Frequency Therapeutics — Hearing Loss Regeneration

It’s sad, shameful, and a tragedy... I wonder a bit though...

How much is it being misinformed, versus the drug companies pushing their products? Look at the opioid crises with emails coming out that the execs knew how addictive that junk was.
Did you ever see a fugly drug rep walk into a doctor's office? I haven’t. ;-)

“Do no harm,”... (unless there is a kickback from the drug company).

 

The company has recently said they expect therapeutic penetrance of the drug to reach 3500 Hz and above (meaning 8000 Hz and beyond). From Frequency's job postings, though, it looks like they are working on a version that will extend further into the cochlea (below 3500 Hz) so there may be a version a year or two later that gets the full cochlea. Seems realistic since Pipeline verified for me their drug does and uses the same vehicle that Otonomy does. So we already know it's possible.

 

Not so fast, there are studies that show to be helpful:

https://journals.lww.com/thehearing...=2017&issue=03000&article=00008&type=Fulltext

https://www.frontiersin.org/articles/10.3389/fpsyg.2014.00587/full

http://canadianaudiologist.ca/issue/volume-5-issue-2-2018/hidden-versus-not-so-hidden-hearing-loss/

Oh so different people might have different responses due to genetics, random factors, etc. I see. Hopefully FX-322 or additional treatments in the future can be including alongside antibiotics when absolutely necessary to prevent or reverse damage.

 

I think so, in fact this doctor has a protocol for hydrops reduction based on a combination of diet, steroids, psychiatric medication, fluids. Some of his patients recover from tinnitus after many years. He attributes this to the ear cells straightening after excess hydrops are eliminated. He says there are not many other explanations why in some people tinnitus may go away after a long time. I am not sure myself, I tried a diet to reduce hydrops but had zero benefits, and my hearing loss/tinnitus is not in the typical hydrops range so I gave up hydrops as a possible diagnosis. Also, he has Clonazepam among the medication he recommends, and we know that alone can be effective in greatly alleviating the symptoms.

If anyone else who is reading this suspects hydrops might be your cause for tinnitus, take a look at this:

https://www.drlatorre.info/hydrops-eng

 

I also tried the hydrops diet strictly for 3 months. Made zero difference for me. I think it's probably worth trying, especially with low frequency tinnitus (mine is all very high).

 

How much hearing do you need to be a potential candidate for FX-322?

My hearing is fine between 0 and 5500 Hz, but I almost can't hear anything above 8 kHz, I have lost 60 to 70 dB at every frequency above 8 kHz. I'm only 27 years old, I guess that's genetic.

 

70 dB is still "moderately severe" which was included in phase 1. They seemed to prefer sudden hearing loss but I'm not positive about that. If you are interested, you should call one of their testing centers and set up an interview. They pay you for your time (but not travel if you don't live near a site) and you may qualify.

 

I have but I'm sure their box of incentives was just as attractive.

 

They set a 70 PTA limit without mentioning which frequencies are concerned but I guess it's every frequency above 3500 or 4000 Hz.

Is this limit set arbitrary or there is a reason it might not work on more severe hearing loss? I read that Otonomy is leading research on severe hearing loss which means that severe cases may not be treated the same way.

I wish I was a candidate but I'm French and live in France.

 

Their exact inclusion parameters have not been made public. We should know more end of this year.

 

Are they still recruiting for this at all? I live an hour and a half away from one of their facilities.

 

According to clinicaltrials.gov, yes. Though I'm not sure if that's true of all the centers. I would call and ask.

 

3500+ till 20kHz, but I don't think that reaching 3500Hz is possible. It just seems too good.

 

They are doing this for phase 2a of the trial that is going on now.

 

Exclusions: “Any conductive hearing loss of 10 dB or more at two or more frequencies in either ear.”

So my “normal” age related hearing loss in the mild to moderate range isn’t “conductive” if I am reading this right?

Thanks!

 

Age related usually isn't conductive but there can be conductive causes that can worsen with age. Your audiologist should be able to tell you which type you have by checking air vs bone audiograms.

 

Closest we have to having a real (people) doctor on this site, IMHO
(Other than the Doctors' Corner)

You would think the audiologist would have volunteered this information about the bone audiogram... especially since the ENT wondered if that was why I was affected do much (bone conduction).
ENTs, Audiologist, Orthopedists, are all scam artists... feel free to add to the list

 

My guess is that if you had a conductive problem evident on your audiogram, they would have mentioned it (giving them benefit of the doubt here). Wouldn't hurt to call and ask to make sure especially if your ENT suspected it might be a problem.

