 So we're going to go ahead and get started. People will probably continue to trickle in, but our first speaker today for Grand Rounds is going to be Dr. Waratsko. She's going to talk to us a little bit about Zalatan and pediatric glaucoma. And Lloyd Williams, our second-year resident, will be discussing something that I have no idea what it is, but an elliptical curve fitting. So we'll go from there, Dr. Waratsko. Thank you. So good morning. This was a study that I was responsible for leading while I was advisor last year, and we recently presented it at AAO. And it actually did get a best poster at the convention, so we were quite proud of the work. And again, it was, the purpose of the study was to get a pediatric indication for Zalatan. And I don't know how many of you are familiar with the status of some of the IOP-lowering agents, but in the United States, there is no IOP-lowering agent approved in children for pediatric glaucoma. And in Europe, the only one that's approved is actually dorsolamide. Tomoptic is approved, but it never went through a formal clinical trial for that approval. So obviously, uncontrolled glaucoma in young children leads to a lifetime of blindness. And especially in Europe and in some of the emerging countries and emerging markets, glaucoma is a problem for these children. They do not have access to medical and or surgical care. And although in the developed countries in the United States, surgery is the mainstay of therapy. Again, in Eastern Europe, you can imagine that surgery is not immediately accessible to these children, so a lot of these children do require medical therapy as they're waiting for surgery. And I think what's so sad too, what we found in the study, is that there's children that are diagnosed at the age of, you know, even in, I would say, eight, nine early teens with very high pressures that have gone undiagnosed. Due to the clinical need, medical treatment for pediatric glaucoma often includes topical and oral IOP-lowering agents. And as I just told you, there are no good clinical studies to really show whether or not these drugs work. A few ocular hypertensive medications have actually been studied in large controlled trials and very few are approved. And the question was, latinoprost is used off-label in pediatric glaucoma patients and we wanted to ask the question, does it really work? Is it safe? Is it efficacious? And should we recommend this drug for this group of patients? The EMA, which is the European Medical Agency that's the regulatory equivalent of the FDA, wanted us to study babies as well. And they asked us to look at three groups of children, ages 12 to 18, three to 12 and zero to three. Why they wanted a three-year-old cutoff? Your guess is good as mine, but that was the cutoff. And they also said, before you go and place these children in a phase three study, you need to do a PK phase one study. We want to know what the blood levels are of this drug in these children. The first study was the phase one, which was our pharmacokinetic study. We had children come in, we switched them in both eyes, 8 a.m. with latinoprost. Again, it's a p.m. drug, but in this case we were administering it 8 a.m. in the morning. And we didn't do punctal occlusion because again we wanted systemic absorption. Three to 28 days later, blood samples were drawn on these children at 5, 15, 30 and 60 minutes post-dose. And we were looking at latinoprost acid. If you recall, latinoprost is a pro-drug that gets converted through the corny and the ocular tissues by esterase enzymes. And we were looking at the acid form. And this was measured with mass spec. We're also assessing safety evaluations as well. The phase three study, which was the large prospective randomized clinical trial, was a 12-week double mass multi-centered study. And if you think about your pediatric patients, you can imagine how difficult it is to do an IOP study in children, especially the babies. Your standard IOP studies usually have three or four measurements during the course of the day. 8 a.m., 10 a.m., 12, sometimes two, sometimes four. Because you wanna look at diurnal IOP variation, very difficult in a baby. You cannot keep bringing that child in, especially the young ones, to do an EUA in order to get their IOP. We had one IOP measurement. And the other thing that the regulatory agents wanted was they wanted the children divided and stratified by age group, as well as diagnosis. They wanted children of all classifications for pediatric glaucoma studied, but they wanted to know specifically, was there a difference in primary congenital glaucoma versus non-PCG? And they also wanted it stratified by IOP. So children with higher IOPs, did they respond just as well? Patients were randomized one-to-one, leptanoprost versus tomoptic, and the little ones got 0.25%. Ocular systemic evaluations were scheduled, weeks one, four, and 12. And the primary endpoint was your traditional endpoint of relative mean change in IOP from baseline to week 12. And again, keep in mind that there was no specific time that the IOP was measured. The EMA was fine with us, the FDA was not. And this, again, we were only focusing on the EMA division. Secondary endpoints included percentage of greater than 15% IOP reduction from baseline, and that was considered responders. And what was interesting, when you think of responders in adult population, we wanna see at least 25% reduction of IOP. Children, when we spoke to a lot of the leaders in this field felt that if you got a 15% reduction with a topical IOP lowering agent, that was pretty good, and that classified as a response. And again, we also looked at efficacy analysis in the two subgroups. So the PK, this was actually what, you know, it's funny because I was more personally interested in the phase three studies, but a lot of people found this most interesting of all. There's very, if not, I think this is actually the first study that actually looked at plasma levels of a topically administered drug in children. And as you can see here, over the span, this is in minutes, so over the span of an hour, 10 to 15 minutes, there's a rapid uptake of Latinopros acid into the plasma, and it's much higher in the babies. So here you've got your greater than 18, we also looked at adults. Here's your 12 to 18, your three to 12, and then again this rapid, very elevated increase in children. However, this was below data and studies that have been done in the past with adults. So this was still within what they call the therapeutic window or a safety margin. No temporary discontinuations, no permanent discontinuations due to adverse events, and there were no treatment emergent adverse events, and no clinically significant changes from baseline in any other laboratory. And I think too, what was encouraging is that within an hour, the levels dropped off. The phase three results, we had 139 patients that were randomized at 42 centers, 137 retreated and were included in the intent to treat population, and 107 out of the 137 were in the per protocol population. And we ended up with pretty nice numbers in terms of the randomization. We had 53 on Latinopros, 54 on Tomoptic, and also in the stratification, the primary diagnosis for PCG was 45% of patients in each group. We found that the IOP levels were actually decreased in both the Latinopros and the Tomoptic groups. 