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Oby: From the campus of Harvard Medical School, this is ThinkResearch, a podcast devoted to the stories behind clinical research. I'm Oby.

Brendan: And I'm Brendan. And we are your hosts. ThinkResearch is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center.

Oby: And by NCATS, the National Center for Advancing Translational Sciences.

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Brendan: Medication adherence is crucial to successful treatment. When sight is impacted by glaucoma, consistent screening and a strict eye drop protocol can often save people from losing their vision. But this standard of care can present many challenges for patients, especially in older populations. Now in the early stages of a clinical trial, Dr. David Friedman and his collaborators at Mass. Eye & Ear are testing a contact lens delivery system for glaucoma medication. David Friedman is the Director of the Glaucoma Service at Mass. Eye & Ear, a professor of ophthalmology, and the Co-director of The Glaucoma Center of Excellence at Harvard Medical School. Dr. Friedman, welcome to the show. Thank you for joining us.

David Friedman: Thanks for having me.

Brendan: You're the Director of the Glaucoma Service at Mass. Eye & Ear. Can you tell us what glaucoma is and how it affects people?

David Friedman: Glaucoma is a disease of the optic nerve. The nerve is damaged, and certain cells die prematurely. They're ganglion cells. When people have glaucoma damage, they lose certain pieces of their vision. They lose some contrast. They can lose some of their side vision. And it's a very slow process. So it's often referred to as the "sneak thief of sight" because it happens so gradually that many patients are unaware of it until it's quite late in the disease.

Brendan: That's interesting. And so what are the first signs of glaucoma? How do people present? What do you look for in a diagnosis?

David Friedman: Most people are diagnosed, really, through screening. And we all think of glaucoma as being eye pressure. The eye has a pressure like a car tire has pressure. It's harder or softer in different people. And the harder the eye is, the higher the eye pressure, the greater the risk of glaucoma.

So one way that everybody knows that they've been screened is to have their pressure checked in a doctor's office. But what we really do when we're looking for glaucoma is we look at the optic nerve to see if it has characteristic features of damage. We can do that visually. And now there are very high-quality imaging devices that can also do that.

Most patients who come in with glaucoma really are surprised to know they have it. Imagine you lose some ability very slowly over many years-- you probably don't even remember what it was like to have that ability. Patients often have complaints of difficulty with their reading, difficulty at night, in particular, with contrast, with lights coming at them. But a lot of these are non-specific and people get those just with age. So it can often be missed.

Brendan: So it's important for screenings to detect this before it becomes a big problem? Yeah.

David Friedman: Yeah. Absolutely. Glaucoma is a disease that requires routine evaluation. And anybody with a brother or a sister or a parent with glaucoma really should be checked on a regular basis because it is linked to families, and there is a genetic component.

Brendan: Doing a little bit of research and talking to you previously, you mentioned that there's a couple different types of glaucoma. I didn't know that. Could you explain what the two different types of glaucoma are?

David Friedman: Sure. I mean there are many types. There's early childhood glaucomas and young glaucomas. So some people very young do get them. But the major forms that we talk about are open-angle and angle-closure glaucoma.

People with open angles basically have the normal anatomy. The fluid that keeps the eye pressure where it is can go out through the normal drain, where it normally goes. With people with angle closure-- which is more common in certain groups like Chinese or American natives-- it can be closed so that the iris is pretty much blocking the exit of water out of the eye. So we refer to open-angle or closed-angle-- and the reason that's really important is a lot of medicines you read will say, don't take this if you have glaucoma. And most of those are referring to angle-closure glaucoma, which is far less common.

Brendan: Could you tell us a little bit about how you became interested in studying glaucoma and treating glaucoma?

David Friedman: I've always believed that it's a real opportunity to help people in medicine. And ophthalmology was extremely appealing because of the importance of vision to people. I worked a lot in global blindness prevention, and glaucoma is one of the leading causes of blindness in the world. So it really appealed to me on that level.

In addition, glaucoma is much more of a chronic condition, which you develop a relationship with your patient. So you get to know your patients over decades, and that really appealed to me as well. And so when I was choosing a sub-specialty, I thought glaucoma had a lot of potential for all the different areas that I had interest in.

Brendan: That's interesting about the long-term connection that you thought was appealing. Could you tell us a little bit more about that-- how you've seen people that you've treated for a long term, how that improves their lives?

David Friedman: Yeah, sure. I mean, you see patients, typically, with glaucoma once, twice, or even more than that per year. And so you're seeing them over and over again, and you really get to know them. Most of what we do in glaucoma care is prevent worsening, at this point. Someday, we hope, there will be drugs that improve vision.

But seeing people-- continue to see-- 20 years later who you thought might go blind while you were taking care of them, is incredibly rewarding. It's a great feeling. I just moved a year ago from Johns Hopkins to Mass. Eye & Ear, and patients still frequently write to me. It's that kind of a long-lasting relationship that you have.

