FX-322 Hearing Loss Treatment: Clinical Trial Data Shows Promise in Hair Cell Regeneration

Brian Taylor 0:00
Hey everybody and welcome to another edition of This Week in Hearing. I’m Brian Taylor. And the topic this week is regenerative medicine in audiology. And at the forefront of this effort to regrow human cochlear hair cells is a company some of you may be a little bit familiar with in the in the press, that’s Frequency Therapeutics. And with us today are two executives from Frequency Therapeutics, Carl LeBel, and Kevin Frank, I want to welcome you both to the broadcast. And I thought a good place to start before we dive in would be for both of you to introduce yourselves and talk a little bit about your background.

Carl LeBel 0:48
Again, I’m Carl LeBel. I’m the Chief Development Officer at Frequency. I’m trained as a pharmacologist toxicologist been in the industry, biotech industry primarily for about 30 years, basically, a drug developer, have worked in a number of different therapeutic areas, worked on – had the great fortune of working on a number of drugs that are approved that help a lot of people today. And hopefully, we’re working on another one now. And I’ve been in the ear for a little bit more than a decade now. So really pleased to be sharing this session with you, Brian.

Brian Taylor 1:23
Right. Thanks,

Kevin Franck 1:25
Hi Brian. I’m Kevin Frank. My whole career has been in hearing, but I’m very new to pharmaceuticals. So in hearing, I’ve been involved on the clinical side, the academic side and the corporate side working in various parts around the world. My most recent job was running audiology at Mass Eye and Ear, Harvard Medical School, and I started here Frequency, just about a year ago. And my job here at frequency is to see that great ideas that started in the lab are able to translate into the clinic and work on the commercial side.

Brian Taylor 1:56
Well, it’s great to have both of you here. I’m excited to kind of dive into this topic. And I thought we could start with the big picture. And talk, because most of our viewers probably it’s been a while since they’ve had a biology class or a biochemistry class. So I thought we could start by having you talk about progenitor cells. And just the the basic concept of regenerative medicine.

Carl LeBel 2:18
It’s sure I can start. Kevin can can jump in after. So, everything that we’re going to talk about today, all of this essentially culminates in years of work in our labs, all the clinical trials that we’re doing all that culminates now in a big trial that we’re doing what we call the 208 study. So hopefully, we’ll talk some more about that. But all that success and all the hard work by our team and all the patients and sites that we work with. That’s what’s gotten us here. So it’s that partnership, in terms of regenerative medicine. So the way that Frequency got its start really, preceding that was work that was happening in the labs of two professors, one at MIT, and that’s Bob Langer. The other one at Harvard is Jeff Karp, those are our co founders, and they have been interested in regenerative medicine. When people think about regenerative medicine, they tend to think about gene therapy CRISPR, the kinds of things that were you really altering the DNA, okay? And that’s not what we’re doing here. So, in the early days, the two of them were studying the small intestine, because that’s one of the most regenerative tissues in the human body. The lining of our small intestine tends to turnover about every four days or so. And they were struck by how regenerative that tissue could be. Yet there were the other tissues in the body, like the cochlea in the in mammals that doesn’t turn over at all. Right? So the question is, why is that the case, in what they were able to identify were cells in the small intestine called LGR5 positive cells. This is a receptor that sits on the surface of some of these cells. And those those cells in particular are what are called stem like cells, they start from stem cells, but then they make their way to a point where they’re pre programmed, they’re there, they’re responsible for doing one thing in particular. And it turns out that those very same cells or cousins to those cells are present in the cochlea. But why do they turn over so quickly in the small intestine, but not in the cochlea? And the reason for that, we believe, is because the cells in the cochlea don’t get the signals that the cells in the small intestine are getting. So the approach that we’ve taken is, well, let’s figure out how we can provide that signal back. And we think when we’ve been able to do that by giving FX-322, the two molecules that make up that drug candidate that we’re working on, it is those two molecules that we believe activate those previously dormant progenitor cells in the cochlea and hopefully You know, the things that it does after that and the benefit of provides in the clinic, hopefully that continuum of biology to to transitioning in to an effect in the clinic. We hope that that continues to bear out.

