 We're going to get started today. We're going to be talking today about gene therapy and what the latest advances are, both with the three fellows talking today. And we'll go from the basics to surgical approaches to, I think, the social and economic impacts of gene therapy. So it's coming to retina. We're going to be leading the way. And I'm going to let Nico start. Good morning, everyone. So again, welcome to the retina grand rounds presentation. So we're excited to give you an update on gene therapy for retinal diseases. So we have a lot of interesting topics to cover this hour. And really what I'd like to have you guys hopefully learn about what is gene therapy, all the important advancements leading to the approval of the first gene therapy for retina called Luxerna. Then I'll give you an update on the ongoing trials of gene therapy in choroideremia and other inherent renal diseases. And then lastly, I'll give you an update on the clinical trials for gene therapy in AMD and with the future perspective of gene therapy and genetic eye diseases. So let me start with some basic definitions. Inherited renal dystrophies or IRDs are associated with genetic defects causing progressive retinal degeneration. These typically cause severe bilateral vision loss beginning early to midlife. We have several prevalent studies. And in the UK last year, the most prevalent of the IRDs is retinitis pigmentosa, or RP, and accounts for more than 50% of all IRDs in the UK, about 10,000. This is followed by Usher syndrome, which is a syndromic form of RP. Then Saragard disease, and then the fourth is Lever congenital amaurosis. According to the WHO, genetic eye diseases is a priority eye disease. But there's no global statistics to evaluate for burden of visual impaired from genetic causes. One of the reasons is that it's difficult to diagnose inherent renal diseases in large population studies, which is unlike cataracts where you can just come in and do a quick exam to have a screening. There are several studies throughout the years. One was last year in 2019, a real population study that screened about 15,000 people in Germany and show that up to 14.5 of what they've defined as having a visual impairment or blindness came from a genetic eye disease. Just to give you a sense, 20% was for AMD, another 20% for cataracts, et cetera. So it's a high number. Other studies show that an incidence of genetic eye disease to be 1 in 2,000. And we also know that it is one of the leading cause of vision loss in the age group of 15 to 45 years old. One of the earliest onset and rapidly progressive of the inherent renal dystrophies is liberic congenital amaurosis caused by mutations in the RPE65 gene. This is a rare disorder. This is a funnest photographs of one of our patients with RPE65. We only have two that we take care here at the Moran of a 49-year-old. This is a 49-year-old female that had visual symptoms by 10 years old and currently has a vision of light perception in both eyes. And you can see that she just has a severe retinal diffuse atrophy in both eyes. So in December of 2017, FDA approved Luxterna or Voronegine naparvovec for the treatment of RPE65-associated retinal degeneration. And the results of the phase 1 and 3 trials were just published a couple of months ago, last fall. And some of the inclusion criteria for the study is that the patients need, of course, a confirmed genetic diagnosis of biallelic RPE65 gene mutations. Again, this is an autosomal recessive disease. They've treated patients as young as three years old and older. Visual acuity should be 2060 or worse in both eyes. And then the patients had subretinal. So that's important. Subretinal injections are the normal copy of human RPE65 carried by a viral vector called AAV2 or adeno-associated virus 2. And Chris will talk more about the technique for subretinal injections or other modalities for delivery of gene therapy. These studies included sites at Philadelphia as well as the University of Iowa. Now one of the key endpoints for the study is improvement in the MLM score and in contrast to how we measure a visual function with visual acuity or even, for example, an ERG's MLMT measures functional vision. I think this is a very important thing to know. So I'll show a quick two-minute video. Beginning with a five-by-10-foot grid. We created a path of arrows for individuals to follow as they make their way through the course. We added objects of varying height and contrast to simulate everyday obstacles. For example, a pool noodle. This represented an ankle height obstacle such as a tree root. We also used a lab stand with a foam circle on top. Depending on the individual's height, this served as a knee or hip height obstacle such as a bush. There was also a soft sign which served as a head height obstacle and was adjusted according to each individual's height. Black squares represented folds in the ground, synthetic grass as grassy patches, and raised lots to mimic the step such as a curve. Additional obstacles were added using objects around the lab, making a total of 15 obstacles throughout the course. To more accurately reflect the real world, we specifically chose seven different lux levels for the MLNT, which is what sets the MLNT apart from existing mobility tests. The lux levels to find the standardized light levels were specifically chosen to represent commonly navigated environments in the real world. The seven lux levels range from one to 400. 400 lux, the brightest level, was similar to an office set. 250 lux mimic the interior of an elevator. 