The Architect of Pharmaceuticals with Azura Ophthalmics’ Marc Gleeson

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In this episode of the OIS Podcast, Azura Ophthalmics CEO Marc Gleeson tells host Paul Karpecki, OD, that early on he wanted to be an architect. Although he didn’t continue in that direction, Gleeson describes parallels between being an architect and developing pharmaceuticals.

“Pharmaceutical and drug development are very similar to architecture in that you have to think long term, you have to understand what the customer needs are, what the environment is going to be like both from a regulatory as well as a payer perspective,” Gleeson says. “Then you put the plans in place and go through the process to make sure everyone does their job, and ultimately have a sign-off and approval.”

Gleeson also talks about making big career moves and gives insight into drug development challenges and opportunities.

Dr. Karpecki asks about AZR-MD-001, Azura’s lead product candidate, for use in meibomian gland dysfunction (MGD). Gleeson explains that the company is looking at MGD from a unique perspective, as a condition that should be treated like a skin disease. AZR-MD-001 is a keratolytic, which he says is a very interesting class of compounds that has been utilized in dermatology for a long time.

Click “play” to hear Marc Gleeson talk about drug development and his company’s unique approach to treating MGD!

Transcript:

Paul Karpecki: Hello, and welcome to the OIS Podcast. I’m Dr. Paul Karpecki, I practice in Lexington, Kentucky. And today I’m honored to have a guest that has been in the industry well a few decades now but has gone from large company level really kind of playing a key role with Allergan for many years where I first met Marc and now running as CEO of Azura Pharmaceuticals, very exciting, Biotech eyecare company, and he of course, based down under in Australia, Marc, welcome to the podcast. honored to have you here.

Marc Gleeson: Thanks, Paul. And thanks for OIS for inviting me to be part of the discussion.

Paul Karpecki: Wonderful. And that’s what we’re gonna have today, just really a discussion I love for people to get to know you and the company, obviously very exciting company in my space, you know, having worked in dry eye for a while I know the importance of the role of keratin and the meibum. And it’s such a huge part of dry eye, evaporative dry eye according to lamp and other researchers estimated to be about 86%, if not higher of all forms of dry eye and you’ve got something noble there. So want to get into that. But let’s start by getting to know you a little bit first, can you take us through a little bit of your personal background, where you grew up? And how you ended up running a company in the US for the time that you did? And then eventually if you gone from the large company space into now CEO of Azura, how that developed?