Brian Taylor 5:15
So maybe Kevin, you could go into a little more detail about what’s happening with these two drugs inside the cochlea?

Kevin Franck 5:23
Sure. You know, I was a graduate student in the late 90s, at University of Washington. And there was a a primary research there, a researcher there who was very excited about the promises of hair cell regeneration. And so we learned all about what that may be one day, and it was always over the horizon. And throughout my clinical career, particularly when I worked in cochlear implants, I’d have patients who’d say, Is there something I can do besides have this thing permanently put into my head? And is there some shot I can get? And the answer was always, maybe one day, but no. And what’s exciting is we have a clinical trial happening right now, it’s called our 208 clinical trial that we’re recruiting subjects for that is that are getting these shots. And we’ve seen data that have shown a positive effect of this drug in previous studies. So, you know, to just feel so lucky in my career to be at a place now where maybe, you know, we’re at that point that we began to learn about when I was in graduate school way back before, before it became the year 2000. It seems like a million years ago. I mean, what’s happening in the cochlea is it’s, you know, these progenitor cells that sit there, the supporting cells do what they did when we were, you know, in utero, and they make hair cells, and then they go back to sleep. And what we’re doing is waking you up again, and having them make hair cells again, it’s, it’s, you’re, you’re giving them a signal to do something that they did very well a long time ago. And, you know, I think we all appreciate the complexity of the inner ear, and a lot of things need to be working together for you to get hearing. But, you know, getting hair cells to regenerate is a key piece, and may lead to other downstream effects that cause us to be able to improve how well we hear how well we perceive words.

Brian Taylor 7:11
Well, I think I want to ask you about some of the studies that you’ve done already the one that was published not too long ago, but I think maybe a question that a lot of our viewers would have is, how does the drug get into the cochlea?

Carl LeBel 7:25
Yeah, the important question, it’s, it’s a basic question when you’re trying to develop drugs. So you have to demonstrate that they get to where they need to go, and that the right amount gets there. And so what what we understand about how the process works, as we’ve taken the two drugs, they’re essentially dissolved in a polymer. And that polymer with those two drugs is what is injected into the middle ear. So in our all of our trials, an otolaryngologist or ENT, does an injection with a fairly small gauge needle, the we put a little anesthetic on the eardrum, and then the injection is made. Basically a fairly painless procedure to administer, it takes maybe 10 seconds or so to inject the material. So it’s pretty quick. It’s done in an office based setting. So it’s pretty convenient. So once the material is injected, the beauty of this polymer is it transitions from a liquid to a gel. And that trans transition to a gel is what gives us a little bit of residence time, it gives the drug some residence time in that middle ear. And the the material that I was setting up over what’s called the round window membrane, that is almost like a screen door between the middle ear and the inner ear or the cochlea. And if that gel is sitting over the wrong window membrane, then the two small molecules that make up FX 322 can diffuse through that membrane into the cochlea. And one of the things that we demonstrated in the otology neurotology paper very clearly is both of those drugs are localized primarily in the highest frequency range, okay, somewhere probably north of about 1000 hertz, right. And we think that’s important, because, you know, we were we know, not in all cases, but we know that hearing, we tend to lose our hearing first in the highest frequency range. And there’s a lot of really important information up in that range of frequencies that we think is all the critical clarity of, of sound and clarity of language and the ability to be able to understand more that is, is what’s the most important thing it’s we think that’s the unmet medical needs. So that diffusion process into the cochlea, activating those progenitor cells, as Kevin was describing, and then once those cells are awakened, they’re dividing. Hopefully they’re generating new hair cells. And the generation of those new hair cells, we think, is what’s associated with this restoration of speech perception or an improvement in speech perception.

