Frequency Therapeutics — Hearing Loss Regeneration

I guess there is still a lot of aspects to improve beyond the mere drug effectiveness, like dosages, frequency, continuous treatment... Hope after the second trial they will improve much more all of them. By purely reading the statistical and clinical percentages I cannot feel excited but the fact it got Fast Track and their public exposure makes me think they have a lot of stuff under the hood to unveil yet.
 
Suppose the initiation of a new hair cell's genesis causes a set of unique growth factors to be secreted from the supporting cell that initiates neurogenesis and neuritogenesis which is what causes the underlying nerves to grow and reconnect in the first place. I understand that there are more supporting cells than hair cells and if true, then FX-322 could cause supernumerary hair cells which would still induce the downstream neuronal improvements. Right?
This is a really interesting thought. I want to look more into this.
I get that some people in the current trial will receive four doses. Do we know for sure that each dose will have a higher concentration of active ingredients than the phase 1b doses? They've said in the past that a larger dose volume probably wouldn't make any difference.
I was told in my interview for the trial it's a higher dose/more drug at each dosing.
 
I also bumped into this article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660910/

"The results suggest that the presence of subjective tinnitus may not be strongly associated to outer hair cell impairment, at least where hearing impairment is evident"

Damn, if the study is right, it means hair regeneration per se could not mean tinnitus cure?

I think I must stop reading about this.
 
I also bumped into this article:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660910/

"The results suggest that the presence of subjective tinnitus may not be strongly associated to outer hair cell impairment, at least where hearing impairment is evident"

Damn, if the study is right, it means hair regeneration per se could not mean tinnitus cure?

I think I must stop reading about this.
From the paper:

"Psychophysical assessments were made of (1) absolute thresholds, (2) compression and (3) frequency selectivity on the assumption that OHC dysfunction would be reflected in both reduced compression and reduced frequency selectivity."

@FGG I'm not familiar with this method of identifying OHC dysfunction. Could you take a look? They even call it an assumption but I'm curious to learn more. I haven't seen this in any other paper I've come across.

"Rather it is more likely that an explanation is to be found with IHC dysfunction or reduced innervation of the auditory nerve (Kujawa and Liberman 2009)."

He's basically trying to corroborate the hypothesis that tinnitus is a result of synaptopathy instead of OHC damage/loss.

So worst case scenario is we look to synapse repair instead of OHC.
 
From the paper:

"Psychophysical assessments were made of (1) absolute thresholds, (2) compression and (3) frequency selectivity on the assumption that OHC dysfunction would be reflected in both reduced compression and reduced frequency selectivity."

@FGG I'm not familiar with this method of identifying OHC dysfunction. Could you take a look? They even call it an assumption but I'm curious to learn more. I haven't seen this in any other paper I've come across.

"Rather it is more likely that an explanation is to be found with IHC dysfunction or reduced innervation of the auditory nerve (Kujawa and Liberman 2009)."

He's basically trying to corroborate the hypothesis that tinnitus is a result of synaptopathy instead of OHC damage/loss.

So worst case scenario is we look to synapse repair instead of OHC.
I'm not sure what they mean by psychophysical measurements. The paper seems to say that while OHC loss, especially in high frequencies, tends to happen in tinnitus patients, not all tinnitus patients have this.

The author seems to conclude that means tinnitus results from IHC dysfunction (which Frequency seems to also address) or synapse loss. The author is trying to point to a universal cause and I don't agree with that. I don't think you will find that IHC loss or synaptopathy can cause tinnitus universally (or everyone with tinnitus would have speech in noise problems, etc). I think interrupting the signal from any structure can cause tinnitus of inner cochlea origin. Why some people get tinnitus from these injuries IMO has a lot to do with the suddenness of the insult and the degree of neuro excitation and plasticity (suddenness would contribute more to maladaptive plasticity).
 
