Frequency Therapeutics — Hearing Loss Regeneration

[Aleksandar]

Is OTO-413 any better? They have their extended release formula, but I can't find any mention of how deep into the cochlea it goes?

Great question. Is there any information as to which part of the cochlea OTO-313 and OTO-413 reach?

 

[Chad Lawton]

Great question. Is there any information as to which part of the cochlea OTO-313 and OTO-413 reach?

Not sure, I haven't followed Otonomy very closely. I'd put my money on OTO-413 succeeding more over OTO-313 as OTO-413 actually addresses the underlying problem while OTO-313 just addresses the symptoms.

 

[Pete88]

View attachment 46978

Has anyone heard how this thing went?

 

[Trevor_phillips]

Great question. Is there any information as to which part of the cochlea OTO-313 and OTO-413 reach?

Not sure but I do think that Otonomy gel can hit the cochlea from the apex to the base. I'm saying that because OTO-413 has recently proved clinically meaningful improvements in word recognition in noise. So basing on the fact that speech frequencies are almost at the base of the cochlea, I think that their gel have a deep penetrance.

 

[Chad Lawton]

Has anyone heard how this thing went?

I asked if the presentation was available for those who did not attend the conference and the company responded "The presentation is open only to conference registrants."

I looked at the website and it was like $700 to register for a day or something like that.

 

[patorjk]

Is OTO-413 any better? They have their extended release formula, but I can't find any mention of how deep into the cochlea it goes?

According to their latest corporate presentation, they claim their gel delivers high drug levels throughout the inner ear. I remember reading something where they said the gel could help drugs could reach the apex of the cochlea too, but I don't have a reference for that.

Also, in their latest corporate presentation they show charts for 4 responders to the OTO-413 study. The charts show various amounts of improvement at various dB signal to noise ratio levels. I would assume this is only possible if the drug is being delivered to various parts of the cochlea - though I'm out of my wheelhouse on this one so if someone knows for sure feel free to jump in.

What I'm not sure of is if their gel would help FX-322. If it could, I would hope one of the companies would reach out to the other one about a possible collaboration. OTO-6XX is a long ways away, and OTO-413 and FX-322 aren't really competitors.

 

[Jurger]

According to their latest corporate presentation, they claim their gel delivers high drug levels throughout the inner ear. I remember reading something where they said the gel could help drugs could reach the apex of the cochlea too, but I don't have a reference for that.

Also, in their latest corporate presentation they show charts for 4 responders to the OTO-413 study. The charts show various amounts of improvement at various dB signal to noise ratio levels. I would assume this is only possible if the drug is being delivered to various parts of the cochlea - though I'm out of my wheelhouse on this one so if someone knows for sure feel free to jump in.

What I'm not sure of is if their gel would help FX-322. If it could, I would hope one of the companies would reach out to the other one about a possible collaboration. OTO-6XX is a long ways away, and OTO-413 and FX-322 aren't really competitors.

View attachment 47067

What's 'throughout the inner ear'? I want a delivery method that can hit all frequencies of the audiogram (250-8000 Hz).

 

[d'Wooluf]

OTO-413 and FX-322 aren't really competitors.

I think they are pretty much. They're both going for improved clarity. Frequency Therapeutics haven't talked about improving thresholds for a long time.

Collaboration between these small biotechs seems to be nil.

 

[Diesel]

What's 'throughout the inner ear'? I want a delivery method that can hit all frequencies of the audiogram (250-8000 Hz).

That means "all frequencies."

 

[Jurger]

That means "all frequencies."

Can you point me to a source or is that your interpretation of 'throughout'. I find it hard to believe it's accurate, because it's well documented that it's very hard to reach the apex of the cochlea via intratympanic delivery, let alone in stable, therapeutic concentrations.

 

[Diesel]

Can you point me to a source or is that your interpretation of 'throughout'. I find it hard to believe it's accurate, because it's well documented that it's very hard to reach the apex of the cochlea via intratympanic delivery, let alone in stable, therapeutic concentrations.

My first source is the American English language, which is my first language. Which happens to be the native language of the presenters and presumably, creators of this presentation. The use of "throughout" is exchangeable with "everywhere." My second source is the medical description of the "inner ear," which largely includes the whole cochlea. Saying in an investor deck, "reaching all frequencies" requires additional explanation and isn't valuable to the audience. It's shop talk. My third source is the Securities Exchange Commission and its many compliance rules relating to marketing/investor/public communication. This company cannot simply use the term "throughout" without evidence to back it up. Anything they put out to the public must go through regulatory review by a compliance officer of some type, or a 3rd party. This ensures that investors are not misled. Breaking these rules can result in fines, prison time, and/or the revocation of certain licenses by their personnel responsible compliance.