 

You are giving them way too much credit!

 

Nice links, although my brain did try to self-induce a protective coma at several points. I'm starting to think that FX-322 might be specifically targeted at me. I'm also getting on board with the idea that the decision by Frequency Therapeutics not to test those high frequencies in 1b was a mistake.

 

Small little point: It seems the Germans have some annual prize for the best research paper written on tinnitus.

That might be a good way of getting the right people to actually compete in concentrating their grey cells on finding the answer.

 

SLIDE 3:
So I just want to spend a moment and really talk through slide number three. What is really important to take away from this slide, Frequency Therapeutics has been focussed, really from our earliest days, on a deep biological justification for all that we do with a process that we call Progenitor Cell Activation. What PCA is, is really accessing underutilised or hibernating stem cells or progenitor cells in the body to create a localized healing response using a pair of small molecules and we've been focussed on that opportunity primarily in the area of inner ear biology.

It's really a platform. This is a disease modifying approach and we're very confident that we can take this well beyond hearing, though we are focussed on our near term hearing opportunity. But as we look at other parts of the body, including MS and the myelination associated with multiple sclerosis.

We have a program FX-322 lead candidate that is in phase 2a study that is currently enrolling. We expect to have data read out for that by the end of 2020, but what is really important to understand about that, is all of that data and the way we structured that phase 2a was really built off a phase 1/2 safety study that really where, for the first time in history we are able to show that we can take a system 'hearing' that typically never regenerates or repairs itself and can show an improvement. It was really with that we have been building this company forward with alacrity.




SLIDE 4 & 5:
So the sort of level set of where we are and try to understand the work that we are doing in hair cell regeneration. Let's all remember that when we are born on each of our cochleas with 15,000 of these sensory cells or hair cells and evolution expected us to take this with us from birth until death. Really important part. So the body knows how to recycle on the system at least one time, when you are in utero. However it doesn't do that a second time, but we know other species, like reptiles, do have that ability. And that is exactly the opportunity that we are driving forward on.

So as we look at the biology of cochlea. And as we take a moment to orient ourselves. It is really important to understand, what you see here is a highly organized system, exquisitely designed. You can look at this as the pianos on a piano keyboard where you are going from high frequency closest to us, all the way down to low frequency. And you have three rows of outer hair cells that are really designed to sort of tune and filter and clean sound and then one row of inner hair cells that is directly connected to the brain to deliver that signal. And this is what we're born with. This is what healthy hearing looks like.



SLIDE 6:
And this is the world we live in. Noise is the epidemic. Whether it's going to a Celtics game, whether it's sitting on an airplane, whether it's earbuds or headphones. Noise is the epidemic. That is really what is happening to all of us, as many people establish or are establishing sensorineural hearing loss, what is really otherwise know as noise pollution in short hand.



SLIDE 7:
This is what sensorineural hearing loss looks like. You can see that the hair cells have been damaged. What happens is, wave after wave of aggressive sound will come into that system and will really cause those hair cells to sort of shake and vibrate. Eventually they would die or apoptose and be removed from the body and be ejected from the body. You have something that is akin to a missing tooth. So you have the biology that surrounds it, progenitor cells, that would have the ability to be regenerative, but there is no cue to turn that system back on. And again that is the opportunity we are focussed on.

Two other key points is, many of the maladies that we are facing as it relates to hearing loss. That is really the front door where sound enter in the cochlea and where so much of the aggressive damage occurs. It's also important to remember that, all these hair cells are designed where the three outer rows are designed for tuning sound and then delivering that to the inner hair cell which communicates it to the brain.



SLIDE 8:
And so what we have here is the ability to say: "I can hear you, but I can't understand you". "I can hear you, but I can't understand you" or said another way by a doctor recently is, you know, nobody has ever come into his house and said "Doc, I've lost 10dB of hearing, you know, my <inaudible>(?)". No, I can't understand my kids when I'm driving the car and they're sitting in the back seat. And that's that unmet clinical need, this idea of clarity of sound. That's what I'm now going to spend a few minutes talking about.



SLIDE 9:
So what you have here is something that is really important. So hearing, like so much of our native biology and our biology throughout our body is interconnected. It's a holistic system and what you have is that hearing loss, recently reported, is the largest modifiable factor for developing dementia. Published in JAMA, untreated hearing loss, there is a 50% increase in dementia and a 41% increase in depression. So you have a system that is so fundamental to our brain health. The ability to have a therapy that can start to regenerate and heal that system, holistically across all frequencies is exactly the clinical opportunity the Frequency Therapeutics team is focussed on.



