 Good morning, everyone. It's my pleasure today to introduce Barbara Orozco, so we can take our seats and get started, that would be great. It's my pleasure today to introduce Barbara Orozco, who has a very interesting history and is unusual, but wonderful role model for our trainees who are interested in drug development or technology. Barbara completed her ophthalmology residency at Columbia University in New York, and then did her glaucoma training at Cornell. Following that, she went on to spend ten years in private practice in Huntington, New York, and at the same time have four wonderful kids with her husband who's an anesthesiologist. About five years ago, she joined Pfizer and was a senior medical director for ophthalmology. So essentially, Barbara was the queen of Xalatan for five years. She oversaw all the phase one, two, and three clinical trials as well as obtained or led the European licensing of Xalatan for pediatric glaucoma. In addition, she oversaw the pipeline development for glaucoma therapy at Pfizer. In June of this year, her family relocated to the Salt Lake City area, and I have been very fortunate to have Barbara join my team in our company called Ivina, which we launched about two years ago for developing a drug delivery device. And in that capacity, Barbara has led a lot of the preclinical and regulatory work that needs to be done for development of a new medical device. In addition, Barbara serves as the chief medical officer for Altheos, which is a San Francisco-based biotech firm developing a kinase inhibitor for glaucoma therapy. So with that, I'd like to introduce Barbara Roscoe, and she will give the first talk. I believe there's a couple of patient presentations to follow as well. Thank you, Bala. So it's my pleasure to be standing up here today and for the University of Utah Moran Eye Center to have welcomed me. When I joined Pfizer, and it was kind of funny, it wasn't really that I was looking to join drug development, and I had no idea what it involved. It was a great learning experience, and it really opened my eyes to how we as physicians use medications and how medications get approved. And I look at diseases and I look at the challenges of getting new drugs into our hands different than we do now. Let me get to my slides. And it's been an absolute pleasure working with Bala. When I joined Pfizer, I actually joined the MacGin team, and I was thrown back into AMD, which I had chosen to forget in PDT. And I didn't want to learn all the therapies that were happening. But with the MacGin team came the understanding of VEGF and the whole world of vascular mediators, and it really opened my eyes to the vascular mediators and how they affect cell walls, endothelial cells, and vascular tissue, and channels. And I want you to keep that in mind as I go through the slide deck, because not only do we have vascular channels that carry blood in the eye, but we have the trabecular mesh work, which is a vascular channel. But instead of carrying blood, it carries aqueous, and it has the same smooth muscle, as the same endothelial cells as blood vessels. And that's how I started to think about glaucoma. You did tell me that I can't use this by the pointer. So again, in full disclosure, I am a consultant and the chief medical officer of Alpeos, and I do work here with Bala. And I do have an academic volunteer appointment. And I am available to residents and fellows if this should be your area of interest. So the objective here is to show you that there is a vascular scheme component to glaucoma that lowering IOP affects and improves the ocular blood flow to the eye to introduce some underlying pathophysiology of ischemic and systemic endothelial dysfunction. And to say, well, maybe we can look at a target in the future and approach glaucoma a little differently. I'm going to present the understanding and treatment of glaucoma, go through some of the evidence for systemic vascular factors, talk about how do you assess those vascular factors in the eye, and also then how do you target it. So we know glaucoma is a multifactorial progressive optic neuropathy. And it's got characteristic loss of retinal ganglion cells. There's several risk factors. And we always think about those as the IOP dependent and the non-IOP dependent. And IOP is indeed a key risk factor that impacts not only the development of glaucoma, but also its progression. And currently, it's the only risk factor that we can modify and actually treat and alter. And our current therapy is aimed at altering IOP. But people are hoping to change that. It's a continuum. We see structural and functional loss. And we're not treating the symptoms or I should say we're treating the symptoms, but perhaps not necessarily always the pathology. So we're not aiming at the retinal ganglion cells. We're aiming at a risk factor, which is a surrogate marker. And I think that's what we have to keep in mind. It's a progressive