 So I'm going to go a little more into depth about corneal collagen cross-linking. We talked a little bit about it, but I kind of want to give a background and Talk a little bit about what we know what studies have been done and what data we're basing our current treatment on So to start just in kind of very basic chemistry of how this cross-linking process works There are a few different ways that you can actually form collagen cross-links and strengthen these or the Collagen bonds there is a natural process of collagen maturation that occurs via oxidative Deamination reaction and that's within the end chains of collagen and that's occurring naturally over time There's a glycation pathway that occurs also with aging and in diabetic patients That's a non enzymatic reaction which forms these advanced glycation end products Which then work to form increased bonds in the collagen and so you can see in these natural pathways why? It makes sense that as time goes on and people age the collagen and the corneas structurally become a little bit more You know stiff and that this is a kind of natural aging process The the collagen cross-linking that we're utilizing clinically is via an oxidation pathway So if you trigger oxygen free radical release You basically can trigger this collagen cross-linking So you can have this after oxidation or photo photo oxidation and what we what clinically has been used is riboflavin? Which absorbs the UV light and then photosensitizes it and generates free or reactive oxygen species? And then that in turn kind of results in this cross-linking formation or pathway So this is again a fairly new Technique that's been developed. It really was the first people studying it were at the University of Dresden And it was in the late 1990s and they started looking at pig and cornea or pig and rabbit corneas And they treated them with riboflavin and UV light. They had a few different other ways They were looking at treating but this kind of emerged as the most successful the corneas were stiffer and better resistant to enzymatic Digestion they found that there was a higher molecular weight polymers of collagen after the treatment and from Least the animal studies there wasn't any damage to the corneas or endothelial damage as long as the corneal thickness was greater than 400 microns that after the Techniques were studied and it seemed to be potentially a pretty safe procedure Human studies were commenced in 2003 a very small cohort of 16 patients that had rapidly progressive Ceredoconus were treated. All these patients stopped progressing 70% of them had flattening in their steep anterior corneal curvatures 65% had improvement in visual acuity and in that group no complications were reported and pretty much this 400 micron thickness is throughout all of these studies is the minimum of corneal thickness that you can use for treatment So a few of the large studies we have now I'll go through the interesting thing about these studies is that everyone defines progression Barely differently and some of the studies as we'll see it's pretty nebulous how they actually define it So that's certainly an area where looking at the results and really kind of Looking at the data can you have to take that into consideration, but at Dresden they Enrolled there as a prospective study of 480 eyes with progressive Ceredoconus only The they had a fair amount of data for you know greater than six months They still had 241 eyes at their greater than three-year data. They're only had a 33 eyes So again, that's a pretty small sample size. We have to keep in mind when looking at some of the data for their progression They said they Defined it as a greater than one day after change in keratometry values over a year a need for a new contact lens spitting That was a greater than one day after change in two years or just that the patient reported decreased vision so Again fairly nebulous like in terms of replicating that but they reported a significant improvement a Statistically significant improvement in best corrected visual acuity acuity at one year in three years decrease in mean keratometry in the first year and then 50 about half of the eyes had Increased in the best corrected visually acuity and at one year 20 of those eyes were presented the eyes were stable at one year and then they reported 87% of the eyes were stable or improved at three years But again remember that's only three 33 eyes that they actually had in that group There was the Sienna eye cross study. This was again just with progressive keratoconus and there was 363 eyes. Yeah Yeah Yeah, yeah, it wasn't exclusion it was just dropped out of the patient so It's not basic So there's all these studies used variations of the protocols the one the vidra one that Well, I'll talk about the FD one here FDA one here And they had a multiple protocols and so in terms of the length of treatment these ones are Kind of more of the longer 30 minute 30 minute protocols But I don't know in terms of the FDA approval why they chose the The you know 30 minute protocol versus the shorter ones Yeah, and we haven't I the data isn't quite all Out there in terms of all of this shorter treatments and as this goes on I think there'll be more data for actual I think essentially at this point We're basing it off of what we know has worked and it's not harmful and as time goes on And I think we get more data for and some of these long-term results the timing will shorten or be modified But yeah, it was only dropped out. It's not post complications or anything like that Yeah, and so we have a CMA I cross studied in Italy and again a large amount of eyes that were initially enrolled and then Again some drop out 44 eyes with greater than 48 months of data post-cross linking Their their definition of progression was extremely vague. They just said clinically and instrumentally to Progressed within six months They did report significant improvement in both manifest Spherical equivalent at one year in four years again four years Group is a little smaller Significant reduction in mean carotometry values by one year in four years and then no significant change in the other kind of secondary outcome measures the Australian study is a Randomized controlled trial, so they have and this is probably kind of the most robust clinical other clinical trial It's not a prospective trial, but they have 46 treated eyes and 49 control eyes the reported data is from three years They're following them out to five years They identified or they defined progression as an increase in cell or manifestor fraction by greater than one diopter Increase in the steepest carotometry value by over one diopter and then a decrease in the back optic zone radius of the best fitting contact lens By greater than 0.1 millimeters their primary outcomes