Frequency Therapeutics — Hearing Loss Regeneration

[d'Wooluf]

I think it's extremely pertinent that they are adding audiograms up to 16000 Hz and tinnitus scores to phase 2a. This tells me that something in phase 1 is prompting them to add these measurements to the experimental arm of the study

They might want to test the hypothesis that drug delivery is the issue? So if there's some movement at 8 kHz, test for 16 kHz, and if there's even more movement there, that's corroboration.

I do wonder if there had been comments about tinnitus reduction and that's why it was added to phase 2.

I still think the 'fallback position' argument could account for this. Or else they Googled themselves and found that the most active discussion on their program was on a tinnitus forum. For those for whom tinnitus is their main problem, I'm happy.

 

[Auron]

Here's the truth.

These types of drugs work. They restore hearing. FACT. Restoring hearing will alleviate tinnitus and hyperacusis PROBABLY FACT. They are also kinda dangerous because they are messing with cellular signalling pathways that can trigger tumors and other stuff. FACT. As long as they don't get into the blood stream then they are okay. FACT. That is why phase 1 was measuring blood plasma levels.

Here's the doom scenario, and I am speaking from experience. An ENT is doing this procedure, and sticks the needle in a little too far and instead of injecting the gel into the middle ear cavity, they inject it into the middle ear epithelium. That will introduce the drug I to the bloodstream. BAD. It can happen. One time Minbo Shim did that to me with PRP, and it hurt so bad that I was cussing him out. It was up there in the most painful things I ever experienced, but that was 1 out of > 100. AND it was PRP so it was okay.

I 100% believe this is a full blown cure for many of us, but success depends on the steady hand of the ENT/Otolaryngologist doing the procedure and it could be the difference between life and death. And it will not be a one time shot, this will undoubtedly require multiple injections.

Make no mistake, this is some high wire medical shit that will require the ENT to be perfect with their hands. Despite the awesomeness of this technology, the major risks might sink this. Hope not.

Looks like a lot of things need to go perfectly right for this to work and if only one thing goes wrong, we might be growing tumors. The way my life has gone, I'm screwed eh. Maybe I should just give up on ever having good hearing ever again. That would be just one less thing that can disappoint me in life.

 

[jeff W]

This could be a potential problem with inexperienced ENTs driving BMWs and having no hand on experience with intratympanic injections. When and if this drug is available, we will then have to search for skilled ENTs. I'd go to Silverstein in Florida, he's invented so many things already, but he's old and deserves to retire. Perhaps one of his protégés as long as he's not high on coke ...

One step at a time. Phase 2a coming soon. Let's jump that hurdle, fingers crossed.

Although I am reconciled to my condition, I still have hope and can dream for a brighter day. I am only human... I think.

So glad you are here FGG, and JohnAdams, you always brighten my day. Thanks.

 

[d'Wooluf]

This could be a potential problem with inexperienced ENTs driving BMWs and having no hand on experience with intratympanic injections.

Hey, sounds to me as likely as a dentist with no experience in tooth extraction. They are surgeons. Doing an injection shouldn't be a problem.

When and if this drug is available, we will then have to search for skilled ENTs

My prediction is that when/if this drug is available we'll all take whatever ENT we can get.

 

[Coleoptere]

Here we have the meeting coverage from the AAO-HNSF conference. Essentially not much news:

https://www.medpagetoday.com/meetingcoverage/aaohnsf/82242

No patient got worse hearing (at least for <8 kHz). So that is good news. As for the phase 2a I really hope they include more variation in testing like different doses, concentrations, period FX-322 remain in the ear etc. At the end we do not want to see a false negative.

 

[Daniel Lion]

Hey, sounds to me as likely as a dentist with no experience in tooth extraction. They are surgeons. Doing an injection shouldn't be a problem.

My prediction is that when/if this drug is available we'll all take whatever ENT we can get.

Nope, not me...

I will research and find out who has the steady hands and good track record...

 

[Frédéric]

It regrew the hair cells in a human cochlea that was donated by a guy that was getting it removed to operate on a brain tumor and the guy was more than likely alive when they did that, his cochlea just wasn't in his head.