Marc Gleeson: Yeah, well, yeah, obviously, it’s from my accent, you can tell that I’m Australian. So I grew up on I actually have a beef and dairy farm in Victoria, about 100 miles outside of Melbourne. So you know, lots of early morning starts getting the cows up for the dairy farm and so forth, but went to boarding school in Melbourne, and then studied Bachelor of Science in Pharmacology and Physiology at Monash. What was interesting about sort of my education was really right up until I suppose my halfway through my last year of high school was all I ever wanted to do was become an architect. Now, people may say, what the hell is architecture and pharmaceutical and drug development had in common, but I was sitting in my office one day at Allergan in Irvine, in Tower 2 on the 5th floor, and I was describing to somebody what I actually did in my role, and I thought to myself, gee, I’m an architect. And so, you know, there’s a lot of parallels in terms of thinking about, you know, when you’re designing a building or so forth, you’ve got to think about what the environments gonna look like in 5 to 10 years, you know, what the needs are of the person giving you the brief. And then you’ve got to work through all the regulatory elements. And then as I say, you’ve got to make sure that the plumber, the builder, and the electrician do their thing. And I suppose pharmaceutical development and drug development, in a way is very similar to that, in that you really have to think long term, you really have to understand what the customer needs or what the environment is going to be like, both from a regulatory as well as a payer perspective. But then also then put the plans in place and go through the process to make sure that the plumber, the builder and the electrician, do their thing, and then ultimately have a sign off and approval. So having finished my Science Degree at Monash, I was offered honors and couldn’t find me down the academic route. However, I joined as a sales rep for Eli Lilly and company in Australia. And sort of that was my first entree into the industry. The yeah, the first products that we were selling were Project 20 and cyclol. So that sort of gave me the sort of the background and training as to sort of the front end of the industry. 18 months after sales role, I’ve got moved to Sydney to the head office to work in a marketing new product planning area. So it was that early understanding of your clinical development, your Phase 2, Phase 3, that really got me excited as to what some of the opportunities where was really being able to shape you know how a drug was developed and increased my interest in actually getting really early on in the development process. I spent about five, five and a half years at Eli Lilly and then join Janssen Pharmaceutica where I was the Marketing Director for eco, or Apex in Australia was licensed. Time changed I had license up from engine, have a bit of a family history and politics here in Australia and actually set up the corporate and government affairs role at Janssen, and then I had a phone call from a headhunter just said, would you like to join Allergan? You know, having worked mainly in sort of immunology, transplantation really hadn’t heard of Allergan and did my due diligence and saw it as a great opportunity to become the Pharmaceutical Sales and Marketing Director in Australia and New Zealand. We were very small at that stage, but Botox was just starting to become an interesting product from the therapeutic side. So in 2000, I joined Allergan as the Sales and Marketing Director. And then that was my first entry into ophthalmology. So we launched alpha, again, here, and across Australia, New Zealand, we launched a number of artificial teeth lines. But I also had the opportunity to launch Botox Cosmetic across Australia, New Zealand. And then once we launched the cosmetic indication, then I became 100% focused on ophthalmology. As I said, I’ve always wanted to have the opportunity to, you know, get early on in the development and an opportunity came up within the global marketing group with Allergan, to move to California. You recall, Allergan, had acquired a company called off Oculeve, which was the drug delivery system for Ozurdex and Durysta. And I moved to California, or the family and I moved to California. And I started that role lighting 2005 as the Senior Director of Global Marketing for the retina franchise. And so that was my first entry and get moving the family halfway across the world was an interesting challenge with a 3-month-old, 2-and-a-half-year-old and a 4-year-old. But you know, like a lot of these expatriate assignments, you convince your family to move halfway across the world, but for a period of time, and 3 years turned into 8 very quickly.

Paul Karpecki: Wow. Now that is really, truly have been a bit as getting to know you and architect of pharmaceuticals, because you do think with that strategic foundational kind of thing. And we’re going to get into that more, because I know even Azura, you know, we have very exciting drug, they’ll work in the meibomian gland dysfunction, phase or area at some point as it gets through the approval process with FDA, but the company’s a lot more structural than that a lot more going on in terms of its base and its potential and want to hear about that, too, as you’re going through these different pathways. Marc, you know, being with a big company, and then obviously, you know, heading up that sales and marketing first in that area, and then expanding your role as the Ozurdex and now Durysta came along for Allergan, fun, did you pick up a lot of key lessons that have helped you well, in a big company like that, to now be able to run a company at this stage? Were you involved at every level like that? Or did you have to kind of learn a little bit more of that regulatory path and all of that, throughout it, to be able to get to running or being the architect of all these facets for a pharmaceutical company at this stage?

Marc Gleeson: You know, the drug development process is a very complicated process, you know, there’s so many factors involved in it. And I suppose one of the benefits of working in the corporate environment at Allergan, you got exposure to a lot of different projects, you know, I think at one stage Allergan had 50 ophthalmic projects, all different levels, you either discovery, early development, or in Phase 3 development. So, as part of being project teams, you were across lots of different projects at different levels of development. So, you’ve got to interact, understand, learn. And because there are multiple projects, you know, some failed, some succeeded. And so you’re able to learn all the various different nuances across that, and then have exposure to lots and lots of challenges, but also lots of lots of opportunities. And so, that definitely is a key learning for me in terms of understanding the process. But on the commercial side, we also had the opportunity, as you know, for example, if we take Ozurdex, for example, it was Allergan’s first ever submission to the UK reimbursement agency. Nice. And so as that got approved, and right from the early development, the Phase 2, Phase 3 clinical development, you’re going through the regulatory process, and then right up into working with our global health economics and health outcomes group, to actually put in submissions to get funding and reimbursement. So you had the opportunity to touch a product, you’re almost all the way Alliance Development Cycle right through the launch. And that was immensely helpful as you come into a role like at Azura where you really do need to not only think about the early side of things, but you really need to understand the journey that you’re about to embark on, because the things and the decisions that you make now have a material effect on things that might happen in the next three or four years because of timelines that we have to work with. I think you’re on mute Paul.