SLIDE 10:
You have about 720M people worldwide affected with sensorineural hearing loss. A tremendous population and there are no restorative therapies that exist. Right now, of course we understand that there are mechanical overlays, but what they're trying to do is really pump sound to a broken system underneath. When you think about Frequency Therapeutics, when you think about the sophisticated work that the men and women in our organization are doing, you need to think about that we're trying to commit to healing that underlying biology.



SLIDE 11:
To give a context of where we are with the lead programs. We have first of its kind data. Phase 1/2 results that were presented a year ago. We presented this data at the world's leading ENT conference back in September at a late break-in session. Susan King our primary investigator of that study presented it and we had a lot of constructive feedback and positive feedback from that results. We have also gone out and are committed to reach out to the KOL's, both in the hearing space and the audiology space, to communicate to them and to share with them this data first-hand. We currently have a phase 2a study that's going to read out at the end of this year. We have fast-track designation with that study. We continue to have a very constructive partnership with the folks of the Astellas Pharmaceuticals, where they retain global rights and Frequency Therapeutics retains 100% the US rights for FX-322.



SLIDE 12:
And then stepping back, what really excites me is not just our hearing program, but the ability to have multiple waves of shareholder value and we see that embodied with our MS program, where we see having an IND filed by 2021 and we're looking at numerous opportunities that are presented to us and that we're actively seeking, as we're thinking about a larger pipeline and developing that. We've also been very savvy and shrude as we think about our IP portfolio and the related application for that. Make no mistake about it. We're building a company that is going to be here for long term success built of the progrenitor cell activation insights and platform.



SLIDE 13:
So part of my job and which I'm really honoured to lead an outstanding team of men and women at Frequency Therapeutics, is being able to have the proper financing for this organization. From the very beginning we've always taken an approach where we want to spent our investor's cash with respect in a very disciplined way. So by the time of our IPO in Q4 of this last year, we had close to a quarter of a billion dollars in hand and have really laid out and have been working against a plan where we're going to have cash into 2022, with a number of key milestones to achieve between now and then.

 

SLIDE 14:
So let's just take a minute and shift gears and talk about our clinical program, which has really gathered a lot of attention and has really been an important step in the evolution of people really coming to understand the power of this idea of progenitor cell activation. We're taking stem cells within our body and harnessing them for localized healing response.



SLIDE 15:
What you see here is a visualisation of two small molecules that are delivered together to the middle ear and working with our body's underlying biology and activating progenitor cells and it's having an effect on these progenitor cells in a way where you are getting a short term drug effect, but a long term physiological effect.



SLIDE 16:
Another way to look at this and to see this, is to see on the next slide, where you have these hair cells actually be regenerated or be restored.



SLIDE 17:
So, we all need to step back and understand how do we think about hearing. What are the measuring sticks that are typically used. Audibility has been, not the only one, but the primary one, has been used for such a long time and that's really when you are in fifth grade as I was and need to have your hearing tested and you hear the beeps. That's certainly a valid way of thinking about things at the cross and what specific frequencies, but the area where I'm going address your attention to, is how do we interact with the world we don't just interact with the world with beeps. We interact with the world with the sounds and communication and engagement. This is the idea of intelligibility or clarity of sound. This is the ability for our ears to hear the difference between shore and sure, or hear the difference between lag and nag. And it's there that's our sort of biological line of scrimmage as we think about building shareholder value and helping millions and millions of patients around the world.



SLIDE 18:
I love this slide, because it really visually represents for us all what does sound look like in a visual way. So what you see is when you go from the low kHz to the high kHz, how this saying "Oh say can you see, by the dawn's early light", how is that represented in terms of information or digitally? I think the key take away is, where you see the dotted line, that critical information is lost in the high frequencies in the current standard care and that's exactly what we are focussed on bringing back into the fall biologically and allowing for this idea of hearing clarity to be established.