Brian Taylor 10:13
Well, let’s talk about that. Next, I was really struck by the data that was in the paper. And for our viewers, it’s an open access paper, I believe, neurotology, otology, neurotology, published maybe last August, or September, and we’ll put a link in the show notes so people can have access to that paper. But maybe, Kevin, if you could talk a little bit about some of the findings, I was really struck by a few of the subjects how much improvement they had, and word recognition scores, both in quiet and to noise, and the fact that you accounted for sort of the natural variability and wordless. So if you could talk about some of the data that you collected?

Kevin Franck 10:56
Yeah, I’m happy to do that. So this one study, and there have been a number of single dose studies. But this is the first one that’s published in otology neurotology, which, you know, maybe your your readers be able to follow along, as I described, there’s a figure in there, figure number four, actually, which shows speech perception performance, and I’ll describe the speech perception performance, and I think you’re alluding to so the we looked at Maryland CNC words are relatively standard CNC word test and presented these these word lists to people before they got the drug. And people after they got the drug we looked at various time points, but we are predominantly looking around 90 days, three months, to see the greatest effect. That’s also short enough that if they went back into a noisy environment, perhaps, you know, they wouldn’t have changed the hearing for the worse. And we see a range of baseline performances that go from, you know, 10%, up to, you know, quite high, you know, 90% or so. But there are people in the middle of that range, you know, between, say, 20 and 60%, on the graph, who show remarkable improvements. And as, as you noted, you know, these improvements are more than what clinically you might think of as as a noticeable effect, you know, 10% improvement, we might believe is, oh, yeah, a patient could notice that in their lives. But we also use Thorton Raffin, of course, to make sure that there was a bar that was consistent with how many words are presented. And of course, everything we present is recorded. And with 50 Word Lists, we have a lot of confidence that the it’s not test retest we’re looking at, we’re looking at a change. So yeah, I mean, I’m looking at a subject now on this graph, who started around 20 and ended around 60. That’s remarkable.

Brian Taylor 12:39
And it’s pretty remarkable. And it was 90 days after the drug

Kevin Franck 12:42
was 90 days after the drug. And when you in I’ve had patients who’ve experienced the type of benefit with other with a cochlear implant, and what they noticed in their lives is unbelievable, you know, when you have that type of change, it’s, it’s transformational. And more than one subject had that degree of performance. And when we looked at later on studies, we also saw some other some other studies that had similar results, where people really showed that change from their baseline to to where they are at 90 days. So when we were designing this next trial, this 208 trial, we learned from this published study, as well as all of our other studies to really design something where we can replicate that effect, with enough placebo patients to really power the study to make more definitive statements about the efficacy of the drug. This study you’re reading into one was a very important study, but it was a phase one study in some efficacy there too. But we were looking for safety. And of course, the speech reception is a safety score, because if it got worse, that would have been a bad thing. When you see the the test was really not designed to make a definitive statement on efficacy, efficacy, but it showed it quite well. So through all the planning, Carl has been doing, we now have a study underway that’s going to look at a power in a powered way. We’re gonna make real comparisons between a placebo controlled double blind, of course, and the the active FX 322 group.

Brian Taylor 14:09
Well, let’s talk about that study. The second study that you’re working on right now, what’s the difference? I’m assuming it’s just it’s a much higher and a lot more participants. Is there any other key differences between the published study that you you’ve mentioned, and the one that you’re working on now collecting data on?

