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It is also noteworthy that tinnitus can develop from just reduced auditory input such as with earwax, sound deprivation etc. with no injury from sound or toxins.

Seems difficult then to tease out the relative contribution of NMDA activation and OHC loss to tinnitus generation by salicylate.

Another study with no surprises linking hearing loss and tinnitus/hyperacusis. Review: Neural Mechanisms of Tinnitus and Hyperacusis in Acute Drug-Induced Ototoxicity

Heck, why not recruit all unilateral, high frequency tinnitus subjects to stack the deck.

Below is an estimation of the number of subjects in Phase 2a who will report tinnitus improvement: Total = 96 Non-placebo = 72 Estimated 70% have tinnitus = 50 Estimated 50% have unilateral tinnitus = 25 (only one ear injected, untreated ear still ringing) Estimate 50% require 2 or more...

Unfortunately, Will McLean's highly informative YouTube "Toward a Cure for Hearing Impairment" has been removed. Wished I had at least recorded the audio. Probably too many forward looking statements.

More evidence linking hearing loss, brain plasticity and tinnitus: Tinnitus-like “hallucinations” elicited by sensory deprivation in an entropy maximization recurrent neural network

Below is Dr Lustig's audio snippet from presentation around 1:16:30. He made no mention of hearing loss leading to tinnitus nor of hearing restoration's effects on said disorder. Sounds like he has felt powerless for so long to help countless patients with this that he's given up on it...

Firstly, let's talk about the stock, one of the few times in life that free $$ was staring you in the face. Having researched FX-322 to death I bought a ton following the IPO and I'm risk averse (still rather have no tinnitus than 8 figures though). Secondly, Dr Lustig's reply concerning...

I tend toward predicting a product launch late 2022 if endpoint results are met in the the three currently running trials with no adverse effects. That does put some faith in the FDA to do their job in a timely fashion and award Breakthrough Therapy designation. If tinnitus results are also...

Animal models apparently could not withstand multidosing (presume anatomical differences) but human subjects can. Good news if multiple injections yields proportionately better results.

Attached below is an MP3 of today's webcast (Q&A only since the initial part was just a review of company's online presentation). I learned that they were unable to multi-dose in their animal studies due to membrane vulnerabilities. The tone was rather zip-lipped though; as it should be given...

Here is a screenshot I took from the WSJ article a while back:

Quoting a Wall Street Journal article: “Fast track drugs often go to market after phase 2” I believe Frequency Therapeutics added the two additional studies to substantiate this. This is a huge unmet critical need.

With bilateral tinnitus cases comprising 39% and patients reporting poor localization at approximately 8%, TFI scores in the aggregate will not reflect the drug's full potential from treating only one ear. Characterization of Tinnitus in Different Age Groups: A Retrospective Review

In order to arrive at a better understanding of what FX-322 can do for tinnitus, they really needed to shoot up both ears in Phase 2a. Results will fall short of the drug’s potential.

I am revisiting @Diesel's post regarding the audiogram differences between having tinnitus and not. This is, I believe, a pivotal finding. His chart may have answered a question I previously posited on this forum: "The evidence overwhelmingly points to tinnitus as a maladaptive manifestation...

Below is an excerpt from an article posted by @annV which suggests a link between improvement of SNHL and reducing/eliminating tinnitus. More evidence in support of FX-322.

Variations in susceptibility to tinnitus can certainly be attributed to sound processing variations among the population. An example would be tone deafness and the ability to recognize perfect pitch. Latest theories regarding tinnitus include the stochastic model of auditory central gain, of...

Tinnitus improves with 83% of patients following tympanoplasty, a procedure which can restore function of the tympanic membrane and improve hearing. So yes neuroplasticity is reversible. Also, tinnitus outcomes in Phase 2a will likely fall short for subjects with bilateral hearing loss/tinnitus...

