Frequency Therapeutics — Hearing Loss Regeneration

#61
Samir said:
I hope this means that they will use FDA Accelerated Approval Program.


:ROFL:
Click to expand...

I'm pretty sure it means they are quickly trying to get all of the details worked out on this program in the next 18 months, not that they are going to use any FDA accelerated Approval program.

It would be nice if they did that though.
 
#62
Samir said:
If you have "mild" unilateral, sensory hearing loss, do you then qualify as 389.17? So you have sensory lesions but because your audiologist classified it as "mild" you may not be able to get reimbursement for the treatment from the insurance company.

I predict that the access to treatment in the first years will be a struggle between patients, insurance companies and audiologists. From the looks of it, audiologists might have the final and decisive word. Because people that don't have sensory lesions severe enough won't get reimbursement from their insurance company for the treatment. They will have to pay out of their own pockets. I'm sure many will do just that. But this is another reason that we need a treatment on the market as soon as possible. So that many more people may afford it in the coming years, because with time, and with availability of a successful treatment the insurance companies will have to change their policy.
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I think you are making it too complicated. It will be easy to find an ICD9 code to fit anyone with measured hearing loss. I don't think there is any need to talk about "sensory lesions".

The insurance company will want to know that a treatment works. So if there is an approved treatment for hearing loss, that is a good thing. The problem will be if they decide it is not "medically necessary". For example, there may be an expensive treatment for some condition that an insurance company will cover only if you have tried a certain number of less expensive treatments and found those treatments failed. It is hard to know how they would treat "mild" hearing loss.

I'm not sure how audiologists factor into this. If we keep the topic on Frequency, this will be a drug that is injected through the eardrum by ENTs. Audiologists won't be billing insurance companies.
 
#63
Aaron123 said:
The insurance company will want to know that a treatment works. (...)

I'm not sure how audiologists factor into this. If we keep the topic on Frequency, this will be a drug that is injected through the eardrum by ENTs. Audiologists won't be billing insurance companies.
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The insurance company would want to know that a treatment works. But don't they need to know that you need that treatment? On the other hand, you would probably want to know that the insurance company will reimburse you for it. I was thinking that you may need to clear that up with the insurance company before you go get the treatment. I was thinking that they might want to see that you have a need for this treatment. They might ask you to provide audiograms, which are normally done at the audiolgist's office. You can go straight to the ENT and get the treatment of course, and pay the full price. But you may not be reimbursed for it. Also, if it's a very expensive treatment, not everyone will be able to pay the full price up front.
 
#65
I need to rein in my enthusiasm about the frequency therapeutics developments. It "sounds" too good to be true:)
Within 18 Months the first clinical trial!
 
#66
I don't know what to think... This might be the most realistic development to give me hope.

18 months does not sound like a random number. If they had no clue, they would say something like "within the next few years".
 
#70
"Death of cochlear hair cells, which do not regenerate, is a cause of hearing loss in a high percentage of the population. Currently, no approach exists to obtain large numbers of cochlear hair cells. Here, using a small-molecule approach, we show significant expansion (>2,000-fold) of cochlear supporting cells expressing and maintaining Lgr5, an epithelial stem cell marker, in response to stimulation of Wnt signaling by a GSK3β inhibitor and transcriptional activation by a histone deacetylase inhibitor. The Lgr5-expressing cells differentiate into hair cells in high yield. From a single mouse cochlea, we obtained over 11,500 hair cells, compared to less than 200 in the absence of induction. The newly generated hair cells have bundles and molecular machinery for transduction, synapse formation, and specialized hair cell activity. Targeting supporting cells capable of proliferation and cochlear hair cell replacement could lead to the discovery of hearing loss treatments".

That would mean the new hair cells also connect themselves to the nerve ?

http://www.cell.com/cell-reports/ab...m/retrieve/pii/S2211124717301365?showall=true
 
#73
I just did one search on the internet: https://report.nih.gov/NIHfactsheets/Pdfs/HairCellRegenerationandHearingLoss(NIDCD).pdf
Quote: NIH-supported scientists found that newly formed hair
cells and nerve cells successfully reestablish
connections in an organized way, although the
reconnected nerve endings are simpler than those
generated during normal development.
This and other research will help reveal how nerve cells form
connections with newly generated hair cells.
That was 2010!
 
