Frequency Therapeutics — Hearing Loss Regeneration

I've been reading the last bit of this thread. It's remarkable how much is based on wishful thinking. You would think FX-322 is about to be approved.

For background, I've been following Frequency since July 2016: (Inner Ear Hair Cell Regeneration — Maybe We Can Know More) I believe that is the first mention of Frequency on this site.

I've been quite disappointed at the lack of a follow-up paper to McLean et al (2017) - published over two years ago. For those who haven't read the paper, I summarize what they did in this post: Frequency Therapeutics — Hearing Loss Regeneration

In that post I also talk about things to look for in the "next" paper and things that I would expect would be in place before human trials. Since there hasn't been a "next" paper, we don't yet know what other pre-clinical data they have. I am still looking forward to see what is in the next paper.

I am still cautiously optimistic, though the balance has shifted from optimistic to cautiously. Below are some of my thoughts on where we are now.

1) The departure of Weber last year was a bigger deal than his going to Decibel this year. His going to Decibel makes sense though because Decibel is a hearing loss company while Frequency is a company built around a tool - it's just that the first thing they are using that tool on is hearing (It is notable that Weber is a Neurotologist (or at least did a fellowship in Neurotology) while Chin is an endocrinologist. Thus, I think Weber's departure said more about Frequency's expansion beyond hearing. (See below for more.)

2) Based on the paper from 2017, it seemed very unlikely that one injection would work so I am not concerned about multiple injections. I wouldn't read anything into the fact that they said it would be one injection in the past. I'm sure that is what they were hoping for, but they probably knew at the time that it was unlikely. (This is also why you should downplay anything said by anyone associated with a company - e.g., time lines, results, etc - unless it is in published paper or has already happened. Even if it is in a published paper, you need to read very carefully and pay attention to the quality of the journal. And a single paper doesn't prove anything by itself. Pay even less attention to press releases.)

3) The most important thing to keep in mind is that this is incredibly hard and more likely to fail than to be successful. The inner ear is singularly difficult to reach clinically, and the PCA technology itself is unproven even in much simpler settings. It's also the case that regenerating hair cells in adults is much harder than doing so in a petri dish or newborns - this is a constant theme across many studies. The idea that this is figured out and we somehow *know* that Frequency will be successful is wishful thinking not grounded in any publicly available knowledge - or at this point likely any privately available knowledge.

I've responded to a few things people have said or asked in the last few pages of the thread below.

It wasn't "just" a phase 1 study. The two dose levels was the phase 2 component of the trial. While they may have done hearing tests to look for TEAEs. The study is too small to provide useful information about efficacy.

It is a negative, but it is not surprising.The patent applications talked about the possibility of multiple treatments (though patent applications are written to be as broad as possible: they typically seem something like "in one embodiment, this invention uses one or more of 5 million different compounds that may be applied between 0 and an infinite number of times.....") It's also the case that the treatment times were so long in the paper that a single dose was unlikely to be effective. So no big surprise. I'd be interested to know how closely spaced the multiple injections will be. For example, are they spaced closely to try to get sustained exposure or are they more widely spaced.

I assume that larger won't work because there is a limit to how long the fluid/gel will remain in the middle ear, how quickly it diffuses to the inner ear, and how much can be put in the inner ear.

I will talk about fast tracking below, but one comment on believing what people say. There is no cost to talk about fast tracking. What they are attempting to treat has a large unmet need so they are eligible. As far as I know, there is no cost to the company of asking for fast track status (though I am a bit surprised at that and could be wrong), so at this stage it is something they can talk about and it doesn't really cost them anything. Moreover it does speed things up, but not by years.

My guess is that this comes more from pre-clinical studies in animals than the Phase 1/2.

Even if they have measurements - and they may well from there focus on TEAEs, the sample was too small to learn much. It is possible they will say something, but it really won't be meaningful given the sample size. Keep in mind that many trials that appear to be successful in Phase 2 (with much larger samples than in the Phase 1/2 here) subsequently fail in Phase 3. So even seeing something "promising" in these small samples isn't really much information.