Brendan: So you've also done some research on medication adherence for glaucoma, and this ties into the pilot grant that you're awarded, which we want to talk about. But could you just give us, briefly, an idea of what the problem with medication adherence for glaucoma patients is?

David Friedman: Yeah. There is a really large literature in all of medicine showing that when we shifted care from hospital-based to outpatient-based and put more of the burden of care on patients, that was not a complete success because patients frequently failed to take medications as prescribed. And so they don't get the full benefit. I started getting very interested in this because a lot of my research is focused on what really impacts the effectiveness of our care and the life of the patient.

And so we started by looking at insurance-based data-- and that had been done, actually, at Harvard Medical School about 40 years ago-- and showed that patients didn't take their medicines. And when we looked again in the modern era, we found that many patients dropped out of care, in terms of using their drops. And if you looked at the average number of drops taken, it was about 70%. We then did studies looking at actual electronic monitoring of drop-taking, and it was also about 70%.

And so those really indicate we have a problem. We have been able, through coaching and long discussions with patients and helping them manage their disease, to improve those numbers. We did two randomized trials showing you could do that. But that's a real challenge for all patients. And that's one of the reasons that I became very interested in the study that we're going to talk about in a moment.

Brendan: And so, just quickly, you mentioned the drops. So people with glaucoma, they have to take drops once a day.

David Friedman: Yeah. Or more.

Brendan: Or more? OK.

David Friedman: Yeah. And that's a great question. In glaucoma, we have three major ways to lower pressure. One is eye drops, which, we discussed, have some issues with adherence. Another is actually quite effective. It's an office-based laser procedure, very safe. And there have been large clinical trials showing that it's as good as taking a drop as initial therapy. And so that is used, but it doesn't typically last for a lifetime.

A substantial but small portion-- maybe 10% to 20% of our patients-- end up requiring surgery to lower the eye pressure. And the downside of many of our surgeries is that they don't always work. The body tries to heal them, and so they scar over time. If you look at the major surgeries we do, the average survival in success is about 70% at five years. So it's not 100% at 10 years, and a lot of these people need a lifetime of care.

And so there's also a risk of infection after an operation because we're often altering the eye wall to let fluid out of the eye. We're making the eye weaker with our surgeries. And they're not common, but if an infection occurs, it can be fairly devastating after a glaucoma operation. So we have surgeries. They work, but they don't always work all the time and they can put the patient at increased risk of bad outcomes. If we had a contact lens, there would probably be some baseline infection risk, for sure.

In this study, we're putting patients on an antibiotic during the study to try to prevent any infections. That's part of the study. I don't think that would be an ideal system for drug delivery long-term to have to take an antibiotic eye drop while you're taking the drug. But that's always a concern with contact lens wear. There are millions of people globally who use contacts on a daily basis. And so we know it can be done safely.

And that'll be the challenge in this drug development program. First, if it works. Second, if it lowers pressure as well as something that's not so good, which is our surgeries. They're good but not perfect. And then third, can we come up with a system where patients can actually use them effectively and safely?

Almost every drug we give to lower eye pressure is a drop, and the drops are hard to put in the eye. You can imagine an older person with arthritis or a tremor trying to learn how to instill drops on a daily or multiple-time-a-day basis can be difficult. Many patients are on two or three different drugs at different times in the day, and so, really, it's a logistical challenge for them.

And then there's the cost.

Brendan: And so the pilot grant you're awarded, The Sight and Science Pilot Grant, you're studying a contact lens that can deliver glaucoma medication. Instead of putting the drops in, the patient puts a contact lens in that has the drug and elutes the drug. Can you tell us about how you hope this contact lens will improve treatment?

David Friedman: Yeah. I mean, this is one of those really wonderful aspects of working at Mass. Eye & Ear because we have such a strong research arm. We have-- both within our campus and within the Schepens Eye Institute, which is also a part of Mass. Eye & Ear, a research institute-- we have really a great group of collaborators.

So we had an all-faculty meeting-- really pointing to one of the problems with the COVID epidemic, we don't get these opportunities. But just after the meeting, we were having a beer and talking about our research, and one of my colleagues said he was developing this contact lens delivery system, and he'd been looking at glaucoma drugs. And from that, I started reading what he had found.

And this form of delivery can deliver extremely high doses into the eye, which is always a difficult thing to do because the cornea-- the very outer layer of the front of the eye-- is hard to pass. So most drugs don't fully get in. A lot of the drug is not making it there. So when you get these very high doses with this contact lens, there are some animal studies-- some monkey, primate studies-- showing tremendous pressure lowering, which is much better than what we currently get out of our medicines.