optic neuropathy. The surrogate marker is IOP, very similar to cardiovascular disease. It's a vascular disease with atherosclerotic plaques and the surrogate marker is cholesterol. So we treat cholesterol hoping to improve the progression and impact those vessels. So here we treat the surrogate marker IOP. We hope to slow down the progression and treat the disease. And there's numerous risk factors. Well, how are patients affected? And this is sort of more for the residents. Well, there's functional loss. And when we talk about visual function, that's visual field, end stage, we see changes in visual acuity because it's central. But there's also other things that can change. And in contrast sensitivity, there's numerous papers out there that show that patients with glaucoma have decreased contrast sensitivity. And I think that's very interesting from the standpoint that the regulatory bodies, the FDA, EMEA, the European Medical Agency will say that, yes, if you improve contrast sensitivity in a patient, that's clinically relevant. And we will approve a drug that impacts contrast sensitivity. We will also approve a drug that improves visual fields and will approve a drug that improves vision. So we have loose sentence for that example. Memantine try to improve or slow down progression of visual fields. I don't know how many of you remember the Memantine study. But again, it was a very difficult long study for various reasons, but it was looking at an endpoint of visual field as a marker of visual function. There's structural changes. The FDA and the NEI and ARVO have put out several recent collaborative meetings looking at structural changes as an endpoint for glaucoma. Up till now, they will not accept structural endpoints, retinal neurofiber layer as an endpoint. So if you develop a drug or some sort of therapy that slows down retinal ganglion cell loss or structural loss, Wiley Chambers, who heads upcedar of the FDA for ophthalmology, says, well, I don't know what that means to the patient. If you slow down the loss of neurofiber layer by five microns, well, what does that mean to the patient? Does it make the patient see better? Does it improve his clinical function? And he will say, no. And he will say, therefore, I will not accept a drug that slows down neurofiber layer loss. So it always comes back to the impact on the patient, the function of the patient, the clinical relevance to the patient. So we know that lowering IOP reduces the risk of glaucoma. And there's numerous studies, large, well-designed, prospective, randomized studies that have shown us that, yes, if you alter IOP, lower IOP, you will slow down the progression of this disease. And we can alter that. We can alter IOP. So we decrease aqueous production or we improve aqueous outflow. And we talk about other aspects of IOP. We talk about peak IOP, we talk about IOP fluctuation. Because when all is said and done, patients with elevated IOP, despite IOP lowering, can progress. And patients without elevated IOP can progress. So there's definitely a component to this disease that we're not treating when we manage IOP. Furthermore, studies have shown that despite IOP lowering with conventional one monotherapy by five years, 75% of those patients require combination therapy. So our IOP therapy is failing to maintain those patients in a therapeutic target area. What are we doing when we lower IOP? Well, could we be actually affecting other parameters? And the question is yes. There's non-IOP risk factors. So we have the ocular risk factors, the neurodegenerative risk factors, the cardiovascular risk factors, and primarily the vasospastic vascular risk factors. Migraines, vasospasms, rainotes, hypotension. Even positioning. If you lay a patient down and then sit them up, their IOP will vary. During nighttime hours, IOP tends to be higher, but yet blood flow and perfusion and blood pressure tend to drop. What's happening to the eye? Is that patient who's recumbent on their right side all their life? Are they going to have asymmetric glaucoma present later on? These are some of the questions that come up. One thing that I found that was very, very interesting is out of the Canadian glaucoma study, Bell-Shohan has been a big proponent looking at vascular mediators and different proteins that affect the vascular chirp. He looked at patients over several years, and he found that women who had elevated anti-cardiolipin actually had higher incidence and more progression of their glaucoma state. You think about your rainote's patient, your younger, thin woman, hypotensive woman. Maybe that's the woman that has normal tension glaucoma. That's more of a vascular component. But when we think about anti-cardiolipins, that's also a marker for endothelial damage. If you look into the cardiovascular literature, they'll show you that if you have elevated anti-cardiolipin antibodies, you may be at a higher risk for strokes, heart