 Thanks Eric. Up next we have a visiting medical student, Paul Sellad. He's visiting from the University of North Dakota School of Medicine. And he's going to talk about a topic today. It's going to be very interesting to some of our Redmond colleagues and a lot of residents alike. A Vastin versus Ilea in Exadata of AMD. Apparently more than anecdotal evidence. OK, thank you, Dr. Joss. And good morning, everyone. Today I'm going to take this opportunity to talk about a research project that I did with a classmate of mine during our third year of medical school. And what we did is we looked at the two drugs of Vastin and Ilea and how they are used in wet type or exudative age-related macular degeneration. But before I actually talk about the research project, I'd like to talk a little bit about the history and the progression of wet type age-related macular degeneration treatment and then how this research project fits within the existing data out there. And then I'd mainly like to focus on within this project the methods, results and the discussion of how we're able to place this within the existing data. So prior to the 1980s, my understanding is that the way we treated wet type AMD was we diagnosed it, we drew the lesion and then there was not a lot that we could do for these patients. But in the 1980s we developed something called laser photo coagulation that worked OK but it never really improved vision and it was only aimed at decreasing the progression of the choroidoneovascularization. In the 1990s we developed something called photodynamic therapy with vertebrate porphyrin that was probably a little bit better but still not optimal. In 2004, we developed this drug called Pagatinum which is brand-name macugin and that kind of in some ways probably revolutionized what we were doing in the wet type AMD treatment and we've continued that over the next eight to nine, 10 years. So in 2004 I mentioned macugin that was kind of put on the map I think in part by this study in 2004 called the vision study which showed that macugin was better than sham injections and placebo and improving visual acuity or at least maintaining visual acuity. If we progress two years and we go to 2006 we get this anchor study which looked at a drug called Ranabizumab which brand name is Lucentus and that showed that Lucentus was better at preserving or improving visual acuity compared to the previous gold standard which is photodynamic therapy. So we kind of transitioned from the photodynamic therapy into the medical realm of treating wet type AMD where we did intravitrial injections of medications. So if we continue this, Lucentus came into the market and it's developed by this company called Genentech which also made this drug called Bevacizumab. Bevacizumab has never received FDA approval to treat wet AMD. It was mainly designed as a drug to treat metastatic colorectal cancer and there was some creative ophthalmologist who decided that maybe this drug would actually work to treat wet AMD. So they've done that and they started that I think in about 2005 and we continue to use it today. So another study that's kind of a sister study to the anchor study is called the Morena study and that was in 2006, looked at Lucentus and said that Lucentus was better than placebo in treating wet AMD. And then in 2010 plus some other studies in the British Medical Journal said that Avastin was better than photodynamic therapy or macudrin depending on whether it's a cult or classic type chloride on the ovascularization. So now we're kind of left based on these studies with Avastin and Lucentus and then in the years preceding in 2011, November, we developed this drug called Afliversept which is Ilea. So today we're left with Avastin, Lucentus and Ilea mainly to treat wet AMD. So there's been a lot of research between these medications, especially Avastin and Lucentus. I list five trials up there but there's many more and they've looked at visual acuity outcomes in patients treated with Avastin and treated with Lucentus and they've said that they're basically equivalent in terms of visual acuity outcomes. Now there's also been studies between Lucentus and Ilea, the view studies in 2011 that I think helped bring Ilea FDA approval. But there's no studies that I know of at least since May of 2013 between Avastin and Ilea. Now it's interesting because Avastin's a relatively treat medication I think the literature says it's about $50 per intravitrile injection whereas Lucentus and Ilea are more like $18 or $1900 per intravitrile injection. So when I was in North Dakota working in comprehensive ophthalmology care clinics I'd see a lot of Avastin and a lot of Ilea injections in some Lucentus and I always wondered, why are you choosing which? And they would just say anecdotally we think the ophthalmologist would say that Ilea might be a little bit better. And I took this opportunity to during my third year of medical school to look a little bit more into that and that's what I'd like to present today. So this is a picture that I took in Lake Sakakawia this summer. It's a reservoir of the Missouri River System in Western North Dakota