Therapeutic Interventions for Genetic Hearing Loss: Inside the SKY-GJB2 Trial

Hello, and welcome to another episode of This Week in Hearing. I’m your host, Brian Taylor, and today we’re going to be talking about genetic hearing loss and some of the therapeutics that can be used to address it. And joining me are 2 executives from Skylark Bio, Dr. Alexa Kozak and Dr. Jodi Cook. Alexa, Jody, welcome to This Week in Hearing. Thank you for having us. I always like to start the interviews by just kind of telling us a little bit about your background. I know you’re both audiologists. If you can kind of talk a little bit about your background and then if you can kind of touch on Skylark Bio and what your company does.

Great. Take it away. I was going to say, take it away. So my name is Alexa Kozak, as you introduced, and I’ve been a practicing clinician for 20 years, patient-facing. I’ve been in Boston for my entire career. A majority of it was at Boston Medical Center, which is the largest academic— I’m sorry, it’s the largest safety net hospital in New England, and it’s associated with Boston University. I was a director there for 10 years, leading clinical operations, being a 4th-year extern supervisor, and then most recently, I attained my MBA from Boston University.

Jodi? And joined us when? That’s— I joined you, I’m sorry, I joined you in May, so a little over a year ago. And it’s been really, really exciting to use my clinical acumen and being part of something that is truly pivotal in the field of audiology. Thanks, Alexa. And hi, Brian, I’m Jodi Cook. I’m the CEO of Skylark Bio. I began my career, as you mentioned, as a clinical audiologist. I did my fellowship at Johns Hopkins and was involved in cochlear implant research when we were still investigating it for pediatric use.

Spent a number of years in audiology, was an assistant professor, worked at Mayo Clinic, and then left audiology for the business side of things. About 15 years ago, I first got involved in gene therapy. I was in a company, I was a founding chief operating officer of a company that looked at rare central nervous system disorders. And we were able to take a treatment from an idea and actually get it onto the market in an indication that essentially is baby Parkinson’s. And it was amazing and transformative. And about 4 years ago, Arch Venture Partners out of Chicago called me and said they would like to do that for hearing loss?

And would I join Skylark Bio and start working on, can we do gene therapy for hearing loss? So I’m happy to say that the company has grown from a handful of scientists and idea into 19 people sitting here in Cambridge, Massachusetts. And we are working on GJB2 mediated hearing loss, and we have just gotten into the clinic for that indication. Great, and that’s what we’re going to spend the rest of our time talking about. So I’d like to start with this JGB2 mutation. I think some people know that as connexin26 related to that.

So if you could kind of talk a little bit about connexin26 and how it’s related to this mutation. Sure, I’ll start with that one. So if you are born with a different mutation in the GJB2 gene, you will not be producing the protein connexin26. Many of us, when we learned about this initially, it was just connexin26. Since then, we have identified a number of different genes that cause hearing loss, so we’ve gotten more descriptive in that. So what we’re doing, so let me talk about the underlying biology first, that, and from many decades of research across many institutions and great people that came before us, we have a really good understanding of the biology that we didn’t have when I was first trained as an audiologist, or many of you out there as well, that the cochlear needs to have a nice environment of the potassium-rich environment needs needs to be there in the endolymph.

And the connexin really creates connections between supporting cells and cells of the lateral wall that enable a recycling of this potassium so that, that the— it’s in a beautiful homeostasis environment that allows the cochlear cells to function normally. So if you have a mutation in your GJB2 gene, You could not be— you might not be producing Connexin26. Therefore, you don’t have good intercellular connection, and the cochlear doesn’t work effectively. And many children end up with severe to profound hearing loss at birth as a result of that. So can you tell us how your company has gone about trying to ameliorate this problem?

Talk about maybe the trial that you’re involved in right now. Sure, let me talk about the strategy behind this, and then I’ll hand it over to Alexa to talk about the trial. So we’re using gene therapy, which is a way to take a, basically a vector, which you could think of like a ball, and you put inside the ball the correct gene. We directly deliver it into the cochlear, through a surgical approach by an ENT into the round window membrane, and it diffuses into the cochlear. And the idea being that the cells take up this gene therapy and turn on the production of Connexin26.

So you want to talk a little bit about what we’re doing in our first trial? Sure. So our first trial has 2 cohorts. There’s Cohort 1, which is taking a look at older children ages 2 to 7, and then Cohort 2, Cohort 2, which is taking a look at children who are 9 months to 2 years old. And 9 months, we chose 9 months, one, because it’s critical. It’s a critical time in terms of when we would consider implanting children with a cochlear implant. We wanted to kind of use a good marker in terms of when another intervention would take place.

That’s really— any further questions about it? Oh, well, that’s, you know, I guess a couple of questions come to mind would be like, at what age would be it— is it appropriate for somebody to be entering the trial? If somebody— if you’re an audiologist in a clinic, what are some, you know, what do they need to know about this mutation? What do they need to know about genetic testing? You know, I’d like to kind of explore some of those areas a little bit with both of you. Sure. So in terms of, you know, GJB2 is the most common cause of genetic hearing loss that’s out there.