Our expectations regarding tinnitus results from phase 2a need to be tempered with the fact that subjects are being treated unilaterally. Although tinnitus manifests a slight majority of time unilaterally, bilateral hearing loss sufferers may not have any reduction in their TFI scores. I can...

Attached below is a link and snapshot to an article (Wall Street Journal) describing drug approval. There is a chance that the drug can go to market after phase 2. Fast-Track Drug Approval, Designed for Emergencies, Is Now Routine

As the gel solidifies it must be positioned against the cochlea, if the patient swallows during this time period or the IT injection is misplaced I believe that could impact the treatment. I was merely listing the possible impediments to full hearing restoration with FX-322.

There are several limiting factors such as the drug's diffusion through the round window, whether the gel was positioned properly against the round window, whether there are viable progenitor cells within the cochlea, and whether the newly generated hair cells make the appropriate synaptic...

They got a doubling of the normal HC count in intact cochlea as revealed by Will McLean (18:29). I'm thinking a "damage signal" from adjacent HCs is not required to activate LGR5s. Or, maybe LGR5s are more receptive adjacent to a damaged/missing HC.

I thought the drug only activates the LGR5 cells which are usually dormant and are proximal to damaged and undamaged hair cells. If there is cross signaling between these two types of cells is an interesting question. If not then the action may occur regardless of the health of the local hair...

There may be many more "small molecules" in FX-322 than there are receiving sites in the cochlea; it's just they are not getting deep enough diffusion. Let's use Sodium Valproate as an example since it's one of the small molecules in the cocktail. Molecular Weight 166.19g/mol A typical drug...

Here are 2 adjacent tones at 8000Hz with a 15 dB difference (one subject was tested with that difference from baseline). Be sure to turn system volume down before playing since the 2nd tone is much louder. My informed albeit unscientific opinion is that gaining 10-15 dB of hearing...

I am reposting this link and excerpt supporting the notion that regenerating OHCs will help with hyperacusis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383716/

Below is an 8000 Hz pure tone which changes upward 10 dB. It's significant. Be sure to turn your system volume down before playing.

How much a single ear treatment will improve bi-lateral tinnitus should be considered in the phase 2a study. There may not be stellar results until both ears are treated.

It is interesting that in their updated August corporate presentation on their website they have decreased the frequency of action down to around 6500 Hz from 8000 Hz according to the graphic on page 17. They may have updated that number based on reviewing the still blinded results from phase 2a.

Below is a study with a few attached excerpts detailing link between SNHL and tinnitus including correlation of intensity. https://www.frontiersin.org/articles/10.3389/fnins.2020.00592/full

Getting into a clinical trial means maybe a few squirts of placebo, and if you happen to get the drug it will probably be in only one ear which may not help bilateral tinnitus. The probability is much greater than 0.01% that by 2023 we should have access to FX-322 and it will bring relief to...

Why regenerating functional hair cells looks so promising: https://www.sciencedirect.com/science/article/pii/S0929664615003848

With the prospect of a reformulation to reach lower frequencies and zero depletion of progenitor cells (numerous dosage potential) FX-322 may exceed your expectations.

Studies have indicated that when hearing is restored there is a correlated reduction in tinnitus. For example: 82.6% of patients had improvement or elimination of tinnitus after tympanoplasty. https://www.scielo.br/pdf/rboto/v73n3/en_a14v73n3.pdf Also, cases where the auditory nerve is...

In phase 2a they are giving 4 injections which should demonstrate deeper diffusion into the cochlea resulting in lower frequency restoration. The drug has shown to regenerate functional OHCs and IHCs; even a modest db boost using the natural biology of the inner ear and the modulating effect of...

Within this paper there is evidence that OHC regeneration may be helpful for hyperacusis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383716/

Not sure if anyone previously posted this study. Again, we see the positive effects of hearing restoration on tinnitus: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971248/

It does seem plausible that repopulating with functioning IHC/OHCs will increase signal gain, thereby inhibiting tinnitus. We shall find out more when phase 2a results are released.