were the decrease in k max they did find a statistically significant Difference in the treated group versus the control group which had the treated group have had a decrease in flattening The control group had an increase and their secondary outcomes Uncorrected visual of QT was improved in the treatment group worsened in the control group otherwise Manifest Refractions really didn't have a significant difference in either of the you know comparing the groups the corneal thickness was stable in the control in the treated group, but it did there was increasing thinning in the control group over 36 months and Then we have the US FDA phase three trials which way of the avidro trials, which is just based it's called that based on the the The actual hardware that was approved and the drops that were approved and who got the patents So there are 11 different sites In care to conus, maybe there's more now But from what I found 204 enrolled eyes and they also include included post refractive ectages or other ectages with 178 enrolled in rolled eyes, and so I there's an I didn't find results of The trial that's been published other than there is a group that did publish their data Hersch et al within the avidro trials and they Looked at progressive ectasia some postlacic And they actually did a treatment versus a sham group the sham group didn't have epithelial abrasion They just got the riboflavin and then no UV light and so they I They defined progression over 24 months as an increase of one diopter in the steepest K increase of one doctor more in manifest cell and increase of point five doctors or more in manifestor faction Spherical equivalent so they did find a statistically significant improvement in the Carotometry values in the treatment group and a significant improvement in the visual acuity in the treatment group no again No change in the spherical equivalent or cell Manifest refraction in the treatment group and then there really wasn't change in the sham group over this time the interesting thing and that was The criticism of this study is that the patients who were allowed to have the sham who had the sham Treatment were allowed to pretty quickly crossover into treatment and so Some of them crossed over at like three months, which again the FDA had to eventually say that wasn't allowed because We really needed the long-term study, you know the data to compare it but and Really for well, I'll talk about the complications that have been reported. Yes. Yeah Yeah, you know, I don't know. I don't know that off the tongue. I had I mean I don't know if any of you guys I Don't believe that any there are yeah, I guess I don't know the youngest age group I think that would probably be the exclusion criteria As long in that rate, I don't think there were exclusion criteria, you know with age other than within that range But I don't know average age, you know Patients Right Yeah, I yeah, absolutely I think in terms of like talking to Dr. Mifflin about the patients that he treated here 50 patients Basically the younger the care to conus patient the more improvement and stabilization, but And he really didn't feel like and this isn't you know, we don't have the numbers But there wasn't really significant results or noticeable results for the post-lastic ectasia But I think that's again another area where probably we can nail down the ideal treatment age range and you know with data of how likely it is to prevent progression And and so though the studies that we're the Moran was involved in they there was extremely a much smaller treatment time frame of 2.54 or 8-minute treatment After a 20-minute induction with the riboflavin and for Texra was that is the kind of Now the name of the riboflavin that was approved So it's been approved for treatment and the FDA approved it in April The Moran has kind of finally gotten it approved here and gone through all the hoops So I think Dr. Mifflin has done one and there's a few of this week or next week So it's kind of going to start ramping up, but I'll talk a little bit about our protocol, but it's going to be a lot longer than the ones we were involved in so Again because this is fairly new the you know the approval is for care to conus But and we can see from the data We really have data mostly from care to conus although as more data comes out from the FDA trials trials There were some on other ectasias, but things other you know diseases You can consider treating polis and marginal terrarium Post-refractive surgery ectasia and then the kind of more off-label things that we touched on earlier of potentially treating you know infectious ulcer or other corneal diseases, but There's no definitive criteria for who should get this and what progression you know defined by what progression The the cutoff for progression to get corneal cross-linking But clearly if you're having a patient who is having a change in refraction Changes in visual acuity changes on topography and tomography It's reasonable to consider it Contraindications You know if the cornea again is thinner than four hundred microns that has been a contraindication because it will worried about endothelial damage herpetic infection in the past and current infection if you have severe corneal scarring or a pacification the patient has a history of poor epithelial healing and severe ocular surface disease or autoimmune disorders, so Those all make sense so for the surgical technique in you know, we touched on the fact that the Actual protocol and timing has varied in terms of what the studies are and so I think this is a moving target But at the moment there's pre-operative and biotic and anesthetic drops And you have to do an epithelial disruption at least that's what it is approved at the moment for the FDA The riboflavin will be Administered and up to and that will take 30 minutes and then you can actually see the riboflavin in the anterior chamber by Blue filter on the slit lamp and then the UV light treatment will take at least 30 minutes But you have to here. We'll have to check the corneal thickness and potentially change the riboflavin Kind of consistent or the actual drop Consistency and then continue to treat so essentially for each eye what we're looking at at the Moran is a 75-minute treatment Total with the induction and then with the UV light. Yeah, so there are like two medications There's this viscous riboflavin, which is like the standard one and It has an osmotic effect so it actually can succorn you the one that you're supposed after the first 30 minutes You're supposed to take the corneal thickness and it's less than 400 you open up another vial this less viscous stuff That kind of swells the cornea and there's like a lot of debate Email lists and stuff about using because if both of the vials are at $400 each and you