Frequency Therapeutics — Hearing Loss Regeneration

[Diesel]

My concern with FX-322 is that is focuses just on restoring the hearing hair cells. But we know that greater damage occurs to the synapses. I wonder why none of these companies try a two pronged approach. Like using the hair regeneration drug plus a drug that regenerates synapses like OTO-413 and PIPE-505. Maybe with this kind of more aggressive approach using two medications instead of one we would see clear results.

I think for now, the need is to verify that one drug focused on one underlying cause works as anticipated. In the ideal future state, treatment might be something like: the first pass is synaptic regen, then hair cell regen if outcomes aren't favorable.

The challenge with creating cocktails - like an FX-322+OTO-413 is that right now, there's no pre-clinical data on the effects of the drugs interacting with each other or within the cochlea at the same time.

There's also the problem of competition; The two different firms don't have a mutual benefit to partner on the drugs in the clinical stage. If these drugs were in the market, might be a different story. There's also no pre-clinical data to show to the FDA that the combination produces any more favorable data than a single drug.

 

[Street Novelist]

Does anyone know when Frequency Therapeutics plan on starting their next trial? Do they still plan on this year?

 

[Tezcatlipoca]

Please refrain from discussing trial recruitment. Have we learned nothing?

 

[Pete88]

I disagree. In Phase 1/2 the drug didn't result in PTA improvements and WR scores improved marginally in about 35% of patients. Frequency Therapeutics didn't even talk about WR until after the results of Phase 1/2. I wasn't impressed after Phase 1/2, and for good reason.

I can't be bothered to bring up the exact numbers and percentages but I remember that if you really looked at the numbers, there was only a small percentage of people that had the room to get better by an amount that could be classified as statistically meaningful. So it actually was a decent outcome.

Regarding the PTA, these people also had improvements at 8,000 Hz and extended audiograms were not done. This led to a reasonable theory that the extended audiograms would have shown improvements.

The results were good enough to warrant excitement. This was in combination of various pre-trial experiments that showed hair cell regeneration. Unfortunately, every trial since has not lived up to what the safety trial suggested. They haven't even been able to replicate the previous results, let alone prove what we assumed regarding extended audiograms. They included extended audiograms but the company has not mentioned the results on that. The lack of details suggest there's no exciting news.

The "good news" from the newer trials is a fraction of what we got from the safety trial. "Multiple people double their word scores" along with a detailed breakdown of numbers has become vague statements along the lines of "some people had at least a 10 percent increase".

 

[Lucifer]

Does anyone know when Frequency Therapeutics plan on starting their next trial? Do they still plan on this year?

They mention Q4 so they could start at the earliest in October. I really hope these phases can go by quickly. A year for each phase is too long.

 

[Lucifer]

I wonder when they will announce the severe hearing loss trial results. Hopefully the end of this month or early October.

I have a feeling, when they announce the severe hearing loss trial results, that it is when they will start Phase 2 again with single dosing of FX-322 this time.

 

[Amv]

That's not right, no. Tinnitus is usually from damage to hearing, so having a drug that can regenerate the damage would treat the underlying cause of tinnitus AND would also improve hearing perception and clarity. It would also address such issues as hyperacusis that again are caused by the structural damage.

My concern with FX-322 is that is focuses just on restoring the hearing hair cells. But we know that greater damage occurs to the synapses. I wonder why none of these companies try a two pronged approach. Like using the hair regeneration drug plus a drug that regenerates synapses like OTO-413 and PIPE-505. Maybe with this kind of more aggressive approach using two medications instead of one we would see clear results.

Probably, theoretically, you are right, but in a more realistic way, I believe we are still far away from regenerating our ears wisely. I believe neuromodulation is far ahead in terms of research and is probably a less invasive and safe way to treat tinnitus today.

 

[Chad Lawton]

It is also the case that Frequency Therapeutics did do only single dosing as an element of their mucked up Phase 2 trial too.

Ehhhhh kind of/sort of. They did administer some patients a single dose of FX-322 but then subsequently shot 3 doses of placebo into that same ear as well so I don't count that as a clean, single dose.

 

[Chad Lawton]

I disagree. In Phase 1/2 the drug didn't result in PTA improvements and WR scores improved marginally in about 35% of patients. Frequency Therapeutics didn't even talk about WR until after the results of Phase 1/2. I wasn't impressed after Phase 1/2, and for good reason.