Carl LeBel 14:29
A lot of important features. So it’s it is the sixth trial now that we have done so we’ve the last four years, you know, in the otology neurotology paper, that’s the very first trial we did. We started that study back in 2018. And so now we’ve done five trials and it takes this long to get through to learn about your drug to make sure you understand that it’s safe, and you have to keep doing that. So the 208 study that is running now. It is, as I said at the beginning, it really is. It’s the culmination of four years and five trials and all of the biology work that we did that preceded that. So when we talk through design components, it’s firstly, what is the population of subjects that we’re going to be studying. And what we have learned is that if subjects he either have medical history that’s associated with either noise exposure, or if they have a sudden sensorineural loss, but that hearing, that loss has to be permanent, okay, so those are the two groups of patients that we’re looking at. And then remember, hearing is sort of comes in all different severity levels. And so the range of severity that we’re generally testing is from the moderate to roughly the low to mid severe range, okay, those sort of three categories. So to etiologies across three categories of severity, and that’s the group that we are currently recruiting. Another thing that we have learned over the years is, it’s really important to establish a really stable baseline measure. And the way that we go about that in the current trial is, once patients qualified, they go into what we call a lead in period. And that lead in period doesn’t have any drug intervention whatsoever. It’s simply our patients coming in every two weeks, and they do that three times. And they establish a single average baseline value on all of the tests that we perform. But we get that value by averaging across three different visits. Okay. And that way, we can know that patients are stable in their in their condition, then at that point, it’s determined if they’re if their criteria, if the values of their test sessions meet the criteria, then they can get what we call randomized to the trial. And in this case, they’re either randomized to receiving one injection of FX 322 in one ear, or an injection of placebo. Okay, the number of subjects that are going to get randomized the trial, a goal is to randomize 124 subjects, so it’ll be the largest trial that we’ve ever done. And we think probably one of the larger trials ever done in the hearing loss space. So once they’ve been randomized, and they received the treatment. Throughout this study, there’s about at least six to seven visits that they come in roughly every month, we’re doing a number of different tests on them. We’re testing speech perception in both quiet, speech perception in a noisy background we’re doing and we do multiple tests, to understand that we do all of the pure tone thresholds, we do the standard frequency range, we do the extended high frequency range, and there’s lots of other measures. So it’s a really thorough measure of now being able to show efficacy by showing improvements in speech perception, and then also making sure that we can continue to demonstrate a good safety profile. The other thing, probably the most important thing is the measure of speech perception is is what patients have told us is the most important thing to them. Now, this came about out of a session that was run by the Hearing Loss Association of America, also with FDA, so this was a patient focused drug development event sponsored by FDA and others. And in that event, it was patients that said, Look, we can hear sound, we just can’t understand it. And if if there’d be a way for us to better understand, well, that would be remarkable. So that output from that meeting, and our design of the trial lineup great on what is the most important endpoint and again, speech perception. So we will be testing for speech perception in this trial. Once 124 subjects have completed their 90th Day of the study. And once that happens, we’ll do the analysis. We’ll all get unblinded. And we’re really hopeful that we’re able to show a statistically significant effect here.

Brian Taylor 19:28
I guess the obvious question, then is when can when can we expect to see that publication?

Carl LeBel 19:34
Well, we’ll we will we said last week, we disclosed that a an investor meeting that we would be seeing the results and sharing the results, either in the fourth quarter of this year. So towards the end of this year, or in the first quarter of 2023. We don’t know exactly when the results will become available because we’re recruiting patients to get into the study and all of us in the, you know, pharmaceutical development space, we’re all running clinical trials in the face of a pandemic. And so we have to be mindful of that. And, you know, we got to make sure that our patients are safe and our, our sites are safe. And they’re following the, you know, the policies that they need to according to their local jurisdictions. It’s just a reality that we have to deal with. But we’re working as hard as we can.

Brian Taylor 20:27
That’s good to know. Kevin, you’re an audiologist. And I’m curious to know your take on where these sort of treatments fit into the broader picture of, of clinical audiology? Yeah, if you had a crystal ball, three, five years down the road? How do you see your formal pharmacological treatment fitting into the clinical picture?