 

[Jurger]

My first source is the American English language, which is my first language. Which happens to be the native language of the presenters and presumably, creators of this presentation. The use of "throughout" is exchangeable with "everywhere." My second source is the medical description of the "inner ear," which largely includes the whole cochlea. Saying in an investor deck, "reaching all frequencies" requires additional explanation and isn't valuable to the audience. It's shop talk. My third source is the Securities Exchange Commission and its many compliance rules relating to marketing/investor/public communication. This company cannot simply use the term "throughout" without evidence to back it up. Anything they put out to the public must go through regulatory review by a compliance officer of some type, or a 3rd party. This ensures that investors are not misled. Breaking these rules can result in fines, prison time, and/or the revocation of certain licenses by their personnel responsible compliance.

View attachment 47073

Why the thin-skinned reaction? It's not like it would be he first time a company overpromises and underlivers in the hearing field.

"Local intratympanic administration into the middle ear would be a preferable option in this case, and the only option for many newly emerging classes of drugs, but it leads to the formation of drug concentration gradients along the extensive, narrow cochlea. The gradients are orders of magnitude and well outside the therapeutic windows."

Local Drug Delivery to the Entire Cochlea without Breaching Its Boundaries (nih.gov)

"Intratympanic administration of drugs relies on their remaining in contact with the round window membrane (RW) (a membranous opening in the bony wall of the cochlea into the middle ear) long enough to allow their diffusion into the perilymph of the scala tympani (ST). The ability of drugs to pass through the RW does not, however, guarantee their sufficient distribution along the cochlear spiral. Drug distribution in the ST is limited by the low flow rate of perilymph within the cochlea and by cochlear geometry. The longitudinal flow of perilymph in the cochlea has been shown to be relatively slow, if present at all (Ohyama et al., 1988), and drug distribution in the perilymph is dominated by passive diffusion. Passive diffusion along the ST is, however, constrained because the cochlea is a relatively long and narrow tube with a cochlear cross-section that decreases gradually from the RW at the base to the apex. It is in the cochlear apex where human speech processing is initiated (e.g., Nuttall et al., 2018) and where drug delivery to the cochlea has greatest potential therapeutic and socioeconomic impact."

Frontiers | Drug Diffusion Along an Intact Mammalian Cochlea | Cellular Neuroscience (frontiersin.org)

"In many of these cases, the drugs are delivered at the basal end of the cochlea, where the highest audible frequencies are detected, around 20 kHz in men. However, the frequencies that matter most for speech range from 300 Hz to 3 kHz and are sensed by hair cells further towards the apical end of the cochlea. This leads to the next stage of the delivery problem: distribution of the drug once it has been administered to the cochlea. Whilst there are methods such as micropumps, which can inject and distribute a drug, most of the current drug delivery methods rely on passive diffusion to reach the mid and apical region. This process is slow, inefficient, and difficult to control or verify."

Steady streaming as a method for drug delivery to the inner ear | Scientific Reports (nature.com)

"In general pharmacokinetics, the term bioavailability is commonly used to describe the rate and extent of drug input. For extracochlear applications, such as intratympanic injections to the round window niche, the percentage of drug entering the inner ear (bioavailability) is relatively low."

Principles of Local Drug Delivery to the Inner Ear - FullText - Audiology and Neurotology 2009, Vol. 14, No. 6 - Karger Publishers

"Thus, intratympanic drug administration faces the fundamental problem of limited passive diffusion within the cochlea, which undermines drug efficiency due to the inability of drugs to reach their targets within the therapeutic concentration window."

Drug distribution along the cochlea is strongly enhanced by low-frequency round window micro vibrati (brighton.ac.uk)

"For instance, IT delivery of drug-loaded gels to the round window niche is reliant upon permeation of compounds through the RWM, a process sensitive to numerous factors including the size, charge, and lipophilicity of the molecule [20,21]. In addition, permeation rates between individuals and between species vary widely, presenting challenges in terms of the number of studies and replicates required to gather reliable data, and for future regulatory approval based on the performance of the delivery technology."

Intracochlear drug delivery systems: a novel approach whose time has come (cilcare.com)​

I can go on, and on, and on. The drawbacks of intratympanic injections are a well documented and fundamental challenge with regards to hearing restoration.

 

[tommyd87]

I don't think it's the dosage that is the issue, it's administration. By using intratympanic injection, the drug is only diffusing into about the first 15% of the cochlea. This was confirmed with both their cochlear implant studies as well as their computer modeling.

The blue shaded region is all the further FX-322 is reaching.

View attachment 47042

Not a lot of sq footage or I should say sq millimeters are dedicated to our high frequency region of hearing. There are about as many hair cells dedicated to the 6,000 Hz to 20,000 Hz range as there are hair cells from the 4,000 Hz to 6,000 Hz range alone. If they can find a method to get it deeper, I really think that is where we would see more significant improvements.