As the company has stated, they need to find out who their drug works on and who it doesn't since they are a leader in the field and this has never been done before. All these little studies are exploratory to find that out. So the Phase 1/2 had a range of etiologies and severities and they said that those with mild hearing loss have little room to improve so since mild hearing loss patients were included in the study, 35% of patients improving isn't that bad.

Then on top of that, just because those with mild hearing loss don't "improve", it doesn't mean the drug isn't working/helping for them. It just means that current clinical tests aren't refined enough to detect the nuanced improvements that may occur in mild patients.

 

[Diesel]

As the company has stated, they need to find out who their drug works on and who it doesn't since they are a leader in the field and this has never been done before. All these little studies are exploratory to find that out. So the Phase 1/2 had a range of etiologies and severities and they said that those with mild hearing loss have little room to improve so since mild hearing loss patients were included in the study, 35% of patients improving isn't that bad.

Then on top of that, just because those with mild hearing loss don't "improve", it doesn't mean the drug isn't working/helping for them. It just means that current clinical tests aren't refined enough to detect the nuanced improvements that may occur in mild patients.

Every so often, the reminder needs to be made that the FDA approval process, if it were to be simplified depends on three criteria:

1. Risk: Is the drug safe enough to be administered to humans? Or, do the benefits outweigh the possible side-effects?
2. Patient Population: What specific patient population has been identified that this drug can help?
3. Clinical Outcomes: What specific assessment data shows that the Patient Population improved in a significant way vs. Placebo?

These 3 factors are very might interrelated. However, clearly defining #2 is the seriously big problem for hearing loss pharma right now.

One that continues to become more clear from this drug's trial, Otonomy's, Pipeline's, and others, is that being really specific in terms of Patient Population will decide whether or not these drugs get approval. Turns out, that the nuances between one type of / underlying cause of hearing loss or another matter.

Currently, the Phase 1 datas aren't that impressive, when only 1/3 of the participants move the needle. We all want that to be better. But, for both of them, they casted a wide/vague net to capture willing participants. So, by ignoring those nuances in hearing loss that matter, factor #2 doesn't look so great.

If Frequency can improve the specifics of the Patient Population in the next Phase 2, then they should see improvement in 2 and 3 mentioned above; and have a much less risky path to FDA approval.

I think this is another reason to explain why they published that PR the other day about patients responding to the drug much later than others. It's possible they think there is a nuanced difference between those "late bloomers" verses "early bloomers." This information might help strengthen their knowledge on #2 above.

 

[Chad Lawton]

If Frequency can improve the specifics of the Patient Population in the next Phase 2, then they should see improvement in 2 and 3 mentioned above; and have a much less risky path to FDA approval.

And now they have over 175 patients that have been dosed with FX-322 across all their trials so they should have a pretty good idea of their target population. It sounds like R&D day is when they are going to spill all the beans on all their learnings and how they are going to shape the new Phase 2 trial.

 

[tommyd87]

Ehhhhh kind of/sort of. They did administer some patients a single dose of FX-322 but then subsequently shot 3 doses of placebo into that same ear as well so I don't count that as a clean, single dose.

The question is though whether the placebo would have mucked up the dosing of the medicine in the same way. At present there is no information to confirm or deny this.

 

[Joeseph Stope]

Just for a recap.

It seems that tinnitus research is working broadly speaking on three fronts:

1] Accessing the cochlea so as to grow hair cells and/or synapses
2] Sound therapy with massaging some nerve
3] Channel blockers or something that I don't know anything about

 

[Gb3]

 

[Pete88]

View attachment 46978

Without investing too much emotion, this seems like a good sign. Basically a secret trial that if it had bad results, would be swept under rug. I know people will point out the possible sketchiness of the scenario but this is promising!

 

[AfroSnowman]

View attachment 46978

Got to like the title. Does anyone know which cohort this trial was testing on?

 

[Jurger]

Without investing too much emotion, this seems like a good sign. Basically a secret trial that if it had bad results, would be swept under rug. I know people will point out the possible sketchiness of the scenario but this is promising!

How is a "previously disclosed" trial a secret? If I'm correct this is the study of which they already shared results concurrent with the failed Phase 2a study.

 

[Pete88]

How is a "previously disclosed" trial a secret? If I'm correct this is the study of which they already shared results concurrent with the failed Phase 2a study.

