bit fancier. But if it works... once in my or your live time for the rest of it... who cares? First come... first gain.

Frequency Therapeutics is hampered by the FDA impediment. So they are risking to run out of money stuck in a false negative. While Audion has the support from a big pharma.

 

I would still believe that the Audion/Regain researchers wouldn't mind to go down in history as the first to produce a hearing regeneration drug, and I don't think all parties involved in Regain would despise the financial success that follows. I don't see why Audion wouldn't give it their best shot. I also like the fact that university and company work together. Perhaps as you say the Frequency guys need to prove themselves more but I don't see why people talk about FX-322 95% of the time and Audion is mentioned only 5%, given the points above.

 

No that's pretty much the gist of it at least.

 

Do we know what the dosage was on the cochlea they pulled out of the cadaver? Or the time they left the cochlea in the solution? Or how it was dispersed within the cochlea? It supposedly worked there?

They all know more than we do at this point and hopefully they have an explanation for the results they got.

Maybe Astellas is just gambling...

But yeah, that's a really good question.

 

I wonder what would make someone write this when Frequency Therapeutics is about 20 employees’ company, where half of the staff can be found on their web page with all the fancy titles - CEO, CMO, CFO, COO, you name it O. What entire staffed research facility you are talking about?

 

They are looking for trial participants, if you're feeling game.

 

Well, if you suffered another acoustic trauma and ruined your chances of recovery you would...

But, you'd surely be more careful and an extra chance, while not as good as infinite chances, is better than no more chances. So I agree, who cares? Enough to poop on this?

 

See my previous post comparing them to Biospecifics. Same sized company, millions in operating costs.

 

Are they still looking? My impression from an email I received was that the recruiting had completed. Also, they say that if one is bothered by tinnitus more than by hearing loss then one does not qualify.

 

A few years ago the CEO of Audion was on the Dutch radio where he explained that the idea was that multiple treatments were possible. So all depends on the number of supporting cells I guess. But let's see that it works anyway.

 

Audion is pretty silent. So yes.

 

Did they suggest you apply for Phase 3 trials, if they go ahead, or is your hearing too 'good' to qualify?

 

Why? I want anything that helps. Anyway, how abaut OTO-413 (or OTO-313)?

 

They just told me all recruiting was complete, but that they will contact me if other opportunities show up.

 

I think for CGF-166 they have to surgically remove your eardrum to apply the treatment before reattaching it.

 

Because they surgically remove the eardrum, use a laser to burn a hole in the cochlea and then inject the hole with a reprogrammed virus to infuse your cells with ATOH1, then put your eardrum back on.

I am actually hopeful about OTO-413, but not so much for OTO-313.

 

Geez. I follow clinical trials constantly, I am also on their mailing list. I had no idea they had even started recruiting.

I shit you not. Next time I'm at home in Boston, I am going to chain myself outside their headquarters and go on a hunger strike until they shoot my ears with some goop. I'll write them tomorrow.

I need a pint of Guinness now... They kept telling me to check the clinical trials... Am I missing something?

 

Are we sure CGF-166 is in phase 3? And of course do we know of any results of phase1/2?

 

Chinmoku was talking about Audion completing recruitment for Phase 2, not Frequency.