Frequency Therapeutics — Hearing Loss Regeneration

[Princebeyel]

I'm sorry to keep asking the same question but can someone please answer me?

Where have they stated they are now also looking to test FX-322 on severe hearing loss patients and is that a separate trial to their current one? I can't find any info on this.

Yes it is separate and it hasn't started yet. I'm going to try and get into it. It's supposed to start this quarter so hopefully they will start recruiting very soon!

 

[wwtsai]

I'm sorry to keep asking the same question but can someone please answer me?

Where have they stated they are now also looking to test FX-322 on severe hearing loss patients and is that a separate trial to their current one? I can't find any info on this.

From their most recent press release:

"FX-322 Phase 1b study in patients with severe SNHL (ages 18-65): This study is expected to start this quarter and the complete data readout is anticipated in Q3 2021."

Source: https://frequencytx.gcs-web.com/new...erapeutics-announces-expanded-fx-322-clinical

 

[Piney]

Finally, a trial those who have severe hearing loss have a chance to enter.

EDIT: Nevermind, the criteria says the trial is open only to those in the upper age spectrum. Still waiting.

 

[Princebeyel]

From their most recent press release:

"FX-322 Phase 1b study in patients with severe SNHL (ages 18-65): This study is expected to start this quarter and the complete data readout is anticipated in Q3 2021."

Source: https://frequencytx.gcs-web.com/new...erapeutics-announces-expanded-fx-322-clinical

Really it makes me wonder if FX-322 is in fact working as intended and they've seen huge success with it! Why else would they start two more trials?

 

[tbuzz89]

This may be a bit off the beaten path and "unscientific," but the fact that Frequency Therapeutics' website has been redesigned a bit and contains more information regarding the specifics of hearing loss than it did when I first browsed it back in May seems like even more encouragement that they know they have something good coming down the line.

Or maybe it's just me being overly optimistic.

 

[dan]

@FGG not sure if this was asked before, how can drugs cause ototoxicity by reaching the cochlea and destroying hearing cells, but a drug like FX-322 cannot reach if injected into the ear? Thanks.

 

[Koz]

From their most recent press release:

"FX-322 Phase 1b study in patients with severe SNHL (ages 18-65): This study is expected to start this quarter and the complete data readout is anticipated in Q3 2021."

Source: https://frequencytx.gcs-web.com/new...erapeutics-announces-expanded-fx-322-clinical

Thank you. Shame that these are just safety studies (phase 1b) for severe SNHL and age-related SNHL.

Please correct if I'm wrong but this study is the one that will lead to their final mass/largest population study for efficacy in all populations (except profound hearing loss), right?

If that's the case, it would seem that a hope of this working for those in the severe hearing loss range might be in May 2021 but a full confirmation (if it works) would be in 2022?

I am mostly in the severe hearing loss range so will keep an eye on OTO-6XX as well in the meantime.

 

[Diesel]

Thank you. Shame that these are just safety studies (phase 1b) for severe SNHL and age-related SNHL.

Please correct if I'm wrong but this study is the one that will lead to their final mass/largest population study for efficacy in all populations (except profound hearing loss), right?

If that's the case, it would seem that a hope of this working for those in the severe hearing loss range might be in May 2021 but a full confirmation (if it works) would be in 2022?

I am mostly in the severe hearing loss range so will keep an eye on OTO-6XX as well in the meantime.

See link to the Age-Related Phase 1B -

FX-322 in Adults With Age-Related Sensorineural Hearing Loss

It is more than a typical safety study. The secondary outcomes are the same assessments of hearing function as the on-going Phase 2A.

If the 90-day Phase 2A results look promising in Q1-2021; I would be very hopeful for those with Age-Related or Severe hearing loss would stand to see some kind of benefit from FX-322.

 

[sssing]

Really it makes me wonder if FX-322 is in fact working as intended and they've seen huge success with it! Why else would they start two more trials?

I pray it be so!!

 

[tommyd87]

See link to the Age-Related Phase 1B -

FX-322 in Adults With Age-Related Sensorineural Hearing Loss

It is more than a typical safety study. The secondary outcomes are the same assessments of hearing function as the on-going Phase 2A.

If the 90-day Phase 2A results look promising in Q1-2021; I would be very hopeful for those with Age-Related or Severe hearing loss would stand to see some kind of benefit from FX-322.