Wow, I feel dumb. You are right. I read it as "previously undisclosed". This got less exciting. Now it sounds like they're just trying to salvage the lackluster results of one of those old studies.

 

[Joeseph Stope]

Wow, I feel dumb. You are right. I read it as "previously undisclosed". This got less exciting. Now it sounds like they're just trying to salvage the lackluster results of one of those old studies.

Dare I say it? You seem to be implying that that German fellow Toby was spot on. (Well, he was right on the money.)

I have to say that Frequency Therapeutics and Pipeline Therapeutics and maybe Hough Ear Institute deserve our attention and admiration in so far as that the method of intratympanic injections delivers a therapeutical agent to the local area where we assume tinnitus and hearing loss is located -- so this is a new approach and could be a game-changer, block-buster.

It might be an imitation of one of nature tricks -- both fish and birds can regenerate damaged hair cells.

However, maybe the crowdfunding method would be a better approach to conducting research. I have no doubt that there are lots of people in the tinnitus community and the hearing impaired community who are financially secure (sure ain't me) and would like to fund research.

I guess a lot comes down to the people who are conducting the research.

Having said that, if Frequency Therapeutics can deliver the goods, then all is forgiven.

 

[Lucifer]

Dare I say it? You seem to be implying that that German fellow Toby was spot on. (Well, he was right on the money.)

I have to say that Frequency Therapeutics and Pipeline Therapeutics and maybe Hough Ear Institute deserve our attention and admiration in so far as that the method of intratympanic injections delivers a therapeutical agent to the local area where we assume tinnitus and hearing loss is located -- so this is a new approach and could be a game-changer, block-buster.

It might be an imitation of one of nature tricks -- both fish and birds can regenerate damaged hair cells.

However, maybe the crowdfunding method would be a better approach to conducting research. I have no doubt that there are lots of people in the tinnitus community and the hearing impaired community who are financially secure (sure ain't me) and would like to fund research.

I guess a lot comes down to the people who are conducting the research.

Having said that, if Frequency Therapeutics can deliver the goods, then all is forgiven.

Yea I agree with everything you said, especially the last part about forgiving Frequency Therapeutics if they can deliver the goods.

At least this time the participants will either get placebo or FX-322 in the Phase 2 trials instead of multiple dosing where the placebo may have mitigated the effect of FX-322 doing so well in the previous Phase 1 trials.

 

[Pete88]

Dare I say it? You seem to be implying that that German fellow Bob was spot on. (Well, he was right on the money.)

Yeah, possibly!

Again, remember when he showed up and so many people jumped down his throat and aggressively mocked him?

 

[Joeseph Stope]

Yeah, possibly!

Again, remember when he showed up and so many people jumped down his throat and aggressively mocked him?

One or two things to remember in this regard:

a) Quite few people were emotionally involved in this new medical approach and had pinned their hopes on a successful outcome. On the face of it, it seems quite logical or at least plausible that hearing loss and tinnitus are connected. Lots of army personnel (think guns and explosives), lots of firemen, lots of musicians and lots of grade school teachers too (all those high-pitched screaming kids) come down with tinnitus.

b) Some people had placed their hard-earned on the markets in the hopes of a retirement nest-egg.

For @Toby1972 to come along and tell everyone that he was an expert and show his winnings (taxed too!) and tell all and sundry that he had got out before the "fit hits the shan" -- need I go on?

It almost had its comic side to it except that tinnitus is such a life-changing disaster.

 

[Chad Lawton]

Wow, I feel dumb. You are right. I read it as "previously undisclosed". This got less exciting. Now it sounds like they're just trying to salvage the lackluster results of one of those old studies.

The company has openly said that these are all exploratory studies to find out who FX-322 works on and who it doesn't. They need to first learn their target demographic so they can know who to target in future trials in order to gather enough evidence for the FDA to show it has clinical significance. To call the results lackluster because it only worked on a subset of patients (about 1/3 of patients in that trial) with hearing loss is like being disappointed if a new blood cancer drug came out and you consider it lackluster because it didn't treat all forms of blood cancer at once even if it shows efficacy for one or two types.

 

[Pete88]

One or two things to remember in this regard:

a) Quite few people were emotionally involved in this new medical approach and had pinned their hopes on a successful outcome. On the face of it, it seems quite logical or at least plausible that hearing loss and tinnitus are connected. Lots of army personnel (think guns and explosives), lots of firemen, lots of musicians and lots of grade school teachers too (all those high-pitched screaming kids) come down with tinnitus.

b) Some people had placed their hard-earned on the markets in the hopes of a retirement nest-egg.