7.1 millimeters of mercury in Latinopros, 5.8 in Tomoptic, and in the PCG group, we had 50% responders for Latinopros, and 46 responders for Tomoptic, which surprised us. And respectively, in the non-PCG group, the responder rate, again, it's 15%, greater than 50% drop in IOP, was 72% in Latinopros, and 57% in Tomoptic. The hypothesis was that we were not inferior to Tomoptic, and our non-inferior was a margin of minus three millimeters. Usually in most adult studies, it's one and a half millimeters of mercury. We chose to go higher, because again, in kids there's so many variables, you're dealing with thicker corneas that also can impact on the pressure. A lot of times you're doing tonopens, so you're not doing aplenations. So again, there were a lot of variables in this study that could kind of found that. And we said, okay, if we are within three millimeters, we're not inferior, and that was acceptable with the agency, and also the people that we were consulting with. We were non-inferior, but what's interesting is that in all groups, Latinopros actually appeared to be superior in terms of numerical numbers. These were not all statistically significant, especially in the PCG group, but in the non-PCG group, again, there was a clear difference in numerical value of greater IOP lowering in that Latinopros group. The last one was, yes. So the IOP reductions in the safety at baseline, and again, when we think about Latinopros and how long we wait for it to work or take effect, we were pleasantly surprised that at week one, we actually had IOP lowering effect that was then maintained out through week 12. There was a little bump in week four, not sure why, and here's your, I'm sorry, the tomoptic. The tomoptic group bumped up in week four when the Latinopros held. The other thing that was very, very interesting is you exclude, if you think about when you wanna run a clinical trial and you're putting a patient on a beta blocker, so you wanna exclude for anything that could be contraindicated. Respiratory cardiac issues. So we did exclude children with a prior history of asthma, respiratory, any sort of confounding systemic effect, but if you remember, these are babies, and a lot of these babies are not yet diagnosed with their respiratory problems, and what did emerge is a lot of these children, especially going on to tomoptic, did have upper respiratory infections, viral infections, coughs, and again, were we unmasking a prior non-diagnosed condition, or were these just kids getting up with respiratory infections? In terms of the safety, both drugs again were well tolerated, but we did see this difference in treatment emergent adverse events. So the discussion, well, the phase one pharmacokinetic study showed that we did have high levels in very young infants. Overall, the consensus was that this was not a safety concern, and that it was probably attributed to lower body weight, lower blood volume, and lower hepatic blood flow for these children. But it just begs the question that what about other drugs that are applied to children at this age? And again, there are no good studies looking at plasma levels, but just keep that in mind when you do put your pediatric patients on topical beta blockers. And obviously, Alpha-Gan is contraindicated in these children for exactly those reasons. The adult dose administered once a day was not inferior to tomoptic in reducing IOP levels. However, again, there was a greater numerical mean IOP reduction for latinoprocity measurement points. And again, as I said, it was not always statistically significant. I think the takeaway here was that it was very, very surprising to see an outflow agent work in primary congenital glaucoma. That was basically what I took away, and most of us took away from this study, is that really surprised us. We did not expect a prostaglandin to work in primary congenital glaucoma because of the anatomical abnormalities. You would think that only the aqueous reduction or the aqueous reducer or suppressor would actually work in these patients. But this was surprising. So again, there must be something going on the uveal scleral outflow system that's being affected by prostaglandins that improves the outflow and helps to lower the IOP. And I think that's exactly what I just said. Although the IOP lowering effect on the panopros was greater in the non-PCG patients, it also demonstrated a clinically relevant IOP lowering effect in PCGs. So in conclusion, this was what the regulatory agency was after, was it's at least as effective as tomoptic, and it produces a clinically relevant IOP reduction across all patients, including PCG and non-PCG. We also had some patients with Sturge-Weber, we had some patients with aniridia, we had some patients with AFAKE glaucoma, and we tried to break that down to do further sub-analyses, but it was very difficult because again, it's far and few between, and there's so many other confounding variables that are affecting the outcome of these children. And we also measured corneal thickness, I didn't even bring that into this poster or into this presentation, but that was another interesting analysis that we did on these children. And if there's any questions, thank you. Yes, Randy. So, first congratulations. Exactly, exactly. And we also looked to see if prior surgery actually also affected the outcome, but again, the analysis, the numbers were too small, and we- Get it again. You're right, so it's, and it's funny you bring that up because this really was a medical push. This was really us, you know, as you said, it's a business, you know, there usually has to be commercial value for a company to want to do this, but a lot of it was the medical value that this brought, so it was nice to get it recognized. Thank you.