SLIDE 19:
Again, just to orient everyone again on the procedure. This procedure is a transtympanic procedure. It's done around the world, every day thousands if not tens of thousands of time. It's a small needle where you deliver a gel into the ear. You're not going to violate the cochlea. Just to remind everyone the cochlea is behind a sealed system behind the hardest bone in the body. So drug delivery is such key functionality to this. So having Dr Bob Langer and that expertise by not just doing drug delivery, but by understanding the deep biology of the inner ear has been critical to our success and building out our IP. So we drop a gel on the outside of the round window membrane with two small molecules co-formulated in that and then what you have is, is then you're getting great distribution from the higher frequencies from 20 kHz all the way down to 4000 Hz. It's is really within there where so much of our hearing has declined. It's the high frequencies that millions and millions of people have issues with, because again that is where the entry point where sound comes in and takes the most abuse if you will, from this noise epidemic we all live in.



SLIDE 20:
We had a really successful phase 1/2 study. I think there is really two important points that I want to bring home.
All of these patients, and this is based of feedback from our clinical advisory board, had to have stable hearing loss for 6 months. Many patients really had stable hearing for 6 months or longer. Then I think the other important thing was that there were really three controls that were instituted in the study. It was a double blinded placebo controlled study and only one of the two ears got the injection. Typically the worst of the two ears got an injection and the other ear didn't get an injection. So we didn't see a placebo response and none of the ears that didn't get an injection saw an improvement. So with that we had 23 patients and now I'm going to take you into a little more detail.



SLIDE 21:
We had patients who came into the study who scored well, who had mild hearing loss. Remember this was a safety study. So we were looking at were you going to improve your hearing or was there going to be a hearing decline. We saw no adverse events of that nature. Where we really want to focus your attention, is the patients that had a real deficit. Moderate to moderately severe hearing loss. There were 9 patients in that category. 3 got a placebo drug. All of those 6 patients responded. 4 of those 6 responded in a clinically significant way.



SLIDE 22:
And you can see that represented in slide number 22, where out of 50 words on the word recognition test, for example patient number 2, scored 7 out of 50, while it is likely that this patient is cascading towards a cochlear implant. With one injection patient after 90 days, patient number 2 had a doubling in word recognition score. Why that important is that would allow this patient not to get a cochlear implant and that is a critical importance. Patient 4 went to near perfect after having 50% decline in word recognition score and so this is exactly the work that we're building off of and we are expanding that this end as we look into our phase 2a study.



SLIDE 23:
So as we talk about that phase 2a study and some of the objectives it is really to continue to show cohesiveness between the hearing results that we saw in the phase 1/2 study and a larger cohort. It's to look at repeat dosing and it's to continue to clarify end points and the patient population.



SLIDE 24:
So here we are. Again it's a double blinded placebo controlled study multicentered study. We're going to be exploring word recognition, word in noise, pure tone audiometry. So looking at from very low frequencies all the way up to frequencies in the higher ranges up to 16kHz, which aren't typically tested. We're going to have a tinnitus questionnaire and quality of life questionnaire and these patients are going to be randomized over four weeks. They are going to, over four weeks, get four doses and then they are going to be tracked for 6 months and beyond that.



SLIDE 25:
So as we think about our target population, we realize that, right now, there are about 50M people in the United States that have moderate to moderately severe diagnosed sensorineural hearing loss. We think that number can double and that is underdiagnosed as we bring a therapy forward. Overall there are 60M people with sensorineural hearing loss. Doing the work to understand various channel possibilities and pathways and how to think about this to maximize this for patients and the medical community is part of the important work we're going to be doing in 2020.

 

SLIDE 26:
So, I'm just going to spend a few slides on a Progenitor Cell Activation approach. Because we're building a company that's not only going to deliver shareholder value as it relates to hearing regeneration, but well beyond that.



SLIDE 27:
I just want to, again, remind everyone when we talk about progenitor cells, what are we doing, you can think about these as underutilized assets that mother nature had put in your body for a specific purpose and they are hardcoded to do that, but there is not system or cycle to use them or recycle(?) them back on. That is exactly what our small pair of molecules has successfully shown the ability to do. We believe we can take this approach, as you look throughout the body, clearly we're doing work in the ear, in the brain with multiple sclerosis, but there are progenitors throughout the body, where we believe we also can take this approach.



SLIDE 28:
Our remyelination program was done in partnership with the folks at the Scripps institute, La Jolla California. We have a license arrangement with them. We are very pleased with that partnership. We are looking to (sort of) build on their expertise that they discovered now over the last year, that we've been able to apply in a sophisticated and savvy way as we bring program number two forward. Starting of the second half of 2021 and we will really be able to share more about this program as 2020 moves forward.