And depending on how much tinkering they do, they will have to do new pre-clinical work, go through safety trials, etc.

Journalist.

Could you point me to the paper that shows this?

Have you read McLean et al (2017)? In some experiments, tissue was treated 20 days or so - the human tissue was 22 days. They did shorter treatment (3 days) but that was on newborn (2 day old) mice. Thus, it seems exposure time matters.

It doesn't have as much effect as you would think from reading things here

Here's what it entails:

"A drug that receives Fast Track designation is eligible for some or all of the following:

• More frequent meetings with FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval
  
• More frequent written communication from FDA about such things as the design of the proposed clinical trials and use of biomarkers
  
• Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met
  
• Rolling Review, which means that a drug company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed. BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA"

(https://www.fda.gov/ForPatients/Approvals/Fast/ucm405399.htm)

All of this is useful and will, if all goes well, reduce the time, but it will be a matter of months not years.

There would be little point if they had to wait that long in the process. All the information is online so you can read about the process.

Chin was hired in April 2018. When he was hired Weber became "Chief Medical Officer, Hearing Program":

"Peter is the Chief Medical Officer, Hearing Program for Frequency Therapeutics. Prior to Frequency, Peter was the Director of the Ear Institute at the New York Eye and Ear Infirmary of Mount Sinai (NYEE), where he was also a Professor of Otolaryngology-Head and Neck Surgery at the Icahn School of Medicine at Mount Sinai. Before joining NYEE, Peter served as Chief Medical Officer at Cochlear Americas and was a Professor and Director of Otology-Neurotology at the University of Massachusetts Medical School. He was also formerly the head of the Otology-Neurotology Department and Co-Director of the Hearing Implant Program at the Cleveland Clinic, and was previously named Acting Chairman in the Department of Otolaryngology-Head and Neck Surgery at the Medical University of South Carolina. Peter has served on the Board of Directors of the American Academy of Otolaryngology-Head and Neck Surgery and is a former President of the Board of Governors for Otolaryngology. Peter received his B.S. and M.S. in Engineering from Washington University and his M.D. from Albany Medical College. He completed his residency at the University of Pittsburgh Medical Center, a fellowship in Neurotology at the University of Iowa, and received an M.B.A. from Duke University’s Fuqua School of Business." (http://www.frequencytx.com/our-company/bio-cab-peter-weber.php)

Weber left in the summer 2018 - July or thereabouts. So, while he didn't leave recently, Chin is an endocrinologist who replaced an someone whose specialty Neurotology. To me this reflected a change in emphasis at the company as they expanded into juvenile diabetes, muscle injury, and other areas.

I don't think there is any evidence that there is a collaboration.

This has been posted multiple times already.

This strikes me as too optimistic. At this point, it has been 7 months since the Phase 1/2 started, and the Phase 2 trial hasn't started. The Phase 1/2 was small compared to what the Phase 2 and 3 trials will be so setting up trials will take longer. More data will take longer to analyze so I would expect time between trials to increase. We also don't know how long those trials will take. FDA may require some proof of durability of any benefits. Finally, if successful, it will take time to set up manufacturing.

I am certainly hopeful that they will be successful. We will know more with any new publications and when they announce the structure of the trial.

 

It's also worth pointing out that, while we don't have the next paper, there's a new paper out of Albert Edge's lab that is continues work on Lgr5+ progenitor cells: https://www.frontiersin.org/articles/10.3389/fcell.2019.00014/full

This is relevant because Edge's lab did the work underlying what Frequency is doing today - Edge was senior author on McLean et al (2017).

Additionally, Frequency presented work at the ARO midwinter meetings that attempts to better understand how this process works: Lgr5+ Cochlear Progenitor Cell Proliferation is Driven by the Combined Activation of the Wnt, Non-Canonical Notch, and PI3K Pathways.

 

https://www.researchgate.net/figure...lop-skin-lesions-similar-to-that_fig2_6013662
and this
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573859/

If you notice I never said exposure time doesn't matter. I said that the drug probably doesn't need to be in contact while the hair cell grows to maturity.