and I did my best to grow up on this lake as a kid, water skiing, boating and fishing. And just prior to coming to Salt Lake City I caught this walleye. It was about six and a half pounds, one of the bigger ones of the summer down there. So that's definitely one of the things I most enjoy. So actually the research project what we looked to do is determine the outcomes of central retinal thickness and visual acuity in patients treated with Avastin, Ilea and WED AMD. And we did this through a retrospective type cohort study at the Dakota Institute which is a comprehensive ophthalmology care clinic in Bismarck, North Dakota. And we looked at baseline central retinal thickness and visual acudes and we looked at them three month intervals up to one year. And unfortunately the injection sequence was not standardized because this was a retrospective type study. So there was 202 patients in this study, 111 fit into the Avastin arm and 91 fit into the Ilea arm. We determined the baseline characteristics and then we looked at them at three month intervals up to one year. So we obtained our patients using ICD-9 diagnosis for exudative AMD and they had to fit within this time period which led up to October 31st, 2012. Now that's kind of an important date for this study because that was the latest we could get IRB approval for this study and that November 18th is when Ilea hit the market in 2011. So that left us with just under a year of follow up time. So to get the power to make this happen was very difficult in the Ilea arm. We excluded eyes that were concurrent eyes or second eyes that had WED AMD so that we could have the number of patients equal the number of eyes. And then we excluded anybody who had permanent structural damage to the phobia like cystoid macular edema. And then just to be complete with statistical analyses, we talked about the 5% that was consistent here. A p-value of less than or equal to 0.05 was considered significant. And I hope we did the right tests there. Baseline characteristics of our patients in each arm, we had, we looked at the age and most of the patients were in their 80s and most of them were female. We also looked at the baseline central retinal thickness, the log mar and the snel and visual acuties. And in both of these categories, none of the values were different, which I think is important because we need to start with a cohort of patients and look at them through time when some received a vast and some received Ilea. So the visual acuity outcome, we looked at these in terms of log mar which stands for mean angle of resolution. And you can see the lower the log mar, the better the visual acuity. So we can see that especially in the Ilea arm, we see a good result here at six months. It's really able to improve visual acuity in the first six months. And we also see that for a vast but we lose that during the second half of the study. You can also look at this in terms of log mar gains of 0.3 or better or log mar losses of 0.3 or better. Now this corresponds to essentially snel and visual acuities doubling. So we're going from 2080 to 2040 or 2040 to 2020. So you can see at six months that our p-value shows we have a significant difference in visual acuity improvement of Ilea over a vast and but we lose that at three, nine and 12 months. And that may be due to the limited number of patients in the study, the limited number of power where we only had 18 patients in the Ilea arm at one year. We can also plot this in a scatter platform where we look at log mar at baseline and log mar at six months. And then we plot these data, put a best fit line through there. And the way to read these glasses are these figures as if the line is less than one. It's consistent with an improvement in visual acuity. And both drugs showed a line of less than one where Ilea was better lower than a vast was. So a lot of studies will look at the clinical outcomes, the visual acuity outcomes. We can also look at the anatomic outcomes and we chose the parameter central retinal thickness. And we can see that Ilea was better at three, six and nine months at decreasing intra and or sub retinal fluid versus a vast and but maybe due to lack of power, we lose that at 12 months. The mean number of injections, it would be great if we could have standardized the injection regimen to fit many of the studies where we give loading doses for three months. And then we go every month, every six weeks or every eight weeks. But we had to look at what these ophthalmologists had done. And in one year, they'd given over just over five injections to the vast in patients and over six injections to the Ilea patients. And none of them were statistically different. So in addition to fishing and being outdoors on the lake, I've really started to enjoy golfing and while in Salt Lake, I've been able to golf a fair amount and I've really enjoyed it. So to discuss what's going on here, there have been previous studies that have looked at patients on a vast and or leucentus and received multiple injections. And then because they become refractory to a vast in and or leucentus treatment, they'll sometimes switch