I know many of us are looking for reasons that FX-322 may not work but I think it's important to review a few things. Tinnitus is merely a symptom of reduced auditory input incurred somewhere along the signal path. Central gain is compensatorily turned way upwards resulting in perception of...

I think it is important to recognize some possibilities with FX-322 and its probable impact on tinnitus. It is likely that the diffusion with multiple dosages will, with increases in time and concentration, reach to lower frequencies. It is also likely that there are a few progenitor cells...

A question was asked about whether FX-322 would reduce tinnitus and this was my reply: "If your hair cell damage and corresponding tinnitus is > 6000Hz, I would say very high. As they are doing multiple consecutive dosages in the current study we may see lower frequencies restored with deeper...

In intact cochleae they got a doubling of IHC and OHCs which indicated a limiting or clamp down factor on the regeneration process. See Will McLean's YouTube around 18:00:

If phase 2a gets top line results then hopefully that will trigger scaled up production which may allow for expanded access. It will be pricey more than likely (revenue stream) and could be a windfall as far as positive exposure for the drug even before FDA approval. Well it’s fun to dream of...

I remember in their mouse studies they used an ototoxic substance to destroy hair cells and FX-322 worked very well on those cochleae.

From Frequency's paper below. Cell Rep. 2017 February 21; 18(8): 1917–1929. doi:10.1016/j.celrep.2017.01.066. Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells They grew both types in the adult mouse cochlea:

I would not worry about Frequency Therapeutics not testing for tinnitus-related efficacy, with such a varied etiology I believe adding tinnitus would complicate their clinical studies needlessly. Expanding their market with a supplemental indication will be easier once FX-322 is approved for...

Below is a link to a paper on the stochastic resonance model of tinnitus; claiming reduced auditory input as the main culprit. More promising info for the potential of FX-322 to curb tinnitus. https://www.biorxiv.org/content/10.1101/2020.03.27.011163v1.full.pdf

Speech contains a high percentage of frequencies above 6000 Hz. Interestingly, most hearing aids top at this frequency which makes them limited with understanding speech clarity. See link below page 17: https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1

Go to the link below and match your tinnitus tone by adjusting the frequency slider of the oscillator. If your sound is hissing or fuzzy it will be difficult to get a matchup though. https://www.generalfuzz.net/acrn/

If your hair cell damage and corresponding tinnitus is > 6000Hz, I would say very high. As they are doing multiple consecutive dosages in the current study we may see lower frequencies restored with deeper diffusion levels. It may be for some that only a small threshold improvement might be...

Below is a link to a study whereby 82.6% of patients had improvement or elimination of tinnitus after tympanoplasty. Just another example of hearing restoration's effects on tinnitus and why FX-322 is so promising...

Luckily for us, FX-322 appears to regenerate hair cells regardless of the state of existing cells.

Unless I've misunderstood the process, FX-322 causes clonal expansion of Lgr5 cells (progenitors) and then converts them into IHC and OHCs with full synapse machinery. There is no repair of existing hair cells.

Will McLean, Ph.D. addresses this in an excerpt attached below from a presentation on YouTube:

There are many articles supporting the notion that restoration of hearing in the offending frequencies will reverse the maladaptive plasticity causing tinnitus. Tinnitus caused by temporary hearing loss nearly always resolves. https://www.hindawi.com/journals/criot/2012/210707/

In a previous Q and A the question was asked about benefits seen in secondary endpoints (of which one is tinnitus); the reply was "We saw trends across the population." We can reasonably assume that a tinnitus reduction was reported by one or more subjects since it is unlikely that they would...

Regarding FX-322 and its uniqueness among the vast majority of drugs which are typically injected into tissue, sometimes intravenously, or taken orally. Since they are not assessing systemic levels of the drug in phase 2a, their concern for possible adverse events seems limited to local...