Pshhh, you don't know that.

 

Thanks.

Well, not quite sure what distinction you have in mind. Perhaps contact during the growth period isn't necessary once growth has started - though it appears to be necessary in the experiments in the paper. The point is that there needs to be sustained exposure to start the process - again based on what is in the paper.

While it is true that I don't know what the effect might be in this case, if you look at Hwang, Darrow, and Kesselhaim, "The FDA's Expediated Programs and Clinical Development Times for Novel Therapeutics, 2012-2016, JAMA, 318(21), the difference between fast track and not fast track is about 1 year and is significant at p=0.03. I view that as months rather than years. Overall for all accelerated vs non-accelerated drugs is less than a year. Breakthrough status has a larger effect - 4.8 vs 8 years and significant at p < 0.01. The other issue is that unlike something like Alzheimer's or cancer, these trials are likely to be shorter. Thus, there is less scope to shorten things compared to trials that last longer.

 

Just FYI, thanks for your research. Your contributions have certainly been beneficial.

 

Yea, I’ll admit it, I’m one of these people. I don't know about the rest of y’all but I’m going fucking insane. This shit rots your brain.

I think I’ll attempt to get into the phase II trial. I feel like I will not be able to live a happy healthy life while I still have this. If this turns out to be a flop there’s a pretty good chance I’m just gonna jump off a bridge.

 

@Aaron123!

Nice to have you back!! Thank you for your recent contributions to this thread! I remember when it was first created. I'm interested to know what you think of Decibel Therapeutics' potential to help overcome hearing loss. They appear to either be making no progress in their hearing regeneration pursuits or are being extremely secretive about it.

Any thoughts?

 

Statistically/clinically maybe, but... You don't think that even just one participant having their sensorineural hearing loss partially reversed would be huge? I'm thinking in the 'pivotal moment in history' sense. Everything I've ever read on sensorineural hearing loss says it's irreversible. Full stop.

Albert Edge is an interesting player in all of this. He has his fingerprints on Frequency Therapeutics, Audion Therapeutics, and then there's this from last year: https://www.sciencedaily.com/releases/2018/10/181015132953.htm

Thanks for the erudition and thought that goes into your posts.

 

While on the method of delivery and the frequency of injections, there's this https://www.prnewswire.com/news-rel...-of-medicines-to-the-inner-ear-300773226.html.

It probably belongs in the Decibel Therapeutics thread, and I'm not sure if the agreement would exclude Frequency Therapeutics from licensing the tech, but for what it's worth...

From Cocoon Biotech's web page:

"Silk protein can be formulated to release active small molecule or biologic drugs over many months to provide long-term treatment from a single injection."

 

Was browsing through my feed this morning and this came up as a news article in the UK Evening Standard, which is pretty cool. Usually, it's only the sufferers who know about possible treatments, so if news sites are picking this up it's a pretty good sign.

 

https://www.businesswire.com/news/h...herapeutics-Present-Cowen-Company-39th-Annual

Another presentation this monday.

Anyone here live in Boston?

 

Yes. I actually work about 10 minutes away from their Woburn office.

However, the presentation is Monday at 9 AM in Boston.

Could not be a more inconvenient time slot.

Maybe I can make it but I'll have to take some time off.

Anyone else live near here?

 

This isn't something someone can just go to: "Cowen conferences are open to our institutional, venture capital, and corporate clients." (http://www.cowen.com/capabilities/conferences-events/)

 

@Aaron123 welcome back man, it’s good to see you.

 

Crash it. Just look like you know what you're doing and don't look shady.

 

Lol, wear a suit, rehearse your lines, “Yes I'm a representative from TT Capital” and have some confidence, act like you belong, and I’m sure you could get in.

 

Thanks for the great input and research. Some comments and questions:

Do we know that this compound is difficult to manufacture? Or reasons to believe it would be?

I think these are median years, and there are drugs that take longer time and that take shorter time.