So......... you're wrong?

Sorry, I am confused, I missed this piece of news. Can you recall the source please?

 

[JohnAdams]

Sorry, I am confused, I missed this piece of news. Can you recall the source please?

"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. The colonies stained for Sox2, a known marker of inner ear progenitor cells. 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 , suggesting that sensory epithelium from adult human inner ear can also give rise to hair cell progenitors."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395286/

**MPP Chief Science Officer out**

 

[JohnAdams]

Did Dr. Shim aspirate before injecting to make sure he didn't get a flash of blood?

You mean squirt a little out of the needle first?

 

[Philip83]

They might want to test the hypothesis that drug delivery is the issue? So if there's some movement at 8 kHz, test for 16 kHz, and if there's even more movement there, that's corroboration.

Have they announced 16 kHz and tinnitus consideration? Sorry, haven't read the thread for a while.

 

[FGG]

You mean squirt a little out of the needle first?

No, I mean pull back slightly on the plunger to make sure blood doesn't enter the syringe. Standard practice when it's important something doesn't get injected into the bloodstream.

 

[FGG]

Have they announced 16 kHz and tinnitus consideration? Sorry, haven't read the thread for a while.

Yes, it's in their very large IPO announcement file.

 

[JohnAdams]

No, I mean pull back slightly on the plunger to make sure blood doesn't enter the syringe. Standard practice when it's important something doesn't get injected into the bloodstream.

¯\_(ツ)_/¯ probably.

 

[Mr Mister]

View attachment 32014
"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. The colonies stained for Sox2, a known marker of inner ear progenitor cells. 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 , suggesting that sensory epithelium from adult human inner ear can also give rise to hair cell progenitors."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395286/

**MPP Chief Science Officer out**

That is called "in vitro" not "in vivo". In vitro is performed in a test tube or elsewhere outside a living organism. In vivo is taking place in a living organism for example living human. In the prospectus it states that they have tested human cells in vitro.

From the IPO prospectus:
"We tested FX-322 in multiple preclinical studies, including in human cells ex vivo and functional hearing tests in mice in vivo. In in vitro testing of isolated human inner ear progenitor cells with the compounds comprising FX-322, we observed the formation of new progenitor cells and their subsequent conversion into hair cells. We also observed translation across species in our in vitro studies of the inner ear progenitor cells from rhesus macaques in which a similar expansion of cell numbers were observed as in the in vitro studies of human cells."

 

[FGG]

That is called "in vitro" not "in vivo". In vitro is performed in a test tube or elsewhere outside a living organism. In vivo is taking place in a living organism for example living human. In the prospectus it states that they have tested human cells in vitro.

From the IPO prospectus:
"We tested FX-322 in multiple preclinical studies, including in human cells ex vivo and functional hearing tests in mice in vivo. In in vitro testing of isolated human inner ear progenitor cells with the compounds comprising FX-322, we observed the formation of new progenitor cells and their subsequent conversion into hair cells. We also observed translation across species in our in vitro studies of the inner ear progenitor cells from rhesus macaques in which a similar expansion of cell numbers were observed as in the in vitro studies of human cells."

The "ex vivo" is referring to the removed human cochlea that @JohnAdams referenced. It is a bit disingenuous to suggest this is equivalent to a test tube.

 

[JohnAdams]

That is called "in vitro" not "in vivo".

Cool story bro. I never said it was in vivo.

 

[WickedCarnival]

They aren't messing around... Sept 30, 2019. That's a week away. We should keep an eye on the stock to see what it does.

It didn't catch my excitement until now for some reason aha, but yeah that's really soon!

 

[Mr Mister]

The "ex vivo" is referring to the removed human cochlea that @JohnAdams referenced. It is a bit disingenuous to suggest this is equivalent to a test tube.

I am not suggesting anything but just quoting a general definition of in vitro which is "happening outside the body in artificial conditions, often in a test tube".