them to Ilea. And what these studies have mainly found is that we're able to, in these patients, able to reduce the central retinal thickness. So anatomically improve them, but visual acuity really stays about the same. And these studies were done in 2013 and they're not a head to head study like we did, but they kind of intermix the two drugs. And the reason that they think patients may become refractory to the centus and or a vast in is because of some like tachyphylaxis or systemic immune response or sometimes some intrinsic properties that Ilea theoretically has over a vast in and leucentus. And that's a greater binding affinity to VEGF or binding to VEGF B or placental growth factor, both of which leucentus and a vast in do not do. Now the visual acudes that we obtained were Snellen visual acudes. That's what the clinic in North Dakota use. And I think that's what a lot of the Moran clinics use. But when you're doing a research study, it's nice to use the early treatment diabetic retinopathy chart or the ETDRS chart, which is described here on the left. But it's just a more reliant, my understanding is it's a more reliable means to detect visual acudes versus Snellen's. So ideally we would have used that chart. So the limitations of the study, it's retrospective and there's a limited number of patients and it was not randomized. So it allowed for a selection biased. We use the Snellen visual acudes and there wasn't a standardized treatment protocol for the injection sequence. So I think ideally I would recommend doing a prospective randomized control trial where we could have a predetermined injection sequence, use the ETDRS chart and maybe do a cost effective analysis given the difference in prices for these medications. So in conclusion of Aston and Ilya, both improved visual acuity and central retinal thickness. Ilya was better at improving central retinal thickness versus of Aston at three, six and nine months and Ilya was better at improving visual acuity at six months versus of Aston. So I'm from Willis to North Dakota, which is kind of the centerpiece for this oil boom that you may have heard about North Dakota and these are a couple of just the pumping units which are the final piece after drilling. And this is Western North Dakota, the Badlands is what we call it, near Theodore Roosevelt National Park and this is a place where I like to go biking and hiking and fishing and there's some nice golf courses out in that region. So definitely one of the prettier places in North Dakota. So I have to thank Michael Junt. He's my classmate who's responsible for 50% of this work. Alicia Doxin I've been talking to her about coming to the Moran since January. I'm very thankful to be here. Drs. Petty, Mamelis and Hoffman have all been very, very good at answering questions. I ask a lot of questions in clinic and surgery and I've really appreciated their input into my educational process and definitely the residents, technicians and medical students have also contributed to. So I thank you all. If there are any questions, I'd be happy to try and answer them. So interesting study, obviously, one that a lot of people are working. We just had a statistical pop-up. I'll just point out that you're starting out with a bad baseline. It's thickness was about 20, 20. And the P was 0.086. But remember, the difference between 0.086, we think it's you, but it's not mathematically, and 0.05 is very, very little. So you were born or mine statistics and you have to see something like that. And I submit to you in the same thing that you visually, because the thicker retina, also all are not significant, was worse vision than you do now. But mathematically, 0.086, but when you get close, it's a fascinating area. And of course, the big battle on this whole VEGF suppression, I mean, the big issue right now is when is VEGF suppression? Or as some people think, and then now that we are coming in with different mechanisms where you can get continuous, steady state suppression, is what's the effect of that? VEGF is there for a reason, regulatory modulating and continuously. Thank you. Dr. Petty? So North Dakota does not have a... I spent a lot of time, during my third year of school, I was placed in Bismarck, North Dakota, and the big ophthalmology place there is the Dakota Eye Institute. So Dr. Fortney is one of five ophthalmologists there, and I spent a lot of time in his clinic, and like I said, I recognize this, a Baston versus Ilea kind of situation, and I, he was the one who helped me a lot, but Michael Junt and I talked our way through a lot of this, he's my classmate. But he was there for some of the questions, especially the OCT, central retinal thickness stuff. Yep. I think you did a good job, based on the location. Yeah, I tried to convince Dr. Fortney for a prospective study, but obviously that wasn't gonna happen as a third year student. That the drug companies know the odds are very good, that they've spent a lot of time and effort, and more likely than not, the best $30 million to come out, saying you're competitive enough. Sure. I understand that, it's very interesting. Thank you very much.