 All right, thank you so much for the opportunity to present today. So today I'll be presenting on Oxervate, a new therapy for neurotrophic keratitis. Is it the answer? So what is the problem? So as we're familiar with, neurotrophic keratitis is a huge issue in ophthalmology. Here's a photo of stage one, neurotrophic keratitis with epithelial regularity. Here's a photo of stage two with persistent epithelial defect. And here's a photo of stage three with actual stromal ulceration and in the worst case perforation. What are the current therapies that we have? Well, we have preservative-free artificial tears, bandage contact lenses, temporary tarsorophy, serum tears, amniotic membrane. None of these are actually approved specifically for neurotrophic keratitis, although they're definitely widely used and each of them have their own pros and cons. Now, Oxervate, also known as Cenedermin, was approved in August 2018 by the FDA for neurotrophic keratitis. It's made by a company in Italy named or called Dompe. It's a recombinant human nerve growth factor developed in E. coli cells and promotes differentiation and maintenance of neurons. So there have been two phase two trials that have compared the efficacy of Oxervate with placebo in adults with stage two or stage three neurotrophic keratitis. The first one is the one that we're probably familiar with, published in ophthalmology. It was actually a European trial performed in 2018. And the second is actually not published but is available from FDA statistical review and is in the package insert. And this was a U.S. trial performed by the FDA. So for the first trial, which we're probably more familiar with, the author has compared eight weeks of Cenedermin, 20 micrograms per milliliter compared with placebo in stage two or three NK followed by a 48-week observation period. Of note, this manuscript also compared the 10 microgram per milliliter concentration. However, that was not what was ultimately approved by the FDA, so I won't focus on that here. The patients in this study were allowed oculolubricants, antivirals, and antibiotics. The medication was administered six times a day for those eight weeks. The primary outcome was corneal healing less than 0.5 millimeters after four weeks of therapy, and the secondary outcome was corneal healing less than 0.5 millimeters after eight weeks of therapy. Both at four and eight weeks, the study results favored the treatment group. When using in a post-talk analysis zero millimeter defect as the goal, the results were actually still significant at both four and eight weeks. Interestingly, however, visual acuity had no difference between the groups, the treatment and the placebo group, and there was some recurrence in both the treatment and the placebo group at week 56. So for the U.S. trial, the authors compared eight weeks of synedromine, 20 micrograms per milliliter, compared with placebo in stage two or three NK, followed by a 24-week observation period. The primary outcome was corneal healing less than 0.5 millimeters after eight weeks of therapy, and the secondary outcome was corneal healing less than 0.5 millimeters after four weeks of therapy. Although at four weeks, interestingly in this study, the results were not significant at eight weeks they were, and when using zero millimeter defect as the goal, as in complete epithelial healing, the results were significant for both four and eight weeks. Once again, in this study, there was no difference in visual acuity, and there was still some recurrence at week 32 in the treatment group. So what are the adverse effects or precautions? So in this study, the primary side effect was ocular pain and up to 16% of individuals in the European trial, other side effects included ocular hyperemia. There were no serious ocular or serious adverse events related to the medication itself. It's unclear the safety in patients who are pregnant or lactating. However, there were no concerns in animal trials, and this medication is actually approved for patients age two and older. So it's approved in the majority of the pediatric population. So how do we use this medication? What does six times a day actually mean? Your oxervate will arrive in a box that contains dry ice. Be sure to wear protective gloves when removing the box of oxervate. You will receive a sufficient number of devices to apply oxervate. For every week of treatment, you will need seven multiple dose vials of oxervate. You will have one vial per day of the week per affected eye, seven vial adapters, 42 pipettes, 42 sterile disinfectant wipes. You will also receive a dose recording card and spares of adapters, pipettes and wipes, the daily materials needed for each affected eye are one vial, one adapter, six pipettes, six wipes and your dose recording card. Next, let's discuss how to assemble your multi-dose vials of oxervate. First, wash your hands. If you wear contact lenses, take them out before using oxervate. You may reinsert them 15 minutes after using oxervate. Remove the plastic flip-off cap from the vial. Without removing the vial adapter from its blister pack, peel off the back. If the adapter becomes dislodged out of its holder, place it back in securely before peeling off the back. Connect the vial adapter to the vial by firmly pushing it down until it snaps into place over the neck of the vial. The vial adapter's spike should pierce through the vial's rubber stopper. Be careful when handling. After the vial adapter has been connected correctly, do not remove