Yes I think that the administration method might end up being the bigger culprit when it comes to the effectiveness of the medicine currently.

There are a plethora of other options obviously to evaluate when it comes to dosing such as slow release gel, bigger volumes and cochlear pumping. Until Frequency Therapeutics evaluates these though, there is no definitive evidence that the dosing is the problem.

Is OTO-413 any better? They have their extended release formula, but I can't find any mention of how deep into the cochlea it goes?

\
The incredibly difficult thing with OTO-413 is that the depth of the treatment is hard to measure because synapses are actually across all areas and you cannot measure them at a specific point or with a single metric like you could with a specific frequency tone or sound.

Subsequently successful outcomes from medicine like OTO-413 etc may indicate it is working widely when injected, however until a treatment like OTO-6XX which can be measured specifically provides beneficial results, it is incredibly difficult to definitively answer such a question.

 

[Diesel]

Why the thin-skinned reaction? It's not like it would be he first time a company overpromises and underlivers in the hearing field.

"Local intratympanic administration into the middle ear would be a preferable option in this case, and the only option for many newly emerging classes of drugs, but it leads to the formation of drug concentration gradients along the extensive, narrow cochlea. The gradients are orders of magnitude and well outside the therapeutic windows."

Local Drug Delivery to the Entire Cochlea without Breaching Its Boundaries (nih.gov)

"Intratympanic administration of drugs relies on their remaining in contact with the round window membrane (RW) (a membranous opening in the bony wall of the cochlea into the middle ear) long enough to allow their diffusion into the perilymph of the scala tympani (ST). The ability of drugs to pass through the RW does not, however, guarantee their sufficient distribution along the cochlear spiral. Drug distribution in the ST is limited by the low flow rate of perilymph within the cochlea and by cochlear geometry. The longitudinal flow of perilymph in the cochlea has been shown to be relatively slow, if present at all (Ohyama et al., 1988), and drug distribution in the perilymph is dominated by passive diffusion. Passive diffusion along the ST is, however, constrained because the cochlea is a relatively long and narrow tube with a cochlear cross-section that decreases gradually from the RW at the base to the apex. It is in the cochlear apex where human speech processing is initiated (e.g., Nuttall et al., 2018) and where drug delivery to the cochlea has greatest potential therapeutic and socioeconomic impact."

Frontiers | Drug Diffusion Along an Intact Mammalian Cochlea | Cellular Neuroscience (frontiersin.org)

"In many of these cases, the drugs are delivered at the basal end of the cochlea, where the highest audible frequencies are detected, around 20 kHz in men. However, the frequencies that matter most for speech range from 300 Hz to 3 kHz and are sensed by hair cells further towards the apical end of the cochlea. This leads to the next stage of the delivery problem: distribution of the drug once it has been administered to the cochlea. Whilst there are methods such as micropumps, which can inject and distribute a drug, most of the current drug delivery methods rely on passive diffusion to reach the mid and apical region. This process is slow, inefficient, and difficult to control or verify."

Steady streaming as a method for drug delivery to the inner ear | Scientific Reports (nature.com)

"In general pharmacokinetics, the term bioavailability is commonly used to describe the rate and extent of drug input. For extracochlear applications, such as intratympanic injections to the round window niche, the percentage of drug entering the inner ear (bioavailability) is relatively low."

Principles of Local Drug Delivery to the Inner Ear - FullText - Audiology and Neurotology 2009, Vol. 14, No. 6 - Karger Publishers

"Thus, intratympanic drug administration faces the fundamental problem of limited passive diffusion within the cochlea, which undermines drug efficiency due to the inability of drugs to reach their targets within the therapeutic concentration window."

Drug distribution along the cochlea is strongly enhanced by low-frequency round window micro vibrati (brighton.ac.uk)

"For instance, IT delivery of drug-loaded gels to the round window niche is reliant upon permeation of compounds through the RWM, a process sensitive to numerous factors including the size, charge, and lipophilicity of the molecule [20,21]. In addition, permeation rates between individuals and between species vary widely, presenting challenges in terms of the number of studies and replicates required to gather reliable data, and for future regulatory approval based on the performance of the delivery technology."

Intracochlear drug delivery systems: a novel approach whose time has come (cilcare.com)​

I can go on, and on, and on. The drawbacks of intratympanic injections are a well documented and fundamental challenge with regards to hearing restoration.

Why the personal attack? Thanks for flexing the PubMed search? None of them cover Otonomy's formula in an independent research setting, so it's not all that useful of an argument to paste all that. Other problem is, just because something is difficult or challenge, doesn't make it impossible. Otonomy clearly has their delivery gel patented, so they only have knowledge and research to back up their claims.