Paul Karpecki: Terrific insights in terms of the level that you’re at and what you’ve been able to kind of straight attributed to. And now, of course, I want to hear a little bit about Azura Pharmaceuticals. You know, tell us about this company, the uniqueness of it, how you acquired such an excellent team, and how far you are now in the development of your new product?

Marc Gleeson: Yeah, so Azura was founded in 2014 by three Israeli ophthalmologists. One of them in particular, Yair Alster had worked a lot with them in California with Professor Jane Dhawan and foresight labs. But the company was established really to begin developing a medical device to treat Meibomian glands dysfunction. And so, you know, as ophthalmologists, obviously, you have a unique understanding of the clinical pathway. But it became apparent in their observations and under trying to understand the disease, that there could be a pharmacological solution to the problem. And so the company embarked on not only, you know, I suppose this research and understanding of the pathology of the disease, but saw an opportunity given the relationship between meibomian gland dysfunctions and sebaceous glands. So that link between essentially meibomian glands, that glands residing in the skin of the of the eyelid and how they are very similar in pathology to that of other dermatological conditions. And, you know, and this is where I think ophthalmology is unique. And it’s one of the things that I always try to do but really at Allergan. It was, I suppose, drummed into us that you really know your customer, I’ve spent a lot of time with the customer we saw. Yeah, Gavin Herbert would always be at AAO, and other key meetings. Yeah, David Pyott was always with customers, you know, when I first joined Allergan, I think, three months after joining Allergan, David paid a visit to Australia, and we spent a lot of time on the road, visiting customers. But one of the critical things for the founders was actually really understanding what the pathology was. And that led us down to this notion that really, maybe Meibomian Gland Dysfunction should be treated more like a skin disease than that of anything else. And so, given the pathology, it was very similar to what we see in comedonal acne and so forth in the fact that organizations like TForce had put together expert panel reviews, bringing a lot of the science and clinical understanding together. It was a natural progression to then explore the use of these characteristics to try and essentially disrupt and break open the aberrant protein aggregation that occurs in meibomian gland dysfunction. And so that’s where it really all began. And then it became a journey of really just trial and error, just understanding whether there were any compounds or any treatments that were already approved, that could be repurposed. Obviously, in our industry, intellectual properties is critical. So there was a lot of time spent. Once we understood what the chemistry was behind how capabilities work, we spent a lot of time as a company, you know, expanding that closing off some of those opportunities. And like a lot of things in ophthalmology, we basically went straight to the clinic with the medicated shampoo formulation of selenium disulfide. You know, selenium disulfide is our active agent in our lead compound, but it’s actually approved as a medicated shampoo to treat several dermatitis in the US at 2.5%. And so, before the company had raised any major amounts of money, obviously, we wanted to see whether the drug actually moved any clinical endpoints knowing full well that medicated shampoo and the various different other excipients that were toxic for the ocular surface would not be suitable for yeah, ophthalmic application. The company embarked on a proof-of-concept study and had a very good result which then led us to raise more money and then develop an ophthalmic formulation.

Paul Karpecki: It’s fantastic if you think about you know, kind of where it’s at now as far as you know, AZR-MD-001 are one is about just starting Phase 3 clinical trials now, Marc is?

Marc Gleeson: Yeah, we’ve just started a Phase 2B – 3 Program.

Paul Karpecki: Phase 2B is so Phase 2A that’s already completed now beginning Phase 2B. Any surprises in the data on the upside or otherwise that came in. So I was looking at some of the numbers. You know, obviously as a keratolytic, I could expect a significant decrease in keratin, but lipogenesis? I mean, what’s a two over 23% increase in lipid production? To me? That seems just fascinating. Is that something you were expecting to see? Or were there other data points like that, that were that impressive?