For @Toby1972 to come along and tell everyone that he was an expert and show his winnings (taxed too!) and tell all and sundry that he had got out before the "fit hits the shan" -- need I go on?

It almost had its comic side to it except that tinnitus is such a life-changing disaster.

I agree. There was a lot of emotion riding on good results. All I'm saying is that people need to recognize when emotion is in the driver's seat.

 

[Pete88]

The company has openly said that these are all exploratory studies to find out who FX-322 works on and who it doesn't. They need to first learn their target demographic so they can know who to target in future trials in order to gather enough evidence for the FDA to show it has clinical significance. To call the results lackluster because it only worked on a subset of patients (about 1/3 of patients in that trial) with hearing loss is like being disappointed if a new blood cancer drug came out and you consider it lackluster because it didn't treat all forms of blood cancer at once even if it shows efficacy for one or two types.

Yeah you're absolutely right. It's just that if you had the type of blood cancer the new drug didn't help, it would be personally disappointing. However, if you were just an impartial observer, any progress is incredible.

Everyone was hoping FX-322 would fix all the hair cells it touched and idea was it would fix 8,000 Hz and above by at least 10 dB. So the apparent reality that this isn't the case is what makes it relatively disappointing. I guess the bar of expectations were set too high a while ago.

 

[tommyd87]

Yeah you're absolutely right. It's just that if you had the type of blood cancer the new drug didn't help, it would be personally disappointing. However, if you were just an impartial observer, any progress is incredible.

Everyone was hoping FX-322 would fix all the hair cells it touched and idea was it would fix 8,000 Hz and above by at least 10 dB. So the apparent reality that this isn't the case is what makes it relatively disappointing. I guess the bar of expectations were set too high a while ago.

I think that the biggest issue that Frequency Therapeutics has got right now is that it needs to reevaluate both the dosing methodology and also actually whether the medicine properties are sufficiently targeting what it needs to target too. There is evidence which indicates that the medicine is beneficial and working, however Frequency Therapeutics haven't looked at shifting their trials to evaluate alternatives which possibly would work with making the medicine more effective.

There is no issue with continuing the dosing method or the amount of medicine used in the same way which they have done to date, however they also need to look at running alternative trials in conjunction with the existing trials which focuses on alternatives such as bigger volumes or using alternative methods.

There is no certainty that Frequency Therapeutics can completely claim that they have truly completed the required and necessary exploratory elements of their medicine and trial until they branch out and attempt all alternatives to what they have engaged thus far to obtain comprehensive information. It won't be until after Frequency Therapeutics has done this that there will be any certainty over their medicine.

 

[Chad Lawton]

I think that the biggest issue that Frequency Therapeutics has got right now is that it needs to reevaluate both the dosing methodology and also actually whether the medicine properties are sufficiently targeting what it needs to target too. There is evidence which indicates that the medicine is beneficial and working, however Frequency Therapeutics haven't looked at shifting their trials to evaluate alternatives which possibly would work with making the medicine more effective.

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.

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.

 

[sensualmosquito]

I think that the biggest issue that Frequency Therapeutics has got right now is that it needs to reevaluate both the dosing methodology and also actually whether the medicine properties are sufficiently targeting what it needs to target too. There is evidence which indicates that the medicine is beneficial and working, however Frequency Therapeutics haven't looked at shifting their trials to evaluate alternatives which possibly would work with making the medicine more effective.

There is no issue with continuing the dosing method or the amount of medicine used in the same way which they have done to date, however they also need to look at running alternative trials in conjunction with the existing trials which focuses on alternatives such as bigger volumes or using alternative methods.

There is no certainty that Frequency Therapeutics can completely claim that they have truly completed the required and necessary exploratory elements of their medicine and trial until they branch out and attempt all alternatives to what they have engaged thus far to obtain comprehensive information. It won't be until after Frequency Therapeutics has done this that there will be any certainty over their medicine.

Well said.

 

[AfroSnowman]

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.

I would feel better about that interpretation if we saw good data on hearing thresholds above 6 kHz or 8kHz. I'm not saying audiograms are the whole ballgame, but would feel much more definitive than slight to modest word-in-noise improvements.

 

[ploughna]

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.

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?