attacks, atherosclerotic plaques. So again, there seems to be some link there. The guidelines, which I thought were very interesting, this year now include low ocular perfusion pressure, is a risk factor for glaucoma. So as clinicians, are we supposed to be measuring blood pressure? Are we supposed to be calculating our ocular perfusion pressure in these patients? But what is ocular perfusion pressure? We look at comorbid conditions with these patients. So if we're not sure that IOP is the whole answer, what about systemic diseases? And there is a correlation with glaucoma patients and systemic diseases. But we're not clear if one is precipitating the other. Is it just that we're looking at elderly patients? And if you take a cohort of elderly patients, you're going to see a higher incidence of coronary disease and systemic hypertension. Or is one actually predisposing the patient to another disease? There is a rationale for blood flow as a risk factor, because the eyes end to organ. And if you think about the kidney, if you lower perfusion to the kidney, you end up with microinfarcts, glomerular nephritis, various nephropathies, because there's ischemia. Why is the eye any different? You have one major vessel coming in, a lot of small tributaries coming off. And if you decrease the blood flow coming through the ophthalmic artery, what happens to those other terminal arterials later down the road in distal? Well, they either constrict or dilate. And what happens if you lower blood pressure? So if you lower blood pressure, well, those terminal arterials are very sensitive to changes in oxygen. So you have these small posterior ciliary arteries that suddenly are seeing less oxygen. Well, they're either going to dilate or they're going to constrict. And there's watershed areas, which Anderson and a lot of Hayray's work focused on, and again show that if you change vascular chair or change the perfusion, you will see changes in the vascular chair, and you can actually see microinfarcts in the peripapillary area of the optic nerve. Is that what we see when we see disc hemorrhages in our glaucomatitis patients? And how many advanced glaucomatitis patients actually have attenuated, narrow retinal arterials and even sometimes shunt vessels? Well, can you measure it? So, okay, fine. Here it plays a role, but can we measure it? IOP is very easy to measure. You can measure perfusion pressure, and it's a measurement. And this is one thing I want to stress, that it's not a direct evaluation of the vasculature. It's a measurement. And it takes into account systolic blood pressure, diastolic blood pressure in IOP. It makes sense. You increase the IOP in the eye. That's pushing on the vasculature. There's less perfusion of blood to the back of the eye. We've all heard over and over again. And the blood, the optic nerve head, has been, the blood flow to the optic nerve head has been correlated with changes in mean arterial pressure. They talk about mean. And another thing just to keep in mind, when you hear ocular perfusion pressure thrown around, it could be diastolic perfusion pressure, mean perfusion pressure, or systolic perfusion pressure. And there is this theory that patients who have glaucoma cannot adjust their blood vessels to change in perfusion pressure. So if the perfusion pressure drops, these patients can't vasoconstrict. And again, this is very consistent with the migraine patient, the Reynolds patient. There is a dysregulation of their autonomic system to that vasculature. Numerous population studies, and this is why the AAO probably added in their guidelines that perfusion pressure is now a risk factor, you have population-based studies that show if you lower perfusion pressure, you can increase the incidence, the prevalence, and even the progression of glaucoma. And I thought what was Lesky presented, Mark Lesky in the Barbados I studied, at nine years, your relative risk is actually doubled if you have a lower mean perfusion pressure. Can we measure it in other ways? Can we measure it directly? So we can do that for our carotid disease patients. We can look at carotidoplar. We can measure blood flow elsewhere in the body. And again, we're dealing with very small vessels, and there's a lot of variability, so it's very difficult. But you can. You can look at your ophthalmic artery, you can look at your central retinal artery, and this is done with the carotidoplar imaging. And this is, for the most part, been standardized. It definitely is normative data looking at blood flow through those major tributaries with the CDI. The rest of the vasculature is much more difficult to assess. But you can. You can look at it with ICG, you can look at it with fluorescein, you can measure the vessel diameter, you can measure the velocity of the flow, or the velocity of the blood vessels passing, but you can't measure flow. Flow is a calculation. And it's prone to error, and it's prone to variability, and