Kevin Franck 20:56
So let’s let’s make some assumptions to to have that crystal ball. So if we assume you know where our current data is, now that we’re able to improve speech perception, but not improve audibility. So that’s kind of our audiogram didn’t shift, but our speech perception did. So you know, when I think about what Carl said, with the patients with the patients who went to the PFTD said is, ‘we want clarity’, we want to be able to understand better, particularly in noise. And I think many patients felt that audibility, had been well captured through devices. But speech perception, clarity, speech, clarity was still a missing feature. And so I would imagine, and we all know that some of our patients struggle more with clarity than other people, right, if you’re amplifying someone who has a conductive hearing loss, they can hear very clearly. But if you’re amplifying someone who has a severe hearing loss with a lot of distortion in what they hear, they really struggle. And I would love, you know, in the future that a clinician can say we have a variety of things that can help you and many of these things may work together. So if amplification is something you need, we’ve got, you know, a variety of amplification devices. And on top of that, you can have clarity provided for, you know, with additional intervention, so you’ve got audiologists working with ENTs, that can both provide benefits to patients together and with each other, right. So the the physician has a reason to reach out to the audiologist, because clarity, without audibility, is unusable and the audiologist can reach out to the physician saying I’ve got some patients that are still struggling to really understand and can work together. So I mean, I really see a very a good referral relationship that allows physicians to finally be able to treat sensorineural hearing loss beyond devices, and for audiologist to be able to help patients get beyond that understanding issue that many of them have. And you know, the shot is similar to what ENTs do now with steroid injections if someone experiences a sudden hearing loss, so it’s, it’s something they know how to do very well. And something that many audiologists have counseled patients through already saying, yes, you’ve had a severe hearing loss. But since you’re here, right after it happened, you know, the physician able to give you this injection, and they come back and say, Oh, that wasn’t so bad. You know, as we really get going, you can only imagine big cardiology practices that have a physician come visit, you know, a day a week to do a series of injections. So it’s doesn’t entirely mean that at all happens at the physician’s office. You know, to do an injection, yes, you need to have you know, someone lay down, you need to have a proper scope. But you really can envision different ways of assembling care to get where the patients want to be seen. And if you give me a moment, I just want to brag a little bit about the trial, Carl designed, one of the things he put in, there was some audiologic monitoring, where we have a microphone on the patient and we have a video camera on the audiometer. And we’re able to review the visits. And the things that are monitored this is an independent monitors found are the types of things that I could have easily made a mistake on in my clinical career. And notably, you know, when a patient repeats a word back the the audiologist often has a headset on like I have now you know one year for the audiometer the other ear listening to the patient through sometimes, you know a mixture of who’s what. And once in a while the the remote audiologist hears a different word than the audiologist did. And the remote audiologists gets to use you know, noise cancelling headphones and plays it back to the audiologist that site who often is like, ‘Oh yeah, that was the word’ and even in ensuring that the instruction is similar because we want our patients to guess and some people are a little cautious about guessing. So we can even ensure that the instructions are consistent to these recordings. And that’s a level of you know, when we first described is like, is it gonna feel like Big Brother? I think it feels like you know the type of have insight we got one of your graduate students, and to really hone our practice. So it’s, it’s a really great ability to make sure everything is consistent across all of our trial sites. And that those really core measures are done just to the top of our clinical practice.

Brian Taylor 25:16
No doubt I, I hate to admit it, but I think that there’s a lot of practitioners out there that don’t use recorded words and use a half list. And so it’s kind of a lesson for them how important it is to be precise.

Kevin Franck 25:29
Yeah, not in these trials. And so it is it is great. But not only that, but the way you instruct the test and administer the test, it’s really

Brian Taylor 25:40
It’s all really important that it’s done right. I wanted to go back to something that you mentioned is I think it’s a really important point that we unpack for our viewers. And that is, in your trials, you’ve seen an improvement in word recognition scores, but you haven’t seen necessarily an improvement in audibility. Now, to me, that’s a really interesting finding. Um, can you talk a little bit more about that?

Carl LeBel 26:05
Kevin you wanna take that?