#74
I will be the Debbie Downer. They can grow hair, the difficulty is making them able to work like the previous ones they are replacing... ability to transmit sound.

https://report.nih.gov/NIHfactsheets/Pdfs/HairCellRegenerationandHearingLoss(NIDCD).pdf:

To test this theory, NIH-supported scientists destroyed hair cells in a mouse inner ear. Time lapse photography showed neighboring supporting cells migrating to the hair cell region and growing hair bundles on their surfaces. Although the process did not result in restored hearing in the mice, researchers began to investigate whether experimental augmentation of the process might improve hearing loss.

Effective treatments is like finding a needle in the haystack. Maybe this one will succeed where others have failed. Only 1 in 10 treatments make it through the clinical trial process. Seeing we have had a number of failures over the years maybe we will have a success... It will be a long wait and until the trials come out, but I will be one willing to lend an ear for experimentation.




 
#75
I didn't see that:(
On the positive side, researchers and Frequency Therapeutics will be hopeful or even better, discovered something.
Important enough to make them decide to publish that they will start the first clinical trial so soon.
Just regenerating hair-cells that do not improve hearing loss is obviously not their goal.
 
#76
bellringer said:
I will be the Debbie Downer. They can grow hair, the difficulty is making them able to work like the previous ones they are replacing... ability to transmit sound.

https://report.nih.gov/NIHfactsheets/Pdfs/HairCellRegenerationandHearingLoss(NIDCD).pdf:

To test this theory, NIH-supported scientists destroyed hair cells in a mouse inner ear. Time lapse photography showed neighboring supporting cells migrating to the hair cell region and growing hair bundles on their surfaces. Although the process did not result in restored hearing in the mice, researchers began to investigate whether experimental augmentation of the process might improve hearing loss.

Effective treatments is like finding a needle in the haystack. Maybe this one will succeed where others have failed. Only 1 in 10 treatments make it through the clinical trial process. Seeing we have had a number of failures over the years maybe we will have a success... It will be a long wait and until the trials come out, but I will be one willing to lend an ear for experimentation.
Click to expand...

this article is also from 2010. i would expect progress over the last 7 years from when this report was published.
 
#77
Yes they wouldn't say that they want to start clinical trials in humans in 18 months if they weren't able to restore hearing in mouse...
They probably tested ABR
 
#81
Here in the states, most large ENT
Reinier said:
On the other hand. sometimes I feel that there is very little progress. As if there is this invisible force pushing back.
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Bottom line is frequency has a concept and they are going to develop it. It sounds promising. I don't think there is anything that will stop them. No invisible force. We will see what happens and it should be interesting. Keep in mind though that testing in mice doesn't always transfer well to what will happen in humans as seen by AUT00063. If all goes well, clinical trials start in 18 months and then approx 3-4 years after they will be complete with phase 3 and hopefully it is a success and we will have a treatment.

Novartis might have a treatment before then. Who knows, depending on what happens in the clinical trials. It sounds like Decibel is taking a more ground up approach by continuing to do research and figure out everything they can before trying to develop a concept for a clinical trial. 18 months is a long time though and they might have something too.
 
#82
"We further tested the conditions using one sample of healthy human inner ear tissue isolated from a 40-year-old male patient undergoing a labyrinthectomy to access a tumor on the brain. The inner ear tissue was microdissected to remove bone, debris, and nerve tissue. The tissue was then treated identically to the mouse tissue to isolate single cells for culture. The single cells formed clonal colonies after 12 days under EFICVP6 conditions, although expansion was not as robust as that seen for neonatal cells (Figure 6Figure 6F). The colonies stained for Sox2, a known marker of inner ear progenitor cells (Figure 6Figure 6F). After 12 days of expansion, the cultures were treated with LY411575 and CHIR for 10 days to differentiate the colonies. The colonies stained positively for the hair cell marker myosin VIIa (Figure 6Figure 6G), suggesting that sensory epithelium from adult human inner ear can also give rise to hair cell progenitors."

We're almost "past" the mice stage.
 