And is there any drug in the pipeline for that?
I'm happy to say that yes, there is! But from different companies. We have PIPE-505, OTO-413, and the Hough Pill. And Charles Liberman (the author that the paper is quoting) is actually a founder of Decibel Therapeutics who is in preclinicals for a tinnitus/peripheral neuropathy drug.
 
Actually now reading this, I'm not so sure:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927105/

It seems close to 100% of people who have had Cisplatin have had ultra high frequency audiogram changes. Cisplatin is also known to cause inner hair cell (IHC) damage extensively too yet only about a third get tinnitus.

The only thing I can think of is the fact that Cisplatin ototoxicity is not as sudden as other toxins and you can get hearing loss even months after your last dose.

In this paper, (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912237/) greater than 73% of people with sudden idiopathic hearing loss got tinnitus. The suddenness has to be a huge part of the maladaptive neuroplasticity. If it were possible to slowly lose a limb, I imagine there would be less phantom limb, too.

But if tinnitus of cochlear origin were tied to one location as a cause: OHC, IHC or synapse for instance, wouldn't the histology on rodents in tinnitus studies have shown this already? Wouldn't we all have more similar hearing issues to each other?

I would love to hear other view points but I think tinnitus of cochlear origin is multifactorial and even multi etiological in terms of what is damaged.
 
I'm happy to say that yes, there is! But from different companies. We have PIPE-505, OTO-413, and the Hough Pill. And Charles Liberman (the author that the paper is quoting) is actually a founder of Decibel Therapeutics who is in preclinicals for a tinnitus/peripheral neuropathy drug.
When do you expect Decibel Therapeutics will start phase I trials? Next year?
 
When do you expect Decibel Therapeutics will start phase I trials? Next year?

I'm sorry to say they are probably at least a few years off. They are currently heavily focused on their Cisplatin drug. There's a lot of money to be had there, and Cisplatin results in horrendous hearing problems. Believe me, protecting against Cisplatin poisoning would be a lifesaver for those undergoing chemo.

I'm hoping that once they move to phase 1 on that (which they should very soon) they will accelerate their work on their peripheral neuropathy compound.

But in the meantime PIPE-505 should work extremely well for us. They have full cochlear penetrance and NT3 levels of therapeutic benefit.
 
You think if efficacy data is clearly expressed from stage 2 they'll eschew the placebo group in phase 3?
Phase 3 is generally novel treatment vs status quo. Since there is no statuses quo treatment for hearing loss I'm not sure how it will work. Anyone here in the know of that sort of thing?
 
Literally just hearing aids.
I am very curious how they are going to test in phase 3 that it is "at least as safe and effective as existing treatments" as is usually done in phase 3. Part of me wonders if they would be able to skip phase 3 for this reason but maybe I'm being overly optimistic.
 
I am very curious how they are going to test in phase 3 that it is "at least as safe and effective as existing treatments" as is usually done in phase 3. Part of me wonders if they would be able to skip phase 3 for this reason but maybe I'm being overly optimistic.
There is precedent of this happening.
https://www.forbes.com/sites/aroy/2...-after-phase-ii-a-response-to-matthew-herper/

See the above link for the description of the 'conditional approval process'. This does happen.

This might also be referred to as rolling review.

Also see the link below to confirm that this has also happened 30 times in the EU:
https://www.bmj.com/content/357/bmj.j2062
 
How likely would it be approved for secondary outcomes, even if this conditional approval is granted? I'd say this is pretty doubtful, unless there is some insane efficacy data for tinnitus improvement/remission—but even then, they're measuring THI for this outcome rather than more direct measures like MML. While there is some chance that it'd be granted for hearing loss, I'm not so sure about approval for tinnitus patients.
 