Marc Gleeson: Yeah, look, you know, we the mechanism of action of selenium disulfide is really interesting. You know, we know that it’s a kerat aesthetic. So it slows down the cell replication cycle of keratinocytes, and their future keratin proteins. It’s a fairly potent disulfide bond disrupter. So it breaks disulfide bonds, and the potential to loosen the plug. One of the side effects that people complain about its use as a medicated shampoo is that it produces an oily scalp. So we’ve done a bit of work in two different invitro models to show that it can actually increase lipid production from sebaceous cells. So, when you think about meibomian gland dysfunction that has been a disease of block glands and poor lipids, the mechanism of action is a very interesting opportunity to really try it in that indication, I suppose one of the major surprising things for us was just the degree of, I suppose direct translation of the mechanism of action to the clinical endpoints. So our 3 critical endpoints for our Phase 2A study where meibomian gland score, which is essentially a measure of modern quality, the number of glands yielding liquid secretion, which is a measure of the lower 15 glands, and how many are actually producing a liquid, and then also OSDI. But if you think about the mechanism of action of AZR-MD-001, you know, its goal is to essentially open the glands, and then improve the quality. And so we saw significant responder rates, and I suppose that’s the biggest surprise for us is the degree of response. So with the 1%, you know, we saw up to, you know, almost 58% of patients responding to having new normal meibom. So that was meibomian gland score of greater than 12. And so that direct link between the mechanism of action and the endpoint that we’re measuring is critical.

Paul Karpecki: That’s fascinating. And, you know, meibomian glands yielding liquids great score of 12, you know, technically there could be 3 glands that just have expressed naturally, and don’t express me, that’s one of the highest I’ve seen to date, in that field related to dry eye disease. And, you know, we understand the role of meibomian gland dysfunction. So to be able to get to that level, where we’re getting these nice liquid secretions is fascinating data and an exciting for the future. Something we, you know, that’s so noble, in terms of its approach that be compatible with anti-inflammatories, but it really targets were the diseases for the majority of dry eye. Obviously, that’s a good idea.

Marc Gleeson: You say, compatible. And that’s one of the things I think when we again, coming back to the architecture analogy, and also just you’re spending time with customers is, you know, having spent 22 years now in ophthalmology, one of the biggest complaints that we would always hear is, you know, patients have to have used 2 eyedrops, 2 different, they have to put one in wait five minutes. And so as we thought about both, obviously, the compound, the formulation and application, so it’s an ointment, which is very different to what people are used to, to using in dry eye disease. It’s an ointment placed directly onto the eyelids onto the meibomian glands, similar to what you would do if you’re treating acne. And then you apply it just before you go to bed. And so the goal there was to really separate it from the use of eyedrops knowing full well that in a lot of ophthalmic diseases, you have very much combination use different any inflammatory can be used in conjunction with our product if it gets approved as well as other medical devices like with a flow or olux. So there’s a compatibility across multiple different other options.

Paul Karpecki: So the application is how many what’s the frequency it is an agreement and displayed right onto meibomian gland. So almost external to a degree, right? Where are you at the site of where the diseases for at least 86% of dry eye patients? How often were they dosed in the clinical trial?

Marc Gleeson: In the clinical trial, they were dosed two times per week. So yeah, so your keratin lids and our goal in the program was really to get into the clinic very, very quickly. And so the label for selenium disulfide 2.5% shampoo is to be applied twice, 2 times per week. And so we felt that, given one of the studies was a dose and frequency ranging, and after an interim analysis, we saw a fairly significant improvement in efficacy, we felt that the twice per week application before bedtime was adequate. So that is also a unique approach as well.

Paul Karpecki: It certainly is, you know, we don’t have anything currently that we would use in that level of frequency, certainly, from a compliance standpoint, patients will love that and will do extremely well. Now, that’s exciting, that’s certainly going to be a significant contribution as it goes through the regulatory pathway. What are your views for the company itself? Is this what you’re gonna kind of focus on? Is this, are you thinking bigger as an architect? Is this going to be this broad kind of base as a whole cities of skyscraper? What’s the future for Azura, even beyond AZR-MD-001?