So that was very exciting to me. I thought that was a tremendous opportunity. And that's the reason I find it so appealing. Both because it solves the problem of adherence because patients often miss their drops, and also because it might really work even better than what we're doing.

Brendan: And so you're running a clinical trial to evaluate this treatment. And you mentioned the Mass. Eye & Ear research arm is very strong. Can you tell us how you're designing the trial and how you're working with the hospital to manufacture the lenses?

David Friedman: Yeah I mean, it really does take-- you have to have pretty sophisticated capacity to make a drug and put it into a contact lens. Fortunately, this proof of concept is already done. And there's one other trial with the same contact lens system looking at a different indication, and that has gotten through FDA initial approval for the initial studies, and they are able to manufacture using a good clinical practice manufacturing.

The way we do it here is we work with our compounding pharmacy. So we have patients who come in with severe infections, and we compound very high-strength antibiotics or other solutions for them. And our pharmacy can help us to put together the drug. And the drug is a well-known, widely used drug called Latanoprost.

And then we have a GCP lab at the company itself, which is based in Boston. We just use their contact lens and create a film that we can put inside the lens, and then that film will slowly leech out the drug.

Brendan: And so you're producing the film at Mass. Eye & Ear and then assembling it, sort of?

David Friedman: Yep. Exactly.

Brendan: And what is that process like? Was this something that you'd had experience with before, or is this a new area for you?

David Friedman: Yeah. So again, I've never been in drug development. And for me, it's really just collaborating with the experts. So I said, you know, I've done a lot of clinical trials work. I can help you put together the study, and I can bring together the team to do that. And then my collaborator, the inventor, is Joe Ciolino. And he has a team of people and one expert in particular who knows how to assemble the drugs.

And then what you have to do is show that they actually leech out the proper amounts. I mean, you have to go through a tremendously rigorous approach because this is a drug you're actually going to put on somebody's eye. You can't have it just doing random things. So we have to go through all of that.

Brendan: OK. And through this process, did you come up against any challenges in designing the lens or getting it working? Were there any issues?

David Friedman: So again, that's an area where I'd have to refer you to the inventor.

Brendan: Oh, OK.

David Friedman: But it's taken over five years to develop this. So I think it required a lot of different hydrogels and different kinds of approaches. You need to get good kinetics. There's always a burst when you first put them on. So there's a burst with this as well. But you want it to be a slow delivery that comes out at a regular steady rate.

We have data from some animal models-- it did continue to have some effectiveness even after the week of wear. And we'd like to also understand that further. And actually, one aspect of our study is if the pressure is still low at the week, we will continue to check the patients every week for a month to see whether that is sustained longer. And that'll give us another piece of information that might allow us to make a better decision about the final drug-delivery approach.

Brendan: And so you said that people have to use the drops sometimes multiple times a day. So with this contact lens, how will people use it?

David Friedman: So this is a challenge for contact lens drug delivery. You could imagine many models. And that's going to be the next step once we have shown safety, effectiveness, and all those other important milestones. The lens, right now, the way we intend to use it is for patients to wear one lens for a week.

There are publications that show that sleeping in contact lenses increases the risk of corneal infections. So there is no question that there is some concern about that method of delivery. If this drug ends up being substantially superior to drops, that may be a risk worth taking. Alternatively, it could be done as a daily dose. If we get into high-level manufacturing, it's not very expensive to manufacture a contact lens. And it may be that, given the amount you get in the eye, you don't need it every day. Maybe you need to wear it for one day, once a week. So the whole model of wear is not clear.

Brendan: Right.

David Friedman: Again, a lot of our patients are older, and wearing contact lenses may be challenging. And I'm in my 50s. I do wear a contact lens, but not everybody does in my age group.

Brendan: Right.

David Friedman: That will be part of what size of market could you reach? And do you have a family member help? Do we develop systems for teaching and training?

Once you have a drug, if it really looks great and it's going to avoid surgery, then there is much more willingness to maybe make those efforts. So I think that that's a challenge, but not necessarily impossible. But it is a challenge for this approach. But for our studies, we're going to have patients in them for a week.

Brendan: And you mentioned sort of the genesis of the project was a casual work drinks, just talking. And that's something you can't do right now with the pandemic. I wonder if you could talk a little bit about how your research has been affected by the pandemic and maybe what challenges you have now in going forward with this project, and how you're thinking about future projects?

David Friedman: Yeah. So I mean, there have been a lot of challenges. As you know, many of the labs completely shut down. So we haven't been able to do a bunch of final studies on the elution profiles on the contact lens, for example. We're just completing them because we couldn't go into the lab during the COVID shutdown.

The IRB was completely closed, so we were unable to submit to the IRB. They've been very good about taking on all the backlogged proposals, so ours has already been reviewed and we're finalizing any edits. But that was a loss of about a month waiting for them to open up for us.