SLIDE 29:
So as you think about Frequency, as you think about the work that this outstanding team of men and women, based in (?) Massachusetts, just outside Boston, in Farmington Connecticut. We're focussed on reducing the complexity of regenerative medicine. Working with the body's native or niche biology in the case of the ear. Not physically changing the underlying genetics, but just using small molecules to create a molecular interaction that creates this (sort of) disease modifying effect. Then the Ease of manufacturing using small molecules and being able to create a long term disease modifying benefit without having to remove cells from the body, is also highly desirable.



SLIDE 30:
And then finally we have a clear hearing signal established.
We've been very clear at taking this to peer review, you know, ENT is an audiologist used to share that data.
We are pleased with the feedback we're getting. We look to build upon that.
It's a very substantial market.
We have a great partnership with Astellas Pharmaceuticals.
We are very commited to the long term shareholder value by focussing on the platform of what progenitor cells can do, not just in the next 24 months, but well beyond that.



SLIDE 31:
I just want to thank the outstanding group of men and women that I work with every day and thank the investors that supported this company. We'll be taking questions in the next room. Thank you very much.

 

TRANSCRIPTION FREQUENCY THERAPEUTICS Q&A WEBCAST:

Audience:
Ok, so this is the Frequency Therapeutics break out session. David, if you want to introduce the panel with you as well as in the room, we can get started.

David Lucchino (CEO):
Sure, so this is David Lucchino, the CEO of Frequency Therapeutics, I'm joined at the Amadeus(?) by Christopher Robert Loose our Chief Scientific Officer and Dana Hilt who is our Chief Medical Officer, also in the room we have Jason Glashow who is Senior Vice President of all communication and corporate strategies, along with Sherry Pierce who runs our IR* program.

* IR = Investor Relations
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Audience:
Maybe I'll just kick off the Q&A here with you presenting the sort of full phase 1/2 data on the local conference towards the end of last year. Maybe you can talk about the feedback you receive on the emerging profile, both kind of on the positive side and what positions kind of maybe we want to see a little bit more of.

David Lucchino (CEO):
I'll take that and then ask Chris and Dana to share their thoughts. I think that what we saw when we presented our data at the big ENT conference in New Orleans back in September. The data was presented by our lead primary investigator Susan King out of San Antonio Texas. It was in a late break-in session. There was a lot of (I think) buzz and excitement about what we're doing and there were a lot of questions of course. The hearing field has never seen data like this previously. Remember, the historical control is nobody's hearing has ever .. doesn't improve. So, it is really being thoughtful and direct about the questions that people have. Rightfully so.

Dana, maybe you want to answer some of those in more detail.

Dana Hilt (Chief Medical Officer):
Right and you asked about the reception in the sort of KOL* community and what people are thinking of the data. So the team has gone around to a variety of the key opinion leaders in the ENT's world and audiology world. Presented the data, had in-depth discussions and to a person, really, they are very enthusiastic about this. They say that, looking at speech clarity, word-in-noise and intelligibility. This is real world hearing. This is what patients complain of as David mentioned in his presentation. So, they are very anxious to work with the company and see if we can replicate the signal and extend it. So, that's what everyone is focussed on.

KOL = Key Opinion Leader

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Audience:
What conclusions were made maybe by the physician community or by you guys looking more granular into the data on the impact between mild and moderate patients?

David Lucchino (CEO):
Chris, you want to take that?

Christopher Robert Loose (Chief Scientific Officer):
Sure, I think what was informative is when you look at word recognition the mild patients typically arrived with better than 45 out of 50 word scores, so very little room to improve. So they really were there and demonstrated that there was no loss of hearing, so real safety affect. So that's why we all were very focussed on the patients that did have that word recognition deficit, typically moderate to moderately severe and that's where all the 6 treated patients that showed improvement for profound. As we move forward we'll continue to make sure to have patients that do have a word deficit, so we continue to refine that.

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Audience:
I have two questions please.
1) Patient two had very severe hearing loss and a modest improvement. What happens when you give sequential injections to a patient like that? Do you see <inaudible> improvement?
2) Where do you stand in the cartilage* space in terms of regeneration, regenerative cartillage in the <inaudible>?

David Lucchino (CEO):
Chris, I'll take question one, maybe you can take question two. So, the first question was, in the data we shared in the presentation today, is that a patient number two showed approximately 7 out of 50 word response. With our drug we essentially doubled that to approximately 14 or 15. So the question is how will repeat dosing affect that. It's a great question and that's something that we're asking as part of our phase 2a study. So, when that's study is unblinded we'll know more.