I am simply guessing but I think that there is a possibility that Frequency Therapeutics has identified that FX-322 will work with a much broader range of cases than just those that were identified in the initial trial. It should theoretically work because by right as long as you can regenerate hearing you should simply stand to benefit from FX-322.

 

[FGG]

@FGG not sure if this was asked before, how can drugs cause ototoxicity by reaching the cochlea and destroying hearing cells, but a drug like FX-322 cannot reach if injected into the ear? Thanks.

I'm going to over simplify this a bit here because it actually involves quite a bit of biochemical but the gist is that different oral and systemic drugs have different volume of distributions (Vd):

https://en.wikipedia.org/wiki/Volume_of_distribution

(Which is basically an equation for how well it leaves blood and goes into tissues).

Drugs with a higher Vd need a lower dose to get in the "nooks and crannies".

Related is peak plasma levels. That's why IV antibiotics cause way more damage than oral antibiotics.

Liver and kidney metabolism is a factor too but that's a whole extra layer of complication that depends on both health state and Cytochrome genes.

There is also a blood cochlear layer (just like a blood brain barrier) which has specialized endothelial cells that try to "keep out" blood substances so the cochlea is a more protected site.

Very few drugs can get around this hurdle systematically unless they are given in large or prolonged quantities or have excellent cochlear penetrance (typically small, not overly polar molecules).

Ebselen (Sound Pharmaceuticals' drug) can circumvent these oral limitations and Hough Ear Institute's drug can be given in massive quantities (and is systemically very safe--Ebselen might be too but doesn't have to be given in as high a dose).

Anyway, back to Frequency Therapeutics...

Frequency Therapeutics' drug can cause systemic effects in rats (cancer) in the very high oral doses needed to reach the cochlea. You can use lower doses and reach a much higher concentration of drug in target tissues (because it's not diluted in the plasma and other tissues) if you make essentially a "topical" like you have with IT drugs.

Frequency Therapeutics has shown in their German perilymph study that they do reach the cochlea with intratympanic injection. They believe that with frequent repeat dosing, they will reach further than the phase 1 dose did.

Repeat dosing or extended release results in much better penetrance and higher peak tissue levels. As an aside, otherwise OTO-104 (Otonomy's phase 3 extended release Dexamethasone drug) would be pointless as IT Dexamethasone is already available.

Btw, Frequency Therapeutics have also done pharmacological assessment in phase 1 and noted it did not reach high levels systemically after IT injection (which makes it much much safer than oral for their drug).

 

[tommyd87]

I'm going to over simplify this a bit here because it actually involves quite a bit of biochemical but the gist is that different oral and systemic drugs have different volume of distributions (Vd):

https://en.wikipedia.org/wiki/Volume_of_distribution

(Which is basically an equation for how well it leaves blood and goes into tissues).

Drugs with a higher Vd need a lower dose to get in the "nooks and crannies".

Related is peak plasma levels. That's why IV antibiotics cause way more damage than oral antibiotics.

Liver and kidney metabolism is a factor too but that's a whole extra layer of complication that depends on both health state and Cytochrome genes.

There is also a blood cochlear layer (just like a blood brain barrier) which has specialized endothelial cells that try to "keep out" blood substances so the cochlea is a more protected site.

Very few drugs can get around this hurdle systematically unless they are given in large or prolonged quantities or have excellent cochlear penetrance (typically small, not overly polar molecules).

Ebselen (Sound Pharmaceuticals' drug) can circumvent these oral limitations and Hough Ear Institute's drug can be given in massive quantities (and is systemically very safe--Ebselen might be too but doesn't have to be given in as high a dose).

Anyway, back to Frequency Therapeutics...

Frequency Therapeutics' drug can cause systemic effects in rats (cancer) in the very high oral doses needed to reach the cochlea. You can use lower doses and reach a much higher concentration of drug in target tissues (because it's not diluted in the plasma and other tissues) if you make essentially a "topical" like you have with IT drugs.

Frequency Therapeutics has shown in their German perilymph study that they do reach the cochlea with intratympanic injection. They believe that with frequent repeat dosing, they will reach further than the phase 1 dose did.

Repeat dosing or extended release results in much better penetrance and higher peak tissue levels. As an aside, otherwise OTO-104 (Otonomy's phase 3 extended release Dexamethasone drug) would be pointless as IT Dexamethasone is already available.