Marc Gleeson: Yeah, so our focus as a company is really to develop a whole new class of compounds for ophthalmology, really centered around these keratolytic, and really addressing the Oculus, that lid margin driven ocular surface diseases, so keratolytic a very interesting class of compounds. You know, they’ve been utilized in the dermatology space for a very long time. And so, if you take a compound like salicylic acid, it’s a keratolytic. But it’s also used as a penetration enhancer in a lot of dermatological agents. So the way we see sort of the company going forward is, you know, we want to really want to leverage these unique properties. So the first part of it is, you know, these disulfide disrupted, so selenium disulfide is the lead in that, and that’s where we’re really directly tied in aberrant or abnormal protein structures, deposition or aggregation in the meibomian glands. But we have an in-house chemistry program where we’re developing a pipeline of products where we’re actually conjugating care analytics to other known compounds. And the idea behind the conjugation is that the compound the conjugates, are designed to metabolize fairly quickly when they hit the ocular surface. And in doing so, released both the care analytic and the original compound. But when you conjugate compounds with keratolytic, we do a couple of things. Firstly, you have the opportunity to change the physical chemical properties of those drugs. So you can take what may have been a fairly hydrophilic compound, so something that may require a high concentration on the ocular surface, it may end up going down the back of your throat, causing adverse events. And you can turn that into a lipophilic compound. So you can use parts of the structures that are parts of the periocular structures such as even the meibomian glands as part of the drug delivery process under the ocular surface. I mentioned penetration enhancers, and so forth. But, again, we can identify compounds that may be too potent to go on the ocular surface. And by using these penetration enhancers really reduce the concentration of these compounds actually allow us to actually bring some other compounds that may not have been suitable to trading off your surface disease and bring those to potential new indications as well. So we have a very broad approach in the early development, but in the short term, you know, for us as a company, clearly, you’re getting AZR-MD-001 through the development aspect. There is one other program that we have, and this is where it’s sort of coming back to, you know, parts of the learnings over a 20 plus year career in ophthalmology, you know, ophthalmologists and optometrists like to be part of the process, you know that they have lots of different tools, they want to be able to treat patients in the clinic. So we’re actually developing a physician administered open keratolytic that will allow you, I suppose, a more aggressive, more potent capability to be used for maybe more harder to treat patients. So we have a very broad portfolio of products.

Paul Karpecki: Exciting that certainly is the perfect dental model where you know, they come in get the deeper cleaning, you know, when you go in for your teeth, and then you still go home and have the products you know that you’re using for brushing your teeth, flossing, that sort of that’d be an ideal approach. I like that too, to having something in the office that we may be able to then take care of the more significant you know, obstructed, meibomian glands in those patients. You’ve obviously done really well and in large company structures and carried you know, played a key role in that but you seem just perfect and in the role of a CEO and a biotech startup as you’re in right now. Just seems like you and comfortable place. Is that a difficult transition? And what advice might you have for others who have aspirations of be getting into working with a startup or launching a company, like you’ve done with Azura?

Marc Gleeson: The opportunities out there, in the small company world are very large. You know, I think personally, I’m the sort of person that likes to get my hands dirty, get my hands, roll up my sleeve, and be involved in numerous different things. You know, I look back when I moved from Johnson and Johnson, which was Janssen Pharmaceutical to work with one of the largest healthcare companies in the world to then join Allergan in Australia and New Zealand, where you really did have to roll up your sleeves, get your hands dirty, do lots of different things. So I think, you know, if you feel that type of person, and knowing full well that, you know, startups just don’t have the same level of resources as bigger companies do. You’ve got to identify what are the right things to do to really move programs along, and then drive value creation through that. But yeah, I suppose what my only key learning advice would be to really think about the type of person you are the environment that you like to work in, you know, what are the degrees of risk that you’d like to sort of have in your professional life, because, you know, industry, you do get a lot of failures. And you know, you can have the best plans, you have the best execution, but due to some fundamental aspects of the drug, you may not necessarily see the outcome, the endpoint that you want at the end of the day, but, but it is a very fulfilling experience, you know, you get to meet some fascinating people, you have, I suppose, a lot of opportunity to really think about problems and find very creative ways to find solutions.

Paul Karpecki: So outstanding Marc, really exciting time for you and getting the company and it really thankful that you’re willing to share so many insights from kind of, you know, where you began and where you are today, the key aspects that would be, you know, good attributes for success, the way to think about who you are, and where it all fits in, was truly something I think the listener is going to find to be valuable both from an innovation standpoint, as well as even from a development standpoint and growth individually, you’re certainly are an architect as you as you think about all the key components that are there. I love that analogy. And you’re achieving something structurally very impressive. So I want to compliment you on your leadership with Azura and also for sharing so much with our audience today. Thank you very much.

Marc Gleeson: Well, thanks, Paul. And hopefully we’ll get to see each other shortly.

Paul Karpecki: It will be nice to be in person again soon. Absolutely. Thank you, Marc.

Marc Gleeson: All right.