 

[tommyd87]

Why the personal attack? Thanks for flexing the PubMed search? None of them cover Otonomy's formula in an independent research setting, so it's not all that useful of an argument to paste all that. Other problem is, just because something is difficult or challenge, doesn't make it impossible. Otonomy clearly has their delivery gel patented, so they only have knowledge and research to back up their claims.

Interestingly multiple of these papers don't actually rule out the use of intratympanic injections totally and also point to issues such as the technique and substance used among other factors as being the issue.

 

[tracyNYC]

There's a virtual R&D Event for investors on November 9.

https://frequencytx.gcs-web.com/2021_Virtual_R-D_Event

 

[Street Novelist]

I bet they won't have a new trial before the year ends. It's already mid-October. Recruitment takes months. Hopefully they reveal the results from the severe trial.

 

[Lucifer]

I bet they won't have a new trial before the year ends. It's already mid-October. Recruitment takes months. Hopefully they reveal the results from the severe trial.

I really hope these next set of trials are going to be at the maximum a year for each phase. I can't believe Audion/Regain Phase 2b trial is going to start September 2022 and finish in 2025. It is fucking ridicolous.

 

[Chad Lawton]

I bet they won't have a new trial before the year ends. It's already mid-October. Recruitment takes months. Hopefully they reveal the results from the severe trial.

They have been saying since June that they would initiate a new Phase 2 trial by end of year so I'm sure recruiting will begin by then but they probably won't have their final subject enrolled until 1st half of next year.

 

[Amv]

I still think, apart from Prof. Tzounopoulos, that the best treatment for the mid term will be neuromodulation, and probably long term will be pharma and Frequency Therapeutics. But something is saying me they will need to do more research.

But neuromodulation looks promising.

 

[Jack V]

The troubles with the outcomes appear on face value to stem from the way they determined the participants much more so that with the dosing.

No - the troubles with the outcomes appear on face value to stem from the fact that the drug didn't work.

Everything else is conjecture.

 

[tommyd87]

No - the troubles with the outcomes appear on face value to stem from the fact that the drug didn't work.

Everything else is conjecture.

Is that why Frequency Therapeutics had successful outcomes/measures from both in vivo and their single dose trials then?

That doesn't flat out demonstrate that the drug did not work.

 

[Jurger]

No - the troubles with the outcomes appear on face value to stem from the fact that the drug didn't work.

Everything else is conjecture.

The stock could tank even further and people here will tell you it's all part of Lucchino's Grand Plan. The truth is, of course, that they haven't got it (yet?).

 

[Diesel]

The stock could tank even further and people here will tell you it's all part of Lucchino's Grand Plan. The truth is, of course, that they haven't got it (yet?).

Again with the sensationalism?

 

[Philip83]

They're not giving up at least:

Frequency Therapeutics Announces First Subject Dosed in FX-322 Phase 2b Acquired Sensorineural Hearing Loss (SNHL) Study and FDA Agreement on Speech Perception as Primary Endpoint

 

[Jurger]

They're not giving up at least:

Frequency Therapeutics Announces First Subject Dosed in FX-322 Phase 2b Acquired Sensorineural Hearing Loss (SNHL) Study and FDA Agreement on Speech Perception as Primary Endpoint

By now I'm more interested in their R&D efforts than a drug that's not designed to improve pure tone average, not even the extended range. Based on their previous trial, any speech perception gains you make might not even last that long.

 

[Gb3]

They're not giving up at least:

Frequency Therapeutics Announces First Subject Dosed in FX-322 Phase 2b Acquired Sensorineural Hearing Loss (SNHL) Study and FDA Agreement on Speech Perception as Primary Endpoint

They've already started contacting people a couple months ago regarding the trial.

 

[Diesel]

By now I'm more interested in their R&D efforts than a drug that's not designed to improve pure tone average, not even the extended range. Based on their previous trial, any speech perception gains you make might not even last that long.

I don't know about a lot of people here, but I'd much rather be able to communicate with other people better (speech recog) than be able to hear 7 - 10 computer generated beeps in pure silence; even if that meant paying my local ENT an annual visit to get re-up on my hearing regen drug.

 

[rei]

I don't know about a lot of people here, but I'd much rather be able to communicate with other people better (speech recog) than be able to hear 7 - 10 computer generated beeps in pure silence; even if that meant paying my local ENT an annual visit to get re-up on my hearing regen drug.

I agree, with the exception of a situation where a large truck is about to back into you and you don't hear the beeps.

 

[Pharz]

I don't know about a lot of people here, but I'd much rather be able to communicate with other people better (speech recog) than be able to hear 7 - 10 computer generated beeps in pure silence; even if that meant paying my local ENT an annual visit to get re-up on my hearing regen drug.

Assuming that this would be a solution, I wonder how many times an eardrum can be punctured with a needle.