it's prone to technician variability and patient variability. So where this stands is this is still an experimental collection of technology that's usually used in a research department. Well, have some people try to incorporate it into drug development. So if you think you have a problem with blood flow and you want to improve your blood flow, well, you've got to measure it, because your drug has an effect on it. And people are starting to think about that. But again, it's very difficult. I can't go to most of you in a clinic setting and say, okay, enter a patient into this trial and I want to measure blood flow. And I want to look at this drug's effect on blood flow. So there's difficulty in recruiting patients, there's difficulty in finding sites, and there's difficulty in validating the equipment. Japan's a little bit more lenient and a little bit more accepting of different types of data to put into labels. And Tafloprost, which is a prostaglandin, recently got approved in Europe. Merck is actually marketing it. They were approved in Japan and in their label they actually show that if you apply Tafloprost to animal models and actually even to humans, you can improve blood flow. What does this mean? We don't know. What's the clinical impact? What are we helping? What are we doing to our patients eventually? We don't know. But this is sort of the first step that you have recognition that a topically administered drug is affecting blood flow and actually was measured reliable and repeatedly and some validated or actually some data that's yet to be validated but it was included in the label. Can we target the vascular check? Numerous targets. And I'm not even going to try to go through all of these. But I think one of the things that stands out as a pretty interesting target and that I have found of interest is the endothelial cell. And again, when we think about the eye and we think about glaucoma, the endothelial cells line the trabecular meshwork, the juxtacanular and Schemes canal and they also line the blood vessels. So it may be an interesting cell to look at and to target. And what happens if those endothelial cells don't function well? Well, they don't vasodilate or vasoconstrict to mediators. Nitric oxide. Very well-known vasodilator. If an endothelial cell is damaged and or dysfunctional and as you age, your endothelial cells become dysfunctional. They won't respond to your nitric oxide. So even if your blood vessels wanted to dilate, maybe they can't because the cells are older. One thing that's very interesting is VEGF. VEGF affects endothelial cells and endothelial progenitor cells. These are the bone marrow cells that get called into play in angiogenesis. You elevate VEGF in the eye. We know you get CNB, corneobascularization. Well, why? That VEGF activates those endothelial progenitor cells to come in and to form new vessels. But in a normal, healthy state, not in a pathologic state, but in your everyday state, if you want to repair those cells, you need VEGF. Maybe VEGF's playing a role. Another very interesting target is endothelin. Endothelin is very well studied in the cardiovascular literature because it causes blood vessels to constrict and it gets elevated if the endothelial cells are damaged. There's clinical evidence that these mediators are actually elevated. There's elevated VEGF in the aqueous of patients with glaucoma. Well, why? These are not neovascular glaucoma patients. These are just patients with glaucoma. Why? Is the eye trying to repair itself? Is it trying to heal itself? VEGF is not always pathologic and you need a low baseline and there's different mediators there. I defer to Bala on that one. It's a very interesting compound, a mediator or a protein. Endothelin 1 is elevated in the aqueous and in the plasma patients with glaucoma. Well, patients with cardiac disease have elevated endothelin. If the patient has an ischemic stroke, they'll have elevated endothelin. Again, we have another marker that's sitting in the aqueous that may be telling us that there's some ischemia going in the eye. There was also lower nitric oxide. Nitric oxide vasodilates. So you've got an elevated vasoconstrictor and a decreased vasodilator. What's happening to the trabecular meshwork? Maybe it's closing down. Maybe there's more resistance. Maybe it's constricting. Maybe it can't dilate like it should because these mediators are in the aqueous. Endothelium is very... is a really, really cool protein. If you think a protein can be cool. And again, if you go into the systemic literature, it is overwhelming with evidence that this is a very potent vasoconstrictor, causes fibrosis, causes inflammation, causes endothelial cells not to function properly and also may cause angiogenesis. If you give it to animals, and again, think about glaucoma and think about endothelium maybe being elevated in the eye because there's ischemia. If you give endothelium into the vitreous, you