Btw, Frequency Therapeutics have also done pharmacological assessment in phase 1 and noted it did not reach high levels systemically after IT injection (which makes it much much safer than oral for their drug).

So when you refer to prolonged doses - I am actually guessing that this means multi dosing like what Frequency Therapeutics is doing with their current trial?

 

[FGG]

So when you refer to prolonged doses - I am actually guessing that this means multi dosing like what Frequency Therapeutics is doing with their current trial?

I was more referring to oral dosing there but there should be increased concentration of drug with repeat dosing intratympanically too.

 

[tbuzz89]

ENTs dont like the word "tinnitus", they like words like ear infection, tonsils, adenoids, deviated septum, pharynx, larynx stuff like that.

This is why I think ENTs should be advocating for a drug like FX-322. It'll make "tinnitus" a word they'll like as then they'll be able make money via administering a routine IT injection. Very little time out of their schedule for a presumably decent amount of payment.

 

[Street Novelist]

So, are we actually going to get early results in March? We won't have to wait until May? Some good news then.

 

[Diesel]

I am simply guessing but I think that there is a possibility that Frequency Therapeutics has identified that FX-322 will work with a much broader range of cases than just those that were identified in the initial trial. It should theoretically work because by right as long as you can regenerate hearing you should simply stand to benefit from FX-322.

I would not be surprised if Frequency Therapeutics has been doing some "extra-curricular" studies with patients outside of the FDA-Approved clinical trials.

For example:
Frequency Therapeutics knows who the patients are from the Phase 1/2 that received placebo. Since they participated in an FX-322 clinical trial, they are excluded from participating in future FDA-sponsored FX-322 trials.

However, since they've already signed proper releases, disclosures, and NDAs; it is possible Frequency Therapeutics could have recalled these Phase 1/2 placebo patients to perform an "independent analysis" of multiple dosing. So, they may already know what multiple doses might do for the small placebo group that had moderate hearing loss.

Total speculation; and it's a little grey from a legal standpoint. But if it happened, these patients may have provided Frequency Therapeutics with some pre-clinical insight on the multiple dose strategy. Which, could be why they're so confident on the 90-day Phase 2A results; and both Phase 1bs.

 

[Princebeyel]

Finally, a trial those who have severe hearing loss have a chance to enter.

EDIT: Nevermind, the criteria says the trial is open only to those in the upper age spectrum. Still waiting.

Where did you find the criteria?

 

[tommyd87]

I would not be surprised if Frequency Therapeutics has been doing some "extra-curricular" studies with patients outside of the FDA-Approved clinical trials.

For example:
Frequency Therapeutics knows who the patients are from the Phase 1/2 that received placebo. Since they participated in an FX-322 clinical trial, they are excluded from participating in future FDA-sponsored FX-322 trials.

However, since they've already signed proper releases, disclosures, and NDAs; it is possible Frequency Therapeutics could have recalled these Phase 1/2 placebo patients to perform an "independent analysis" of multiple dosing. So, they may already know what multiple doses might do for the small placebo group that had moderate hearing loss.

Total speculation; and it's a little grey from a legal standpoint. But if it happened, these patients may have provided Frequency Therapeutics with some pre-clinical insight on the multiple dose strategy. Which, could be why they're so confident on the 90-day Phase 2A results; and both Phase 1bs.

It is incredibly possible that these patients might have done so. Something still tells me that Frequency Therapeutics wouldn't have done the two phase 1b trials if they weren't confident what they were going to get results which were good. We still need to wait for results however there could easily be some confidence behind what Frequency Therapeutics is doing with the multiple dosing strategy - and also the results.

 

[tommyd87]

Finally, a trial those who have severe hearing loss have a chance to enter.

EDIT: Nevermind, the criteria says the trial is open only to those in the upper age spectrum. Still waiting.

I don't think that this matters. My guess is that Frequency Therapeutics has chosen to do this because by rights they can combine two indications into one trial being age-related and severe hearing loss and subsequently this speeds up the trial process pretty favourably. Basically by doing it this way, it kills two birds with one stone because it lowers costs, lowers trial time and also gives relevant groups the information required rightfully. I think there's little issue what groups get FX-322 for whatever reason because conveniently we know now anyone can regrow hair cells with FX-322 on the proviso that they have sufficient support cell to enable it.