Kevin Franck 26:06
Sure. So, of course, when we started while we I wasn’t working in the company at the time, but we were looking for the effects on everything, right, we wanted to see where they would be effects. And so when we saw speech perception and didn’t see audibility, it may just scratch your head and say, Well, why could that be? And, you know, we’ve got really bright scientists and biologists who in we’ve all learned enough about the auditory system that there’s story there, that kind of makes sense. And, you know, the, the parts of the auditory system that deal with detection are often different parts of the auditory system that they will suprathreshold types of activities, and, you know, these speech perception tests are presented, you know, well into people’s sensation level, so that they can, we don’t have to deal with things that are right near on ability. And so yeah, you know, we were looking for effects. And we want to see effects and our PROs, and our thresholds and our speed perception and everything, but we did not see it in the the thresholds. But like I said, that, that’s okay, you know, as long as we’re getting at clarity as long as we’re getting at improving the person’s ability to get on with life. And so it’s, you know, that’s you just follow the science. And this is what the science told us, and did so in multiple trials, and where we’ve seen the signal not just in this one that’s been published, but the others that we have, that we’ve presented on and or contained in our, you know, the information that’s on our website. So, hey, when you see the same answer multiple times you you believe it, and you just keep moving forward, you

Brian Taylor 27:35
follow the science, as they say, Yeah, well I see that we’ve been, I want to maybe wrap things up now, any, any final thoughts, any other additional comments, you want to share with our viewers around your clinical trials around the concept of regenerative medicine?

Carl LeBel 27:52
I mean, I’ll start and just, again, I, it’s kind of where I started today with you. This study that we’ve got running, it has taken learnings over the last several years and multiple clinical trials, and we think, has ended up into a really well designed study that we think is really now going to set the standard for future trials in this space and the elements that we discussed earlier about doing multiple baseline measures in order to make sure that the subject is starting from a really consistent place. If we get that consistency at the start of the study, it increases the likelihood of being able to observe a change or being able to accurately measure that change. And we want to be able to do that because we really want to be certain at this point, that what we’re now seeing we can call efficacy, we want to move away from what we’ve been talking about as a signal of an auditory improvement signal to something that we can say that the drug is efficacious in this study, is powered and has enough patients in it for us to be able to what we think now detect that difference. So for us, it’s all coming down now to the study. And again, we have to thank our sites, the staff at our sites, and we have to thank the patient volunteers that are willing to sign up for because they they appreciate that they may get assigned to the placebo group and and look, we’re we’re going to take care of those patients down the road. Right. But we’re excited about the progress we’re making. We’re looking forward to the results one day and the timing that we talked about. And again, thank you, everyone that’s helped make this this study happen.

Kevin Franck 29:46
And I’ll just add that I feel thankful and lucky, you know, to be you know, there’s a lot that’s happening in our field right now and what an exciting time to be in hearing healthcare and it’s been exciting for you know, little while, but this is a whole new dimension. And, you know, it takes a lot of courage for a company to try to make a difference like this. And all those people that it takes for that to happen is, as Carl said, just so grateful for the clinicians that stick on these long protocols, the subjects who come in and do that over and over again, the monitors who mentioned how many videos you watch, have just got better setting. It just takes so many people for this to work and and everyone who’s interested in spreading the word like you are, we all hope to help people hear better and really think this is going to be a way to do it

Brian Taylor 30:36
It’s exciting, a tremendous amount of dedication on a lot of people’s parts. And it’s, like early on, I share your sentiment about sitting in class 30 years ago talking about some of these things. That’s kind of a pipe dream. And now it’s really close seems like to reality. So hopefully in six months or so after your trial has been published, we can have you back on and we can talk maybe a little bit about candidacy and some other things that clinicians might want to know about based on some of your findings. So Carl LeBel, Kevin Franck, can’t thank you enough for your time and your expertise. Thanks for being with us on This Week in Hearing.

Kevin Franck 31:15
Thanks to you, Brian.

Carl LeBel 31:16
We appreciate it.