actually cause retinal ganglion cell loss. And if you inject endothelium behind the optic nerve or paribulbar, or retrobulbar, you get a glaucomatous optic nerve without elevated IOP. And if you reverse endothelium or block it, you can block that glaucomatous change in the optic nerve. It's been looked at in glaucoma. It's been looked at to have a role in the anterior chamber. It's been looked at to have a role in the posterior segment as well. It's involved in retinal ganglion cell death. It could be involved in vasodilatation of the trapeculomesh work. It can also affect blood flow. There's antagonists to it. You can block it. And it's a very potent class of vasodilators because again, if endothelium vasoconstricts, you block it, you vasodilate. It's an established therapy for pulmonary arterial hypertension. And there's currently two drugs on the market. And I actually got interested in endothelium receptor antagonists when I was at Pfizer because they have one of these compounds by the name of Thelon, Cytaxotin. The other company is Cetlion, which makes Bosantin. They're looking at these compounds also in diabetic nephropathy, peripheral arterial disease, hypertension, kidney failure, anything that you would need to vasodilate. The problem is that these drugs have toxicity. So you can't give your glaucoma patient an oral drug long-term because of the systemic side effects, primarily liver. There is evidence that if you give endothelin, as I said, you can cause glaucoma if glaucoma changes. So if you block it, what happens? Well, there's studies that show that you can actually improve blood flow to glaucoma patients if you block endothelin. It's a very short dose. None of the patients had any toxicity issues. And they did show improved blood flow. Also, if you give it topically, it's blocking vasoconstriction. Vasodilates. It appears to vasodilate the trabecular meshwork at a lowered IOP. So in summary, are there possibilities to manage glaucoma differently? I would say yes. I would say we should look at these other mediators and think about the eye a little bit differently. Think about it as an end organ that has vascular neuronal components to it in addition to the IOP and the trabecular meshwork. So we could vasodilate. That may help. That'll help the trabecular meshwork. And the rokinase inhibitors that are actually being looked at are being borrowed from the vascular space. Vasodilate. Vasodilate trabecular meshwork. You could decrease constriction. You can block endothelin. And maybe again, open up those channels. Maybe you can improve the health of the vascular tissue. Is there any way that we can improve endothelial cell function? Well, in cardiac tissue we can with statins. There's some suggestions that statins can work in the eye. And we can also perhaps try to improve the inflammatory status. So what does this mean for drug development? How would you get a drug that works on vasodilature actually approved and into the hands of clinicians and into patients? Again, very, very difficult path because there's no clear endpoint. And when you think about the effects of glaucoma they're slowly progressive. And from a drug development perspective glaucoma is not very much different than Alzheimer's. You have some people progressing, some that are stable. And at the end, you want to show that your drug has a statistically significant impact on progression and or outcome. And it's very difficult when you're dealing with a slowly progressive disease. We saw that again with the Memantine Study. The challenge is yes, surrogate marker for IOP is easy. So you're going to keep seeing IOP lowering mediators. And that's the easy target for drug development unfortunately. There is this big push from Wine Reb and Paul Kaufman. They were the ones that led Arvo's NEI FDA meeting on endpoints to say we need to look at glaucoma differently. What I thought was very interesting and I just threw in at the end is we may get help from our neurology colleagues and I know some of you involved in neuroop. So Tarsiva is looking at a vaccine for optic neuritis, acute optic neuritis. And they're actually multiple sclerosis, but they're looking at an indication in optic neuritis patients. What that means is they are designing clinical trials phase three to show that this intervention slows down neurofiber layer loss secondary to optic neuritis. So they're actually looking at neurofiber layer structure in a clinical trial as an endpoint. And if the FDA chooses to accept this, this can really open up the way we look at retinal disease. And it can change our endpoints for drugs that treat retinal disease including glaucoma. So I'm very excited to see what happens with this optic neuritis study. You may have seen it in some of the throwaways. It gets a little press and ophthalmology. And again, it's the octagon study is the name of it. So the future, there's challenges. There's clearly an unmet need. We're not