 

[JohnAdams]

Alright chaps, ponder this:

They are starting their Phase 2 very shortly. From the time they finish dosing until the time that they will measure hearing improvement, AND TINNITUS, it will be 3 months. BUT we will have to wait an entire year to know what the results were. That's 9 months that we will all be sitting here going insane and killing ourselves without being allowed to know if this helps with tinnitus.

 

[Phendran]

BUT we will have to wait an entire year to know what the results were.

Somehow it feels like it would benefit them more to tell the entire world of their results.
If positive, people will start anticipating the world to change. Hearing aid companies will start to shiver.

 

[ChrisBoyMonkey]

There was no change in audiogram so according to Occam's razor the most obvious cause is something like bias. Bias is the intentional or unintentional adjustment in the design or conduct of a clinical trial that may affect the results. For example selection bias. The simplest solution is most likely the right one.

I have done word score tests and they are not that scientific and clear cut like an audiogram. So depending on your hearing curve if you are at the borderline you may "figure out" the test after some time. I don't know how they chose the patients in the groups but that could be one explanation.

If I was to look for more extraordinary explanations then I would guess the drug improved some frequencies within the speech range (let's say eg. 500-4000 Hz) and that improvement happened to take place within just narrow range between tested frequencies. Maybe it improved eg. between 3200 – 3500 Hz when they tested only 3000 Hz and 4000 Hz and so on.

I don't actually believe that they did not test up to 16000 Hz. This drug and its basic principles have been researched for a long time and a lot of money has been invested. Then comes the big day when this drug is finally injected into the ear. Would these highly qualified hearing specialists and professional scientist decide that we will only test it up to 8000 Hz? Would their investor agree that lets leave some stones unturned? No no no… That makes absolutely no sense. Testing from 8000 Hz to 16000 Hz adds no costs and takes about an additional

Alright chaps, ponder this:

They are starting their Phase 2 very shortly. From the time they finish dosing until the time that they will measure hearing improvement, AND TINNITUS, it will be 3 months. BUT we will have to wait an entire year to know what the results were. That's 9 months that we will all be sitting here going insane and killing ourselves without being allowed to know if this helps with tinnitus.

Well for those that have good enough hearing there's always Neuromod in the meantime

And hopefully the Michigan device soon after.

 

[Auron]

AND TINNITUS

Is that now your main concern today?

 

[Jurger]

Hi people, longtime lurker here. I'm still reasonably positive about this drug, but I'm wondering if the delivery method isn't part of the reason most patients didn't improve below or at 8000 Hz in this trial. In other words, I have my doubts about the efficacy of intratympanic injections. Frequency itself basically said the same thing by pointing to their previous findings that the highest concentration of the drug is found in the base of the cochlea (high frequencies). A better delivery method would ensure not only that the drug reaches the apex of the cochlea, but also higher concentrations of the drug overall and possibly for a longer period of time. Intratympanic injections have downsides because, among other reasons, not all round window membranes are created equal. A recent article states:

"For instance, IT delivery of drug-loaded gels to the round window niche is reliant upon permeation of compounds through the RWM, a process sensitive to numerous factors including the size, charge, and lipophilicity of the molecule. In addition, permeation rates between individuals and between species vary widely, presenting challenges in terms of the number of studies and replicates required to gather reliable data, and for future regulatory approval based on the performance of the delivery technology."

https://www.tandfonline.com/doi/full/10.1080/17425247.2018.1444026

That might very well explain why some patients in this trial improved at 8000 Hz and others didn't. Aside from permeation rates, a drug delivery method that is dependent on not swallowing or talking for an hour is simply not ideal. How are you gonna get kids to do that for example, for whom these drugs are also intended?

Anyway, I'm wondering if the science (and our efforts?) shouldn't focus more on intracochlear or nano drug delivery to give these drugs the best chance of doing what they are intended to do. Would like your thoughts on this.

 

[JohnAdams]

Is that now your main concern today?

Yeah a little. I'd like to try and be totally healed though. I'm pretty sure that it is the main concern of most people here. My tinnitus is actually gone a lot, but now that I've been on this forum for over a year and made several friends and seen how horrible this is for so many people I am totally obsessed with this issue.