So I think with the introduction and adoption of more genetic testing from programs like Resonate and Amplify, I think audiologists are offering genetic testing Right when a child is diagnosed with hearing loss. They want to know what the problem is. They want to know how to treat it. Is there another specialist that needs to be involved? Let’s say, you know, a pulmonologist, a cardiologist, that kind of stuff. So as I stated, you know, we’re looking at children who are at 9 months of age to 7 years. We’ll just kind of put both cohorts together.

And I think audiologists in clinics, Again, as I’ve noted, are adopting and implementing genetic testing as soon as a child is diagnosed with genetic hearing loss. Let’s talk a little bit more about that because I was trained 30-some years ago and, you know, we talked about these things sort of in hypothetical terms back then. Take us through the process of a pediatric audiologist and how they might recommend or utilize genetic testing. And say an infant comes in, they identify a hearing loss, What’s the— walk us through the process of how genetic testing might work.

Sure. And I also wanted to note too, just to kind of dovetail on your comment, that genetic testing was not very common even when I practiced clinically. Usually we would refer them to a geneticist. There would be a long wait time. You know, you’d need the genetic counselor. So it really kind of bottlenecked the system. And now in terms of You know, the child is born, you know, they have their newborn hearing screening within 1 month of life. Within 3 months of life, they’ve now had diagnostic testing to confirm they have hearing loss.

And then within 6 months to life, excuse me, 6 months to life, we want to make sure that we’ve implemented early intervention, that they’re wearing hearing aids, that we’re considering them for cochlear implants if necessary. We’re making sure that they’re getting enrolled in early intervention speech and language pathology. You know, as an audiologist, we’ve referred them on to the ENT doctor. We want to make sure too that there’s no structural or anatomical anomalies that we’re looking at that could be causing this hearing loss. And then once that’s kind of been ruled out, we also want to consider what’s causing this hearing loss.

How are we going to treat it? What does it look like? Is this going to be a progressive hearing loss? You know, we kind of want to give parents and families an idea of what the future looks like for their child. Follow-up, hearing aids, cochlear implants, that sort of thing. How prevalent is this specific mutation that we’re talking about related to Connexin26? And what’s the typical profile of the hearing loss? Is it progressive? progressive? Is it mild to moderate, severe? Can you give us a little more idea on what that looks like?

Sure. So it’s the most common cause of autosomal recessive hearing loss, and it typically presents as a stable severe to profound hearing loss. You know, there’s really not that much progression. And that’s, you know, there are a few that do have that moderate to profound, but for the most part, they are severe to profound. Let’s go back to the SONIX trial. Can you give us more details? Has the trial started? What phase are you in right now? What are you— kind of give us an idea over the next couple of years what you expect to find.

Sure. Let me take that one for you. So let me back up a second and talk to you about clinical trials in general and what it takes to get a therapeutic approved. We are in phase 1/2. That means we’re in the first-in-human study that is safety and tolerability first and foremost. And so that’s what our primary endpoint that we’re looking at. We’re also looking at efficacy. We’re doing behavioral testing on these children as well. From a Phase 1/2 trial, you move into, in gene therapies in particular, into something called pivotal trials, or sometimes referred to as Phase 3 trials, where you expand the number of patients, you expand the number of sites that do it to get a statistically significant result that can prove either your treatment is efficacious or it is not.

And so that’s a multi-year process. So SONIX trial is the first-in-human Phase 1/2. We announced this summer that we have enrolled and dosed our first participant. And so we will be dosing participants through 2026 for a total of 10. And then we will take a look at the data, including the safety, tolerability, and some early efficacy, and then make decisions in collaboration with the US FDA about where do we go next. Do we expand the trial? Do we do both ears? And a number of other questions along that line. So the participants in our trial today are in the age range that Alexa had already mentioned, that we are enrolling here in the Northeast because that’s where the company is based, and that over time we will expand the trial across the US and hopefully more globally as well.

My next question is a little bit hypothetical, I think, but let’s say that a therapeutic like what we’re talking about here is effective and a child is wearing hearing aids, maybe been wearing hearing aids for a few years. If this therapeutic is successful, does that mean that they can stop wearing hearing aids? Do the hearing aids work in conjunction with the therapeutic? Can you give us a little insight into that? Sure. So even from, you know, after we dose the patient, we want to make sure that the child is having access to sound.

So we ensure that the patient wears the hearing aids throughout, you know, the follow-up. If there is an improvement, typically we’ll ask the parents to keep an eye out if the child continues to kind of pull the hearing aid off. that might indicate to us that their hearing is improving. And then we would do a hearing test to make sure and see that in fact their hearing is improving. If it is, we’d adjust the hearing aids, you know, accordingly. We don’t know, you know, back to Jodi’s point, we don’t know how efficacious this is going to be, you know, so we want to continue to have the patient have access to sound at all times ’cause they’re children, they’re learning, they’re growing.