managing our patients the best we can. And an IOP lowering agent is not giving us everything we need to manage our glaucoma patients. And I think it comes down to the fact that we really don't understand the pathophysiology of the disease. We really don't understand what's happening to these patients. Glaucoma remains a leading cause of blindness. We're probably overtreat. And if you look at the recent papers that came out of oats, we probably do overtreat. And in fact, that's probably a result of the pharmaceutical companies. You know, they gave us IOP lowering agents. And Zalatan is a great example. Very safe, very low risk. So if you've got an ocular hypertensive with a family history of glaucoma, you may choose to treat that patient. But will that patient really progress? And our patients that we see with pressures of 8 and 10 that are continuing to progress, we're still pouring on our IOP lowering agents. But obviously, those aren't helping us because we would like them to do. So it needs to be looked at. It needs to be looked at better. And I believe that there is room to move this science forward and to look at the disease a little bit differently. And with that, I thank you. I thank you for your attention. I threw a lot of material at you. And if there's any questions, I'd be happy to answer any questions. Well, ocular migraine, I don't think not necessarily ocular migraine. But I know that the association has been drawn between classic migraine and then more so renal patients. But I don't know anything about unless other people can comment. I don't know if ocular migraine alone has been looked at. There's a lot of literature. And in fact, Jay and Bala's brother had several presentations on this where there's... So you need VEGF to maintain normal homeostasis and VEGF is very important in cellular repair, cellular function maintenance and retinal ganglion cell function. The concern was that when you blocked all of VEGF-A with your pan... anti-VEGFs, that you would have some decrease in normal function over time. There's a host of... Again, the retin specialist, please chime in. There's some thought that these patients who have long-standing anti-VEGF therapy over time, although their lesions dry up, there's some retinal thinning that's been shown to occur. And people are unclear as to whether an opus is related to that sort of continuous injections of an anti-VEGF. But yes, it was absolutely a concern that you would have decreased retinal ganglion cell and neuronal function. The other thing that's interesting too is the stroke literature and the neurology literature. VEGF is a key... is definitely involved in strokes and I think it's involved with Parkinson's and Alzheimer's as well. So if you have lower, you know, central levels of VEGF, you could have more likely developing some of these other degenerative diseases. That's a good question. So again, I feel like I'm speaking in an area, even my retina colleagues here, the retinal ganglion cells, primarily the macula, have the highest oxygen need of some of the cells in the body. So even a slight decrease in oxygen, those cells are very, very sensitive to any alterations in oxygen. That I don't know. That I don't know. I mean, I would assume the photoreceptor is more so than the retina, the retinal ganglion cells. In fact, George Spath, who's a leading, you know, well-respected opinion leader in Glaucoma, was proposing doing some studies in PET scans and MRIs because the thought is, from a neurologic standpoint, that perhaps some of the changes that we see in retinal ganglion cell thinning and loss actually originates in, you know, the cortex. There's studies that show that if you injure the, is it the striate nuclei, you can affect because of axoplasmic flow, retrograde axoplasmic flow, you can see retinal nerve fiber loss that actually correlates to that loss that originated, or that insult that originated in the CNS, in the central cortex. And they don't know. We don't know where. You know, people propose that the insult is right at the optic, you know, right at the optic disc at the lamina crevosa. Other people propose that it's an insult to the dendritic processes. Another person will say, no, it's the axonal body. They don't know. I think what's pretty neat, I think you can relate when you see patients, is patients with Parkinson's disease can very often have block-homes looking nerves. And that's where they don't, you know, so even if you vasodilate, you can decrease perfusion. So if you give someone, you know, excessive anti-hypertensives and vasodilate them and drop their blood pressure, you're probably doing more damage than you are than helping them. So you're right, it's a very, very fine balance. And I don't have the answer to that. I don't even go into the reactive oxygen species and the oxidative stress. That's a whole other area based on endothelial dysfunction in nitric oxide levels. Thank you. Thank you very much.