The fact that the trials are shorter than e.g. cancer/Alzheimer's trials would be one reason to believe this drug will be out in the market in less than 8 years since IND. I think I read that some drug made it in just three years...

I agree with your reasoning that there might be less of a benefit from the potential "fast track" status.

Great analysis and good find on that info.

My key point was that he did not leave just after the results came from the recent trial which some Tinnitus Talk readers might have been thinking. If they all began jumping ship after this trial it would have been (very) bad news...

I disagree with this statement. The required number of treated patients vs control for proof of efficacy depends on:

1 Sample size
and
2 Effect

If you have a significant effect you can have small sample sizes and still be confident about results.

Scenario 1, Small Sample, Major Effect:
8 patients in control have 50 dB hearing loss before injections. 3 months later they all still have 50 dB loss.
16 patients have 50 dB hearing loss before injection of FX-322. 3 months after injections they have 0 dB loss, i.e. hearing like a newborn.

This would be good proof that it works, even with limited sample size.

Of course we also know that it is extremely unlikely that the 16 patients recovered spontaneously, as the millions of humans with hearing loss never do (kind of like an expanded control group).

Scenario 2, Small Sample, Minor Effect:
8 patients in control have 50 dB hearing loss before injections. 3 months later they all still have 50 dB loss.
16 patients have 50dB hearing loss before injections. 3 months after FX-322 injections they have 40 dB loss on average.

This it not strong proof of effect.

Scenario 3, Large Sample, Minor Effect:
8000 patients in control have 50 dB hearing loss before injections. 3 months later they all still have 50 dB loss.
16000 patients have 50 dB hearing loss before injections. 3 months after FX-322 injections they have 40 dB loss on average.

This is proof of effect.

 

I’m starting to think FX-322 might be BPC-157 lol but not really.

 

No idea, I watched a clip on YouTube.

 

I guess what I can’t wrap my head around is why Frequency didn’t attempt a multiple dose approach in this 1.5 study if they had any inclination that a single dose administration wouldn’t do the trick. Audion, although a different type of drug, administered their treatment in 3 doses per patient in their Phase 1. I feel like this was a huge opportunity that Frequency didn’t take advantage of in this round. I get that this is still a “safety” study, but they already conducted a safety study in their own Phase 1 and Audion was able to utilize multiple doses as well in their safety round. There could have been more learned here behind the scenes if they went the multiple dose administration route right off the bat.

I posted an article before earlier in the thread where Langer for the first time publicly mentioned that FX-322 might need to be administered in more than one dose. This was right before they kicked off the 1.5 round. The design of this study could have been done better in my opinion.

 

Correct me if I’m wrong but Audion’s does not duplicate the supporting cells... FX’s does. Perhaps they were a bit more careful because of that? Just speculating.

 

Does anybody know when we are supposed to hear something?

 

I saw what you did there.

 

This kind of silly tinnitus-humor always makes me grin.

We are a strange lot, we tinnitus sufferers. Being able to joke about it is an important part of coping

 

This is why MPP is so important.

 

Since it would probably be nearly impossible to inject yourself in the eardrum safely, the gatekeepers of being able to experiment on ourselves are people trained in giving intratympanic injections, ENT's and otolaryngologists.

 

Assuming this drug has some type of efficacy, I can't believe no one who got it hasn’t posted in this forum. I guess I’m also assuming they know about the forum.

I also can’t believe there is zero news from the company.

Eventually I will learn the reality of my position and move on.

The news clip on the company now seems like clickbait.

 

If a member of this forum joined these trials I would expect some results here, otherwise not. Unfortunately we do need some patience at the moment.

 

They most certainly signed an NDA.

I wouldn't break it if it were me.

Also, I suspect the participants were given a very small dose, so that even if there were a regeneration of hair cells, it was very few, and it would not be clear to the participant or a hearing test that an increase in hearing capability occurred.

 

There are millions of Americans with hearing loss, and only 16 of them had a FX-322 injection. I guess there are a couple of thousand active members on Tinnitus Talk.

Also the NDA as mentioned!