 

[Billy_Shears]

I would not be surprised if Frequency Therapeutics has been doing some "extra-curricular" studies with patients outside of the FDA-Approved clinical trials.

For example:
Frequency Therapeutics knows who the patients are from the Phase 1/2 that received placebo. Since they participated in an FX-322 clinical trial, they are excluded from participating in future FDA-sponsored FX-322 trials.

However, since they've already signed proper releases, disclosures, and NDAs; it is possible Frequency Therapeutics could have recalled these Phase 1/2 placebo patients to perform an "independent analysis" of multiple dosing. So, they may already know what multiple doses might do for the small placebo group that had moderate hearing loss.

Total speculation; and it's a little grey from a legal standpoint. But if it happened, these patients may have provided Frequency Therapeutics with some pre-clinical insight on the multiple dose strategy. Which, could be why they're so confident on the 90-day Phase 2A results; and both Phase 1bs.

Good point, but I would think that Frequency Therapeutics in all likelihood would have correspondence only with the ENT physicians of those patients, not with the patients themselves. Physicians would provide a much more thorough, professional analysis that answers the questions that the company is seeking.

The ENT physician is heavily relied upon given what they are paid for participating in clinical trials, often serving as the agent for Frequency Therapeutics.

 

[d'Wooluf]

Really it makes me wonder if FX-322 is in fact working as intended and they've seen huge success with it! Why else would they start two more trials?

I think it's just filling in the gaps so they can show the FDA that it's been proven safe- and possibly efficacious - for pretty much everyone. This might be in preparation for a future phase 3 study. I think @FGG mentioned that possibility. As for 'does it work as intended?', that's been done to death and I think we have all agreed to disagree (or at least wait for the results of phase 2a).

 

[tommyd87]

I think it's just filling in the gaps so they can show the FDA that it's been proven safe- and possibly efficacious - for pretty much everyone. This might be in preparation for a future phase 3 study. I think @FGG mentioned that possibility. As for 'does it work as intended?', that's been done to death and I think we have all agreed to disagree (or at least wait for the results of phase 2a).

I think the issue of whether it works as intended has been answered and I think we know that it does what it is intended to do and has shown as much. The question is how well it works on a real ear.

 

[Diesel]

I think the issue of whether it works as intended has been answered and I think we know that it does what it is intended to do and has shown as much. The question is how well it works on a real ear.

The patients who enrolled in the trials had real, living ears. Those patients saw clinically meaningful improvements in hearing function. FX-322 seems to work as intended.

 

[MadsWithT]

Adding to the hype, Verdens Gang, Norway's main newspaper, put tinnitus center of the front page today. The article inside basically discusses FX-322 and Lenire. No mention that the latter is a failure. Positive though, regenerative drugs may very well be the solution. I took a picture of the front page, I might post it here...

 

[annV]

I took a picture of the front page, I might post it here...

Can you share and translate the actual article, it appears to be three pages long, not just the front page?

 

[MadsWithT]

Can you share and translate the actual article, it appears to be three pages long, not just the front page?

Yes I should be able to do that. But as I said, I just skimmed through, there is no news there for anyone subscribing to this thread. I did not buy the paper either. I'd still be happy to translate if anyone is in possession of the body text.

The ingress says that there is new hope for tinnitus sufferers and that 750 000 Norwegians suffer from tinnitus.

I must say you are one fast poster @annV.

 

[Lucifer]

It will be a long wait for FX-322 but I hope the suffering is worth the wait and it will cure hyperacusis, tinnitus and hearing loss.

Each day we edge closer to a cure.

 

[tommyd87]

The patients who enrolled in the trials had real, living ears. Those patients saw clinically meaningful improvements in hearing function. FX-322 seems to work as intended.

I absolutely agree with this. We don't know how immense the results will be yet. We shall see significantly better results if FX-322 gets deeper in although the question still is how much better, especially from the current dosing method. We know that FX-322 works and that it can consequently provide excellent growth all round. We just don't know the full extent of growth it may be able to deliver in an ear yet.

 

[tbuzz89]

It will be a long wait for FX-322

Hopefully not as long as some say.

2022: optimistic
2023: realistic
2024: conservative

 

[Lucifer]

Hopefully not as long as some say.

2022: optimistic
2023: realistic
2024: conservative

When we find out the Day 90 results at the end of March, I will rest easy if I know the results are positive and that there is an improvement in efficacy with more doses of FX-322.