it from the vial. Make sure that the vial adapter is well connected to the neck of the vial. You can remove and throw away the packaging of the vial adapter. Your multi-dose vial of oxervate is now ready to have the pipette attached. Every two hours, you'll use this vial and adapter with a new pipette, so you'll apply oxervate every two hours six times a day in a 12-hour time frame. The vial and adapter must be discarded after 12 hours. Next, let's discuss how to prepare oxervate for administration. Take a single sterile disinfectant wipe and gently clean the surface of the valve on the connector part of the vial adapter. After cleaning, wait about one minute to allow the valve to dry. Remove a pipette from its protective packaging. Firmly push the pipette down and twist clockwise into the connector part of the vial adapter. Make sure that the pipette plunger is pushed all the way down and secure. With the pipette still connected, turn the vial upside down to draw the eyedrop solution into the pipette. Gently pull the plunger until it stops. The plunger in the pipette will hit a stopping point when it's not able to be pulled out any further. Check the pipette to make sure it contains the eyedrop solution. If the pipette is empty, keep the vial with the connected pipette upside down. Push the plunger all the way in and pull it out again. The first time you withdraw the eyedrop solution, you may see air bubbles. If you do, push the plunger back into the vial and draw the liquid out again. Keep it upside down while you do this. After the pipette has been filled, unscrew the pipette counterclockwise from the connector part of the vial adapter. Now, let's discuss how to administer oxervate into your affected eye. Sit or lie down to steady yourself when you instill oxervate, holding the pipette pointing down between your middle finger and thumb. All right, so what are some future questions? So this medication was studied in stage two or three disease, and it's approved for all stages, but there's unclear benefits. How does it compare with placebo or current treatment in stage one disease? I'm curious what the visual cutie long-term data is. What is the role of extending beyond eight weeks if the epithelial defect is not healed yet at that stage, and would insurance even approve this? What is the role of using additional courses? Let's say you have a neurotrophic-haritized recurrence. What's the role of using additional courses? And finally, why I wanted to show that video is I think one of my questions is, you know, are patients going to be able to use the medication correctly? Even when I was watching, I thought it was a little bit confusing. So we'll see. I think only by prescribing will we be able to tell, and certainly good in-clinic teaching and support resources by D'Ampe will help, but I think that we'll have to see how that goes. Now, how do you get the medication? So it's only available via a specialty pharmacy at Crado. So what you do is if you are a physician interested, you go online to the website, and you fill out this patient enrollment form, and then you fax it to D'Ampe. And just so you know, the actual cost of this medication without any insurance or any prior authorizations, the pure cost of it is $14,000, although patients would not pay this amount. And speaking with the representative, in her experience, there's been a few different groups of patients who have had or who have had the medication prescribed for them, and based upon her experiences for commercial insurance, you know, what a physician would do is you'd fill out the form, you'd fax it to to observate who would contact the insurance plan, the physician will get the prior authorization, and it, you know, may be denied if it denied another appeal will have to get filled out. And I think this part is a little bit nebulous. At some point there's some notification, and I'm not sure, you know, to who that notification goes to or if it's always consistent, whether the patient's notified, the physician, a credo is notified, and a credo contacts the patient. So someone gets notified and the patient can contact a credo to start the medication. And the cost is approximately $100 in copay per eight weeks of treatment. Now let's say a patient has no insurance or there's a repeat, you know, prior off or appeal that once again gets denied. Per the representative, patients somehow get this medication without charge. I don't know how that actually applies in practice. I think we'll have to start prescribing and see what actually happens for this population of patients. And finally, for patients with Medicare or Medicaid, it's a similar process to the commercial insurance. There is a certain amount of copay. It's not high. I don't know exactly what that amount is though. Alrighty. So going back to our initial question is the answer. You know, I don't think it's the answer, but I do think it's one answer. And I actually, personally, I'm excited to start prescribing it because I think that the data is very encouraging with the caveats that I think, A, you know, our patient's going to be able to use the medication appropriately. And two, you know, I don't know what the experience will actually be in terms of going through the prior authorization process and the different populations of patients depending upon their insurance. Are they going to be able to get the medication? So thank you so much for your time. Thank you especially to Dan for his help with this presentation and to Dr. Lynn Mifflin-Zog.