How likely would it be approved for secondary outcomes, even if this conditional approval is granted? I'd say this is pretty doubtful, unless there is some insane efficacy data for tinnitus improvement/remission—but even then, they're measuring THI for this outcome rather than more direct measures like MML. While there is some chance that it'd be granted for hearing loss, I'm not so sure about approval for tinnitus patients.
It doesn't have to ever be approved for tinnitus even if super effective. You would just have to pay out of pocket to use it for tinnitus.

Lots of drugs are like this.
 
I don't think FX-322 will ever be labelled for tinnitus because hearing issues aren't covered by insurance currently anyway. They just need the drug labelled for *something* and word scores and audiograms are more rigorous data points for the FDA. But it truly doesn't matter:

https://en.wikipedia.org/wiki/Off-label_use

The exception for this would be if something like the Seniors Have Eyes Ears and Teeth Act actually passes because then a separate trial to specifically get it labelled for tinnitus (instead of just tacking on an experimental arm to let doctors know if it works for this so they can use it off label) would pay for itself with Medicare funds.
 
I've worked for a health insurance company for 15 years.

It's not really correct that "hearing issues aren't covered by insurance". Hearing aids themselves are generally a contract exclusion but insurance covers audiograms, medication, or surgery if needed. It's similar in that insurance won't cover eyeglasses but will cover cataract surgery.

Insurance companies also don't particularly care, or even know, if a drug is prescribed off label for something. They're more interested in making sure that people aren't getting brand names when there's a generic available for the same condition.
 
I've worked for a health insurance company for 15 years.

It's not really correct that "hearing issues aren't covered by insurance". Hearing aids themselves are generally a contract exclusion but insurance covers audiograms, medication, or surgery if needed. It's similar in that insurance won't cover eyeglasses but will cover cataract surgery.

Insurance companies also don't particularly care, or even know, if a drug is prescribed off label for something. They're more interested in making sure that people aren't getting brand names when there's a generic available for the same condition.
They don't cover off label drugs so wouldn't they know what is and not off label?

Do you think they would cover tinnitus drugs in your opinion then?
 
This is a really interesting thought. I want to look more into this.

I was told in my interview for the trial it's a higher dose/more drug at each dosing.
Did they convey how much they increased the concentration from the phase 1b trial, or did they convey how much they're increasing the volume?

I've looked extensively to find this information and haven't come across anything in writing yet.
 
Did they convey how much they increased the concentration from the phase 1b trial, or did they convey how much they're increasing the volume?

I've looked extensively to find this information and haven't come across anything in writing yet.
She would not give me specifics since it's not public information and I didn't qualify so I didn't sign the NDA. She just told me it's significantly more. I do know that 25% of the study participants also get that dose 4x.
 
Did they convey how much they increased the concentration from the phase 1b trial, or did they convey how much they're increasing the volume?

I've looked extensively to find this information and haven't come across anything in writing yet.
She would not give me specifics since it's not public information and I didn't qualify so I didn't sign the NDA. She just told me it's significantly more. I do know that 25% of the study participants also get that dose 4x.
That might change in the future once technologies are developed to deliver more efficient payloads directly to the inner ear with less waste and relinquishing the need for puncturing the ear drum. See: https://otomagnetics.net/technology

 
She would not give me specifics since it's not public information and I didn't qualify so I didn't sign the NDA. She just told me it's significantly more. I do know that 25% of the study participants also get that dose 4x.
English isn't my native language but is FX-322 for noise-induced tinnitus as well?
 
English isn't my native language but is FX-322 for noise-induced tinnitus as well?
If certain kinds of hearing loss are causing your tinnitus, then yes that's what is being tested in the experimental arm of this study. The idea is that if you restore the lost connection, the same neuroplasticity can readjust to normal input again. An often used analogy is like "phantom limb" syndrome.

The hearing loss should be resulting from hair cell death for this to help (sometimes these changes are only evident on an extended audiogram). Other regenerative drugs being tested (e.g.. Otonomy's BDNF drug or Pipeline's synaptopathy drug may help cases where the audiogram is normal but there is still cochlear damage to the synapses).
 

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