Christopher Robert Loose (Chief Scientific Officer):
We're dosing up to 4 doses in that study.

Audience:
Cartillage.

Christopher Robert Loose (Chief Scientific Officer):
The question was asked on cartilage. Certainly arthritis is big on regeneration in that space. That is an area that we have looked at. There is a potential for regenerative therapy in that space. We're not prepared now to make any statements about any programs in the space.

* Cartilage is a resilient and smooth elastic tissue, a rubber-like padding that covers and protects the ends of long bones at the joints, and is a structural component of the rib cage, the ear, the nose, the bronchial tubes, the intervertebral discs, and many other body components.

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Audience:
Besides the word score in phase 1/2, did you look at any other secondary end-points that would give you any indication of <inaudible>?

Christopher Robert Loose (Chief Scientific Officer):
The question is, are there any other secondary end-points? So in addition to the word recognition score, which is a test in a quiet background. We also saw improvements in word-in-noise, which is basically repeating that test in a restaurant type of environment, where there are 6 people talking in the background, in a you know much more challenging environment. We saw similar improvers, improvements in that space. We also tested the loudness, test, the pure tone types of test there. We noticed that a number of patients with the biggest losses had improvements in the higher frequencies which is were the greatest amount of drug is present and people have the most loss. So moving forward we are going to be continuing with those three end-points, but we will also be adding ultra high frequencies going forward cause we know that's where the drug is concentrated, as well as quality-of-life, tinnitus and other end-points that we're thinking could give us a full picture of what this medication may potentially do.

Audience:
Just as a follow-up on that. Did you see any improvement in the secondary end-points in the mild hearing loss category?

Christopher Robert Loose (Chief Scientific Officer):
We saw trends across the population.

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Audience:
Yeah, so I was hoping to <inaudible> improvement <inaudible> clinically meaningful.

David Lucchino (CEO):
Sure, Dana?

Dana Hilt (Chief Medical Officer):
When we look at these real word speech tests, such as word-in-noise or word identification, we saw a doubling, as David showed on that histogram. And that test, retest is one or two words is pretty reliable test and a change of 3 to 5 words is, the audiologists tell us, are clinically meaningfully changes. These are changes that patients can then detect in their every day life. And you saw from that, even that worst patient went from 7 to 16, so they had an improvement of 9 words. Patient to the right, patient four had a doubling from 24 to 48 or 47. So we think that, while we have to extend and confirm these data, we think that is consistent with a clinically meaningful effect in patients.

Audience:
Does the fact that 2 of the 6 patients had no response at all mean that for some patients this will not work at all?

Dana Hilt (Chief Medical Officer):
So, out of the six patients that had a deficit. The four that David showed had statistically significant effects, the other two had improvement. Ok? They just weren't quite as robust as the four that we showed. So all 6 had an improvement. Ok? And that's with a single dose at 90 days. So obviously in this next trial we are going up to 4 doses, we are monitoring the patients for six months. So maybe these patients will show a response in this type of treatment program.

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Audience:
Just moving from phase 1/2 to phase 2a, Chris, you talked about how some of the milder patients they, on the word recognition, already had a pretty high threshold. So when we think about the inclusion and exclusion criteria for the phase 2a, are there differences where we may be able to illicit a benefit in milder patients?

Christopher Robert Loose (Chief Scientific Officer):
So the question was asked, can we learn from milder patients in the phase 2a, because they typically can have some smaller deficits. What we have done is, we've put in inclusion criteria requiring that patients entering this phase 2a study do have some more deficit. We are not describing publically what that exact criteria is, because we don't want to create any bias.

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Audience:
Early thoughts about durability of the treatment?

David Lucchino (CEO):
Sure the question was early thoughts about durability of the treatment? You know, obviously, we believe we are having a disease modifying effect and, you know, we continue to believe and theorise that we should see long term durability, but we really have to measure what that is. We saw that for 90 days in our phase 1/2 study and the data suggest that the durability was continuing to be on the upswing in a favorable way. So now we will be measuring approximately 7 months as part of our phase 2a study. We will have to see what the data says, but we remain confident that that trajectory should remain.

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Audience:
You've got in your phase 2a and you talked about this like multiple sort of cohorts and different dosing regiments. So looking to the second half data, given the full cohorts, in an ideal world, what is kind of your win scenario?