Catalyst has a coaching element where you all get together with the other winners of the awards and you get to meet them. We've done that virtually, but again, you know that there's missed opportunities there. I don't think the group will be as intimate as we might have been if we'd met at some restaurant or at somebody's house and just been chatting and just talking about our work, which is less engaging, I think, on a social level.

In terms of the human subjects' enrollment, it poses real challenges because we are trying to socially distance in the clinics. Bringing people in for extra visits means we have to find a space where there aren't a lot of people. They can't occupy the normal spaces where we might have done this. I think we can overcome that-- sample size is not large. But for any large-scale clinical research, it's going to be a real problem in the short term.

Brendan: And you said, so the sample size that you're working with is pretty small right now. How many patients do you have in the study now?

David Friedman: The way we plan to start this, it's first in humans, so we really want to be very cautious about how we proceed through this. Mass General-Brigham has a very strong research-quality emphasis. And in fact, because I am a IND holder for this, they require me to speak to the Quality Officer to make sure that I understand the responsibilities of having an IND. I think that's a great process and actually will help to make sure we're doing the right things.

In order to get started, we're going to enroll five patients in what we're calling "Phase A," just to avoid the 1, 2, 3 categorization. And that phase is really focusing on adverse events, feasibility, and just seeing if there is any hint of efficacy. But if we don't see any, that's not going to stop us because we're going to still want to see if it's effective. Five is just too small a number--

Brendan: Right.

David Friedman: If we see some failure in one of them, that might not show us what the truth is. So in those adverse events, we want to make sure people aren't getting infections with the protocol we're using, that we're not harming the cornea in some way-- and we have a long history of people using these exact lenses as commercial lenses, but we want to make sure that they're not.

One of the complications that's highly theoretical, but could be real, is this drug, in theory, could cause some swelling in the retina. So we're imaging the retina to make sure that we aren't doing that. And we want to make sure we don't see any signal to that. We also want to make sure we're not causing inflammation in the eye, so we're looking for that very closely.

In terms of the feasibility, it's just to see if patients can wear it, if we can get people to come back, all that stuff to monitor them. And then, we'll just compare. We'll just look at what kind of pressure-lowering we're getting. In any study like this, you have to wash patients out of their old drug.

So these patients are on this drug, and we are going to select only patients who are only on this drug, so we don't want to have other issues in the process. And so they have to go off of it. And we need to make sure they're safe doing that. So we'll be checking them when they stop it, then having them wash out for another week or two. And then we'll see them after that.

Brendan: After this phase, Phase A, then what are you seeing? What are the next steps, and how do you see this study progressing?

David Friedman: Yeah. So let's just assume that Phase A is a success, patients tolerate it, and we think there might be some effectiveness and no horrible side effects. We would then want to enroll patients in a more definitive evaluation-- still a pilot, but one where we compare getting the drug this way to getting the drug the usual way, which is by taking a drop.

So we would actually randomize around 30 patients to either receiving dummy contact lens and real drug, or real drug in the contact lens and dummy drug in the bottle, and look at the different outcomes in those two groups in terms of effectiveness. And that would be large enough that if there were three millimeters or so difference between the two approaches, we should be able to detect that. That's a big difference.

The typical lowering with the major drug is about six millimeters. So you're talking about a 50% extra lowering. But that amount has occurred. That is about what we saw. We saw even more than that in the primate model.

So if we see something close to that, or if we get a non-significant but pretty close to that finding, then that will encourage us to go on. And again, you need these kinds of studies before anybody at the next stage will want to invest in further development. So we need to make sure that it works and that it's tolerated. And then, hopefully, we'll have enough data to start planning additional studies.

And you could imagine other studies of-- like we discussed-- maybe not wearing it all the time, maybe less in the contact lens or more drug in the contact lens. You have different ranges of amount of drug you can put in as well.

Brendan: Yeah. It's amazing how much work is involved in figuring all this stuff out. All these little steps and then you're like, OK, now it works. It's good. Now you have to fine-tune it and say, do you take it for a week? Do you do it every day, every other day?

David Friedman: Yeah. So these are all parts. We're really at the very first steps of what could be an exciting process. I'm very enthusiastic. The Catalyst is a rigorous review process. The submission's pretty rigorous and then they interview you with a panel of eight or 10 scientists, all of whom are qualified to really push you to explain yourself, a little like Shark Tank. And I liked that. It was a way to try to think through with them where I was going to go. And I think there is a path if it works. That's always the big "if."

Brendan: Dr. Friedman, thank you very much for joining us. It was a pleasure to have this conversation with you.

David Friedman: Thanks. I enjoyed it myself. Have a good one.

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Brendan: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes and help us spread the word about the amazing research taking place across the Harvard community.

Oby: To learn more about the guests on this episode, visit our website-- catalyst.harvard.edu/ThinkResearch

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