know, it's not Most places aren't really they're just kind of trying to cover the cost And so a lot of places I've tried to get away with these people that we're using like Sterile water and things like that The one patient we did his His corneal thickness was 375 miles after his this 30 minute application So we just went ahead and did it because Dr. Mifflin's original trial protocol They could do anyone with a corneal thickness greater than 300 The difference is though we're using 30 minutes of UV light and you're you continue to put this viscous drug on the eye During that 30 minute light application So it's gonna get the thing over time where is the protocol we had when it was 12 8? It was I think it was 4 8 or 12 minutes Less than So it's been reported in terms of complications in the studies I mentioned so up to 70% of those patients had reported temporaries Temporary stromal edema pretty much at least like in the Australian study 100% of the patients had temporary days but it resolved 10% had permanent up to 10% has had permanent haze and then things that go along with you know scraping the epithelium and having that Corneal disruption corneal scarring and sterile interval traits have been reported rarely infectious Charteritis rarely and then there was one report of a post-lasic patient who developed DLK But again, that was just one patient and Overall, it's a really low complication risk, but these are just things that go along with the territory Is your myotic given to try and like decrease in theory the amount of light getting to the retina Yeah, no, is there any light getting to the retina? Well, they the riboflavin is in the anterior chamber and that's that to absorb the light And so that prevents damage to the posterior oculor structures. They're probably is like getting to the retina because the patients do report visual symptoms So they can sometimes have weird almost like rainbow aberrations around lights. Yeah, that's temporary act of the treatment. So they probably are something to the retina No Transes Lots of studies on the retina do show a little decline after treatment that comes back Yeah, this is a great presentation office, you know severing going through this the thing that strikes me with this is that many of the Patients are going to benefit the most. We're likely going to see the pediatric ophthalmology clinic So that I need help Separating, you know the kids like we see kids in the Native American population in the Southwest who have 10 12 Diabeters of cylinder it's stable. It isn't progressive at Asia. It's what they have for refractive error So guidelines in who you want to see when you want to see them and what test you would like us to do To separate this out. I have had kids as Parents bring kids in as young as three years of age Having been told they have progressed care of the conus because someone found a stigmatism I rate parents who insisted on having cross-linking today not tomorrow You know a three-year-old so that would lead some guidance as to who you want to see so we don't inundate you with patients You don't need to see but pick out those who are going to benefit the most We've been we've been using I kind of our standards is a penicam so any kind of topography And if they're if they're kind of very severe care of course like any transpire So Cornel think this less than 400 microns kind of like the standard Then we're saying yeah, you're probably not going to benefit from cross-linking and you're kind of push yourself into the Transplant category right but any kind of mild to moderate and if they're borderline work, you know We're happy to see basically we're just kind of valuing people and our standard thing is good We get a topography that a penicam we check their picimetry with ultrasound and then we check their refraction and A lot of times because we've seen a lot of 12 year olds and 11 year olds and for them You know they've been other places and they were just diagnosed two weeks ago And they've been told in the cross-linking today and where's dr. Mipha's boss is you know, let's just see you back in three months It's probably not gonna change that much What we useful is to see Topographies that are separated by some period so we should if we're concerned we should get topography Yeah, and follow them and repeat it and the things are changing some So Okay, and it's the most boring procedure of all time because you sit there every two minutes You're putting a drop on the eye for 30 minutes And then you check the thickness and then while the UV lights going for another 30 minutes You're getting a drop in every two minutes, so we're green pretty selected with our 11 and 12 year olds who we're doing A 12 year old on Tuesday, but he was like a very kind of mature not squirrely at all We have some squirrely kids and we're gonna wait till they're a little older Yeah, yeah, I thought because you know there's a big we have a lot of gowns patients who carry conus, right? We've considered doing it, but you know, that's a bigger Well, can we do it on our channel? Yeah, absolutely you could because the downs kids might benefit hugely because they're also kids We don't wear contact lenses. Well, we just wait until they have you know Some big event then it scars and then hope the other eye doesn't do it Yeah, yeah, you know a lot of our patients are difficult I mean they have an attention span to someone like mine and as a result it's difficult to get them to sit still. Yeah Yes, exactly. No, I think my concern isn't the obvious ones It's the early ones where you've got a kid who's just got myopia and a stick which is looking at Julia's the criteria I mean a lot of the patients I see with just garden-value refractive error could meet those criteria Could have been entered in the study and had a wonderful result The other thing that some of you made We insurance is kind of here We've gotten some approval procedure codes from some of the big carriers in the state like our end of one of the patient The insurance has to pay you they said they're going to so that's kind of the big question It's it's cash price is twenty five hundred dollars, right? That's very similar It's actually some of the big places in town just to cover our cost Cool All around the country to nobody knows how insurance is going to cover it right sometimes they've sent bills to Or they've sent letters to horny a specialist saying do not charge for this, but then they don't tell how much they'll pay for It's different in every single state there were Brett and I are both on a forum that's a cross-linking forum with horny specialist all around the country And Those people are charging are just charging up pocket Okay, well we'll send them and then you can talk to them with their options are it's it'll it'll all change this happens