David Lucchino (CEO):
I think and then I'd like Chris, Dana and I and Carla Labelle(?) who is not here today, who has spoken about this. I'll kick off and then I'll ask Chris to comment. I use the word cohesiveness. I think what we've already demonstrated in the phase 1/2 study is profound and clinically meaningful and I think if we can continue to build upon that in a scientific way, in a biological way, I think that continues to be a real success for us.

Christopher Robert Loose (Chief Scientific Officer):
I think that is the keyword, is cohesiveness of the data. What we'll see in this larger study, it's four times larger. We'll get to understand the dose schedule and how that impacts outcome. And as David said we will be following patients twice as long after the last dosage as in the previous study what will give us information on durability. That's what we're looking for.

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Audience:
But, do you have preclinical models that would suggest that the repeat dosing could have more meaningful benefit? I can't remember.

Christopher Robert Loose (Chief Scientific Officer):
So the question is, do we have preclinical models on repeat dosing? That is not possible in the standard models, which are mouse models. You can't go in and continue to violate the ear drum of the mouse without creating effects. So that's a question we will have to answer in the clinic.

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Audience:
So you demonstrated that you can regenerate hair cells. The patient population are going to have a list of <inaudible> ... biology, including cochlear synaptopathy. Is there any evidence that your drug impacts the synapses?

Christopher Robert Loose (Chief Scientific Officer):
The question is, could there be an impact on cochlear synaptopathy? First, I would say of hearing loss is 90% of hearing loss is sensorineural as we've looked across patients that have donated their cochleas to science after they died. When you have a declining audiogram, it is very common to have hair cell loss. So we think that is really a driving feature. Part of a hair cell being born, it's job is to connect to neurons and create those synapses. So, one could theorise that you could be aiding in that process as well, but our focus is to regenerate hair cells and have them go through the process they go through when they develop and integrate.

David Lucchino (CEO):
And then Chris, there's a follow-up on that question. Would you mind talking a little bit sort of about asymmetric division and the approach that we use as we think about delivering our drug?

Christopher Robert Loose (Chief Scientific Officer):
Sure, the approach in our technology. When it was discovered that there were progenitors in the ear, there have been approaches that have tried to directly force the differentiation of those progenitors into a hair cell directly. Turning one cell type into another cell type. That is not how hair cells are traditionally formed in utero. By following regeneration in the gut in other tissues where the core breakthroughs for our technology were made by looking at regenerative systems. What you see is an asymmetric division where a progenitor copies itself and leaves behind a progenitor and then turns on the right genetic programs to make a fully formed dotter cell, in this case a hair cell. So, we are really steering in a unique direction compared to the prior competitors in the space who have been doing a forced differentiation. We are trying to get a step back with these progenitors to divide, replace the progenitors and kick on all of the genes to form a fully formed, fully integrated hair cell.

David Lucchino (CEO):
And now, we remind everyone, Dr Langer* at MIT who was an institute professor and Jeff Karp* who was a full professor at Harvard medical school. When they had this break-through, it happened in the GI system. They weren't looking to start a company that was focussed on hearing regeneration. That's when they had this insight patent(?) and that's when Chris and I got involved, because at the same time they realized there was a cousin of the type of the progenitor who they had success in the GI track, was in your cochlea. And that really led us to starting to investigate looking at frequency and really understanding the sort of deep biological (sort of) translatability and justification for this.

* Robert Langer
* Jefrrey Karp
* GI = Gastro-intestinal
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Audience:
Where are the regulators kind of in this involving space of novel endpoints? I guess, it feels like they're going to be learning just as much about the data that you guys bring.

David Lucchino (CEO):
So, the question is, where are the regulators? What I can share and then I'll ask Dana to also give his input, is that we had a very constructive and transparent interaction with the FDA. We had a face to face meeting. They've been very open. I think what they've clearly said was that, 'though this is not a life-threatening disease, it is a life-altering disease' and they take this just as seriously. So what I think they've said to us, and they've reviewed our phase 2a study, is 'let's see where the data takes us'. We sort of understand the historical ways how the FDA looked at this, as it relates to hearing aids. So now, let's see where the data takes us for a therapy that can regenerate hearing.

Dana Hilt (Chief Medical Officer):
Just to comment that, as we know, hearing aids are approved as amplification devices, so they are really looking at audiometric thresholds. What we're doing here, and we certainly have some effects on that, but more importantly we are having effects on intelligibility and speech comprehension. So to clarify, all of the scales we are using are validated scales. They are robust. They are accepted by the medical community. The FDA recognizes the medical applicability of these scales. And as David said, they are open to discussion as bringing the results forward and talking about what would the endpoints be in a registration trial and as you know the FDA's focus is factually(?) changing into what impacts the patient's life, what patient reported outcomes, what sort of measures can we use to register drugs that really impact what the patient appreciates. So I think this is a very positive direction.