Well for those that have good enough hearing there's always Neuromod in the meantime

And hopefully the Michigan device soon after.

Or maybe someone with the right authority will allow this process to be rapidly sped up.

 

[FGG]

How are you gonna get kids to do that for example, for whom these drugs are also intended?

You could do that with kids by sedating them or putting them under general anesthesia, if necessary.

 

[Jurger]

You could do that with kids by sedating them or putting them under general anesthesia, if necessary.

You could, but that would obviously seriously impact the "get your injection at your doctor's office" part of the pitch of these companies. You'd be putting them under general anesthesia everytime, so possibly every few days for three or four times in total.

 

[Rb86]

I said I'd post their response as soon as they got back to me so here I am.
Keep in mind I simply asked when they're planning on releasing the results of their study. This response makes no sense but here it is for your enjoyment.

"Thank you for contacting Frequency Therapeutics; we appreciate your interest in our company.

Frequency Therapeutics develops small molecule drugs that are designed to activate progenitor cells within the body to create functional tissue. Progenitor cells are the natural sources of tissues throughout your body and remain present through adulthood. Through the transitory activation of these progenitor cells, Frequency aims to enable disease modification without the complexity of genetic engineering. Our therapies use proprietary combinations of small-molecule drugs to cause dormant progenitor cells to multiply and create new cells.

Please be aware that it is important that you not discuss your condition with anyone at our organization. We take very seriously the privacy of all individuals that may be participants in ongoing or future clinical trials that we sponsor, as we are legally bound by the rules as set forth in the 1996 HIPAA Act. We encourage you to discuss your condition and your interest in trial participation with your healthcare providers, since your potential candidacy is based on their medical evaluation of your health status. Please appreciate that we are not able to discuss this matter with you any further based on the information we've provided herein.

Again, at this time we are unable to provide you with any additional details on the status of our programs. As Frequency Therapeutics is a privately held biotechnology company and not a medical provider, Federal Regulations prohibit the sharing of any information between our two parties. If you would like to stay informed about Frequency Therapeutics and any ongoing clinical trials evaluating our drug candidates, please refer to www.clinicaltrials.gov - You may search by disease, location of clinical trials, or by the name of the company sponsoring the clinical trials. Additionally, you can reference the latest press releases available on our website www.frequencytx.com for information regarding upcoming or ongoing clinical trials.

Thank you again for reaching out and we wish you well. "

 

[lymebite]

This response makes no sense but here it is for your enjoyment.

There is also the situation that with the Frequency Therapeutics IPO apparently scheduled for next week, they are in a strict SEC-mandated "quiet period" when then are not really supposed to talk to much of anybody about much of anything. So that could be influencing their cautious response.

"Prior to a company's Initial Public Offering (IPO), the quiet period is an SEC-mandated embargo on promotional publicity. This prohibits management teams or their marketing agents from making forecasts or expressing any opinions about the value of their company."

https://www.investopedia.com/terms/q/quietperiod.asp

 

[d'Wooluf]

Nope, not me...

I will research and find out who has the steady hands and good track record...

How long are you prepared to wait?

 

[JohnAdams]

You could do that with kids by sedating them or putting them under general anesthesia, if necessary.

I don't think so. Well, depending on how thick the gel gets. When you swallow, fluids flush down the eustachian tubes and the best thing you can do is not swallow or talk when medicine is in the middle ear. When you're asleep and or sedated, swallowing is involuntary. I have probably had more intratympanic injections than anyone else in North America, possibly all of the western world. If not then I'm certainly up there. When the ear drum is numbed correctly, it isn't that bad. It is a little intense but kids can hold still. One thing that happens is that as the middle ear fills with a substance that is a different temperature than the body is that you get transient vertigo for a minute or so.

I also know very well what it is like to have the injections when the lidocaine wears off. It is really painful and intense. There is the pain, the noise of the needle going into you eardrum, the vertigo, etc. BUT as soon as the needle come out all is well and it only takes a second. Some kids probably could not handle that. A better option than sedating them would be to immobilize them.