#84
no idea why this hasn't blown up on this forum. imagine what the knowledge of these discoveries will be 5 years from now! especially if we start fast tracking regenerative medicine. with great advances comes more funding. all good things.
 
#85
Reinier said:
I need to rein in my enthusiasm about the frequency therapeutics developments. It "sounds" too good to be true:)
Within 18 Months the first clinical trial!
Click to expand...
Yes, it's "within" 18 months. Good memory!

Some of the researchers have started a company called Frequency Therapeutics, which has licensed the MIT/BWH technology and plans to begin testing it in human patients within 18 months. "We hope that our work will allow other scientists to pursue studies of supporting cells and hair cells that have not been possible because such limited quantities of hair cells were available," Will McLean says.
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What I keep wondering is how they came up with the number 18? Why not 17? Or even 19? I don't know... it seems like too specific. Like they have the future planned and pinned down to the nearest month.
 
#86
Foncky said:
That would mean the new hair cells also connect themselves to the nerve ?
Click to expand...

I interpret this as if they will form synapses, but only if the SGN axon terminals are intact. How can they be? My understanding is that when a hair cell dies, the synaptopathy begins, followed by neuropathy. The last thing to go is the SGN. Thankfully these can survive for a long time. But they don't spontaneously reconnect to newly regenerated hair cell. So this is a missing bit of the puzzle.

After some reading, it appears to me that inner hair cells are more important for hearing than outer hair cells, followed by their synaptic preservation. We have plenty of outer hair cells, we can afford to loose a few here and there. But the inner hair cells and preservation of their axon terminals is most crucial.

I'm not sure exactly how the axon branching looks like and what nerve endings innervate the outer hair cells, but I know that for each inner hair cell there is one SGN (spiral ganglion neuron). So for 15000 of inner hair cells, there ought to be 15000 SGNs.

Like I said, thankfully SGN cell bodies survive for a long time. But we will need a way not only to regenerate new hair cells but also to regenerate nerve endings so that they may once again make a synapse with the brand new hair cells.
 
#87
Samir said:
Yes, it's "within" 18 months. Good memory!



What I keep wondering is how they came up with the number 18? Why not 17? Or even 19? I don't know... it seems like too specific. Like they have the future planned and pinned down to the nearest month.
Click to expand...

I'm in construction and build restaurants. They will have a timeline that literally gets down to the day. It's called a Gantt chart and they have processes that have been done before and they know how long it takes. So I could be building a restaurant that will be done in 56 days.
 
#88
I'm fascinated by the credence given to press releases by people on this forum. The 18 months comes from Frequency's press releases. I'm sure it is a goal, and I hope it is met. In fact, there may be reasons (described below) to be cautiously optimistic, but they don't come from the marketing department. As an example of why I think caution is in order, consider this article from January 5, 2017 http://www.xconomy.com/boston/2017/...langer-aims-to-fight-hearing-loss-with-drugs/ where it says "Frequency hopes to enter human clinical trials in the next 18 months in patients with hearing loss, according to the spokeswoman." This is almost 2 months ago but they aren't talking about trials within 16 months now. It will be interesting to see if/when the timeline they give changes.

It's also the case that based on the paper in Cell Reports we don't know whether the hair cells are functional. They have many properties of hair cells but that has been true in other cases. In this article (http://www.livescience.com/57952-scientists-grow-hair-cells.html), Edge acknowledges this "These laboratory-grown hair cells appear to have many of the characteristics of actual inner and outer hair cells, although they might not be fully functional, Edge said."

So the cautions are 1) we don't yet know whether the hair cells are functional and additionally 2) the process is less effective for adults. From the paper "While the extent of expansion of Lgr5+ cells from adult mouse tissue was less than that from neonatal cells, the normally quiescent supporting cells from the adult mouse, rhesus, and human inner ear responded to the small-molecule cocktail used on neonatal tissue. However, additional molecules will likely be required to enhance the expansion of Lgr5+ cells from the adult cochlea."