We want them to have good speech and language development. academic performance, all of that kind of stuff. Right. Are there many people in the trial that have cochlear implants? Can you give us an idea of cochlear implants versus hearing aids of children that might be enrolled in the trial? Oh, I was going to— no, I was going to say, so we— the— this first trial, we’re doing it in one ear. And so the opposite ear can have a cochlear implant or Anything else. So we want it in a treatment-naïve ear, which means there’s no cochlear implant.

It needs to be in— the cells need to be intact in the cochlear because we’re trying to treat hearing loss at the root cause, at the cellular level. So if we can turn the protein back on and the cells function normally, the hearing should develop normally as, as you would. So treatment naive in the ear we’re treating, and the opposite ear can have whatever the family decides. Understood. I wanted to kind of, as we wrap things up here, go back to this idea of genetic testing. Your company’s located in Boston, which is of course a hotbed of academic research and research and all kinds of things like that.

So I’m guessing it’s pretty easy access to get genetic testing in a, in a metro area like Boston or New York or LA or whatever. What if I’m in a more rural area and I think that I, I have a child who would benefit from genetic testing for hearing loss? What would you recommend? Or is there, is there a way to— is there a database? Is there a website where I can find out where I can get that testing? So your audiologist or the ENT would have access to— there’s 2 programs run through sponsors.

They’re called Amplify and Resonate, and they provide genetic testing. They also include a genetic counselor as part of their testing package, if you will. And it’s interesting that you say in terms of Boston, so having practiced in Boston for 20 years, it— they— you have a lot of lag time. I mean, we would have kids that would be referred and they wouldn’t have genetic testing for 6 months. Wow. You know, the turnaround time now with these Amplify and Resonate programs is anywhere from 4 to 6 weeks. So you’re getting a lot quicker turnaround.

You’re able to act a lot quicker in case, again, there’s other comorbidities like cardiac issues or renal issues. So in terms of rural, I think you can do the same. Look online, Amplify and Resonate. And the NIH is working on a a program now that would be a database that could also offer free genetic testing. I don’t believe it’s up and running yet, but I know that they’re very actively working on having a public-private partnership where the NIH is a sponsor and they’ve gone around to different private industry as well to see if collectively the field, we can all team up and make this service available to everyone in the US, as well as a database so that anytime a new trial like ours or a new approved treatment, even if it’s a device or anything else comes available, that they, NIH, would be able to send that to the families.

So, I think it’s a great initiative, and we look forward to learning more about it and hopefully participating in that. So, if somebody wanted to do a Google search for that, what would they— what would the keywords be? I don’t know that it’s— I don’t know that. But it’s somewhere on the NIH website. Well, we’ll connect you with the people from NIH that have reached out to us. All right. Well, maybe we’ll put that in the show notes. So I also want to mention that just today, maybe I think this was published in the last couple of days, that the Ear and Hearing, the Journal of the American Auditory Society, several articles devoted to the genetics of hearing loss, a really excellent, like a 10-page article that reviews all the different types of mutations, the most common patterns of hearing loss.

I was just reading it this morning, so I’ll try to post that PDF of at least one of those articles in the notes here so people can see that. Because maybe it’s my own bias, but I feel like a lot of audiologists, at least the ones that are my age, could probably bone up on this concept because there’s a lot of new things that have happened just in the last few years, it sounds like. Yes, absolutely. As we wrap things up here, Alexa and Jodi, do you have any final comments, any final thoughts that you’d like to share with our audience today?

Not necessarily with the audience, but I want to thank the families that have shown interest in our program. They’re putting a lot of trust in us. because this is a first-in-human trial. So I just want to thank the families that are showing a lot of interest in trusting us with their children. Very good. Julie? Yeah, and I just want to say to the audiologists, and I too didn’t know anything about genetics, very little about genetics when I was in training, had been away from it for a long time, but from an audiology perspective, absolutely, you can certainly learn more, but the, genetic programs out there when we diagnose hearing loss, I think all of us should be very aware of what is the root cause, what is the underlying cause.

I actually never thought in my career that we would see a treatment to the underlying genetic cause, and we are. We are just at the very beginning of this, and I think over the next decade or so, it’s going to just explode. So It should be a fun time to be an audiologist. Yeah, I want to echo that. I think it’s kind of hard to wrap your head around all these new breakthroughs because, like you said, back in the day, we didn’t have any idea what the underlying cause would be.

And now we see all kinds of things emerging in this area. So again, Alexa Kozak and Jody Cook, I want to thank you for your time. This is really an important topic. And thanks to you and your company, you know, I think our families and patients with hearing loss, children with hearing loss, are in great hands. Thank you so much. Thank you.