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Audience:
How do you document the stability of the hearing loss <inaudibile> in patients?

Dana Hilt (Chief Medical Officer):
So the question is about documenting the stability of the hearling loss in the patients. So these are patients that had to have previously documented audiograms. So we are not just asking clinically 'are you stable?'. We are actually showing that have not any changes in their audiometric measure of hearing. So they are completely stable.

Audience:
<inaudible>

Dana Hilt (Chief Medical Officer):
That really includes the audiometric profile, primarily. That is really the focus for stability, because that's the one that is done most often.

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Audience:
Are there any safety issues that Frequency Therapeutics or the agency is focussed on?

David Lucchino (CEO):
The answer is no.

Dana Hilt (Chief Medical Officer):
We really haven't seen any pattern of significant adverse effects, certainly not any serious adverse effects. This is very important. It's still early in the development program, so we have to monitor that. But to repeat what David said, the ENT physician does this procedure many times. They administer steroids. They administer antibiotics. This is something the nurse preps the patient. It's a local anesthetic cream. The physician does it in 5 minutes and then moves on to the next patient. So this is something, I'm a neurologist, I would say it's simpler than a lumbar puncture. It's a very straight-forward and simple procedure. It is done, as David said, thousands and thousands of times over here.

Christopher Robert Loose (Chief Scientific Officer):
As you expect on that point, I guess, because this is locally delivered, the systemic concentrations of the drug are more than a thousand fold below pharmacological levels. So really you are just looking at a local exposure in the patient. And we know this is short course of therapy. Maybe up to one dose and maybe up to four doses we're exploring now, but it is not something that is chronically given to patients and both of those really help with the safety profile.

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Audience:
In the clinical trials you saw very rapid concepts(?) in two weeks. Is that surprising?

Christopher Robert Loose (Chief Scientific Officer):
The question is we saw reponse in about two weeks within our clinical work. That is very similar what we see preclinically. Over the course of a number of weeks, we see the responses there. When you look at regenerative species that's what's seen there. I think, what is important to keep in mind is here we have a hair cell that is gone missing and a progenitor nextdoor that need to divide one time. That is the extent of the biology that needs to happen. One division, a naturation and a reconnection. Hours of pushing this cells to get into this mode, to start the program. About weeks makes sense.

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Audience:
How does the treatment compare to an intratympanic injection of steroids? I guess that's probably standard care?

Dana Hilt (Chief Medical Officer):
So the question is how does this compare to intratympanic injections of steroids. Just to clarify steroids aren't really useful for people with hearing loss, but the physicians, the ENT physician of course give steroids hundreds of times. It is a very common procedure. This is really identical, it is pretty much the same sort of procedure that a physician, an ENT physician would use to do an intratympanic injection of steroids. I don't want to trivialise it, but it's an extremely straight-forward procedure.

Christopher Robert Loose (Chief Scientific Officer):
And I add briefly. Steroid can be used right after some kind insult to slow down some kind of inflammation, but obviously are not being used for restoration of hearing downstream. So, same procedure for applying the medicine, but very different population that we are looking at to get that restoration.

 

Hope you appreciate the work. I tried to transcribe to the best of my abilities, but mind you, I'm not English native. Additionally, this is a transcription of a live speaker during a live event, so the sentencing can be a little bit off here and there. I tried to stay as accurate as possible nonetheless.

 

People who believe there is no "auditory information" above 8 kHz should have a good look at slide 18.

 

@brokensoul

I appreciate the quick summary you have just posted. It was very informative.

In slide 22, when Patient 4 went from 26 words correct at baseline to 47 words at 90 days, did they only get 1 injection or did they get multiple injections?

Edit: Just read further along it was stated 1 injection only. That is very good that Patient 4 got 50% improvement with 1 injection.

 

I believe the audience has likely seen an animation for slide 15 & 16, instead of the stills that were present in the slides.

The animation is actually part of this YouTube video (October 2019):

Frequency Therapeutics FX-322 Mechanism Demo...

 

It's actually a complete transcription of the main presentation and Q&A.

It was one injection. It's stated in the main presentation, as well as in the Q&A session.

Phase 2a will have 4 doses.