There are, however, reasons to be (cautiously) optimistic. The paper was initially submitted on December 30, 2015. So the initial work was done in 2015. The revised paper was received on January 5, 2017. So revisions took about a year. What this means is that they have known at least some of these results for over a year and have surely been building on these results over that time. This makes it very likely that they know the answers to some of the questions we have. They may or may not be the answers that they or we would like, but they know more now than is in this paper. What will be interesting will be to see the next paper. How quickly will there be a second paper? Will they show that the hair cells are actually function? Will Frequency have the additional molecules needed to enhance the expansion of cells in the adult cochlea? Will they be able to demonstrate that injection of these molecules into a living mouse can restore noise damaged hearing? Assuming they get that far, will that work if the damage is "old"?

Additionally, based on my reading of regenerative medicine trials, assuming we get to trials (which in spite of the press releases isn't guaranteed yet) there may not need to be separate Phase 1 and Phase 2 trials. Unlike "normal" medicine where it makes sense to test for side effects in healthy volunteers, in regenerative medicine trials it doesn't make sense to regenerate things in healthy people so pure Phase 1 seem not to be done. Thus, my expectation would be that like the Genvec trial, we would see a small Phase 1/2 trial with the possibility of a separate Phase 2 or maybe even Phase 3 trial next. Another question about trials is how long they will need to be. Improvements in hearing should happen relatively quickly. The question would be how long the trials would need to be to address either safety concerns or the durability of any initial benefits.

Lastly, completely missing from the focus on "18 months" is the more immediate benefit. Assuming it is replicated by others, this approach immediately dramatically increases the number of hair cells that can be generated for research. This will speed tests of drugs, understanding of development, etc. This has the potential to be very beneficial for many labs working with hair cells. (I also don't know how Frequency's patent application(s) will affect anything.)

As an aside, it is interesting that the revised paper was received by the journal on January 5, 2017 and Frequency "went public" and announced their board of directors on, you guessed it, January 5, 2017 (http://www.frequencytx.com/news-events/pr-01-05-2017.php). On Jan 5, they wouldn't have known with certainty that the paper would be published (it wasn't accepted until the 25th), but they would have had a good idea that it would be. Who knows whether they were related but interesting timing nonetheless.
 
#89
Thank you for this great info! wonderful to read! I had no idea. And to make things more exciting, there is another company-Decibel Therapeutics, that is working on the same concept! "The company is testing a number of potential drug candidates for drug- and noise-induced hearing loss, genetic conditions and tinnitus." So there is motivation to be the company to come out with this first!
http://medcitynews.com/2017/01/biotech-startups-hearing-loss/?rf=1
 
#90
Mricha37 said:
I'm in construction and build restaurants. They will have a timeline that literally gets down to the day. It's called a Gantt chart and they have processes that have been done before and they know how long it takes. So I could be building a restaurant that will be done in 56 days.
Click to expand...
Well, I don't work in construction but I'm familiar with Gantt charts. The type of work they are doing here surely requires a lot of planning and project management skills. Using Gantt charts is inevitable. I was just wondering why I kept seeing this number 18 all over the place. Then I saw Aaron's post where he questions the credibility of the press, and rightfully so. From the looks of it, they seem to copy and paste from each others' articles.

Not sure if it's been posted already, but there is also this one in Endpoints, also from Jan 5, 2017:

They plan to jump into human studies in about 18 months.
Click to expand...

https://endpts.com/another-langer-b...ims-for-the-clinic-with-hearing-loss-therapy/

The opening of this article begins with:

Over the last 18 months the team at Frequency Therapeutics' Kendall Square office has been making quiet progress with its preclinical work on a new approach to curing hearing loss, exploring the potential of a therapeutic technique that emerged out of the lab of MIT's serial science entrepreneur Bob Langer and his colleague Jeff Karp.
Click to expand...

No wonder I kept seeing the number 18. Then there is also the "press release" release on Frequenciy's own website, from Feb 21, 2017:

"Frequency's development of a disease modifying therapeutic that can be administered with a simple injection could have a profound effect on chronic noise-induced hearing loss, our lead indication, and we are rapidly advancing this program into human clinical trials within the next 18 months," added Chris Loose, Ph.D., Co-founder and CSO of Frequency Therapeutics.
Click to expand...

http://www.frequencytx.com/news-events/pr-02-21-2017.php

So what's this now? Frequency referring to the news articles in their own press release? If I didn't know better, I would say the time is standing still. I hope it means they were too busy working on a cure that they didn't have time to formulate a fresh new statement.
 

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