50 lux, an outdoor train station at night. This was equivalent to a party lot at night. And finally, one lux, the darkest level, a moonless summer night. Each lux level was assigned a score code. Score codes were used to quantify results along with accuracy and time to completion, which we'll be explaining later on. So that's the MLNT. So the results of the phase three clinical trial for Lux Turner showed improvement in MLNT score. So what's shown here are the individual patients. For example, in the first patient age five years old had an MLNT score of five and showed improvement to MLNT score of six. And this is all tabulated. As you can see, most of all the individuals had an increasing MLNT score. And that the results also show that the MLNT improvement is durable up to four years. And so this is how long the study has been going on. And it is still, the observational study is still ongoing to see how long really we can keep this. The other big question for gene therapy that this trial answered is the safety profile for sub-rentinal injections of AAV2 with RP65 gene. There were a lot of initial concerns of immune response to viral particles that may cause unwanted immunological responses or retinal toxicity issues. And the phase three data show that the safety profile of the procedure is consistent with just the risks of having a vitrectomy. I boxed here and read the cases of eye inflammation. There were three, two were not severe inflammation. One was a case of endothelitis, which is a known complication of any intraocular surgery. So what's on the pipeline? Now that we have L'Oxterna approved, the next disease that will be coming is for gene therapies Choroideremia. This is an X-link recessive disease with mutations in the CHM or our Rep1 gene. This is a photo of one of our patients with a Choroideremia. As you can see, it has extensive atrophy as well. So the phase two trial, the 24 month results were just published a couple of months ago. And like L'Oxterna, the L'Oxterna trials, this uses an AAV2 Rep1 viral vector and they have injected sub-bretinol injections in six male patients, more adults ages 32 to 72 years old. And what they've showed that in the initial trial is that 90% of the patients shows improvement of a best corrected visual acuity by at least 15 letters, or I'm sorry, that 90% of patients in 24 month did not have a decline in best corrected visual acuity and about 21% have improved a visual acuity of 15 letters. And this is compared to the natural history study which predicts or shows that only 1% of untreated patients have any improvement in visual acuity. So this trial is being conducted by Biogen which acquired Nightstar last year. They have a phase three study called the STAR study. It's a randomized mass perspective clinical trial with 170 adult males. And based on the phase one two data, the primary endpoint is improvement of best corrected visual acuity of at least 15 letters in 12 months. Again, a little different from the L'Oxterna trial where one of the end points is the MLMT improvement. And they have completed enrollment just in November of 2019. So we're excited to see the results of that hopefully in the next year or so. Now, we've talked about L'Oxterna for RP65, then Croideremia, but there's a lot more clinical trials for gene therapy and other diseases. This is just a partial list of what's being targeted right now. Some things that I'd like to highlight includes ABCA4 for Stargard as well as RPGR mutations and X-linked RP. Another thing that I'd like to draw your attention, maybe it's very hard for you to see, but for CHM, they use AAV2 virus for the RP65, the AAV2 virus, but there's newer studies now that are using other AAV viruses, including AAV5 and AAV8. So I just wanted to give you just a quick teaching point on adeno-associated viral vectors. So there are 12 known serotypes of AAV and these can all transduce RPE cells. These viruses, 2, 5, 7, 8, and 9 can transduce photoreceptors, and this is what, which is why AAV2 has been popular because many of the inherital diseases has genetic defects in photoreceptors and not in RPE cells. And it's just kind of the workhorse in the field. For our glaucoma colleagues, it's interesting that AAV2 can also transduce retinal ganglion cells. And again, our glaucoma colleagues are interested in that. The newer AAV viruses, including AAV7 and AAV8, have altered capsids that allow greater transduction of photoreceptors just with intravitural injections. So this holds promise of intravitural injections with a virus going through all the barriers and getting into the photoreceptors. And I mentioned RPGR for X-linked RP, and it's been reported that this is the strategy that they're doing, and they have a natural history study, which the Moran is participating in. So to add to the complexity of gene therapy, there are multiple strategies to how to correct genetic defects. The strategy for RP65 and CHA mutations are similar, and it's to introduce a normal functioning gene inside cells that have a bad functioning gene. Now, there are other strategies, including genome editing or correction therapy. And one of the clinical trials that I'd like to talk about is our Lieber's Congenital Amorosis Type 10, caused by SEP290 mutation and how this is done. This is one that I'm particularly interested in. So there are mutations in the gene called SEP290 that cause aberrant splicing of mRNA causing mutant protein. So the mutation is intronic and causes splicing problems, causing decrease in the protein, translation of protein. They've used an anti-sense oligonucleotides, which is just a chain basically of nucleic acids that bind to the mutation and redirects for normal splicing of SEP290 mRNA, making normal protein. So the ProQR, the company ProQR has a phase one, two trial at Iowa, Pennsylvania, and at Ghent University in Belgium, studying intravitural injections of this oligonucleotide fragment. So again, this is just the intravitural injection of SEPA-Farsen or QR-110-110, which is the fragment. The phase one, two concentrated on a dose range finding and the 12 month results of the study was just reported back in October, 2019. It's not published, but on a press release, they've shown improvements in best corrected visual acuity as well as they've used the mobility course and showed some improvement in the mobility course. There is now a phase two, three illuminate trial that will enroll 30 patients and they've started enrolling now. So, I've talked about a lot about inherental diseases. So a lot of exciting things going on, but a bigger market and what people are doing are also gene therapy in AMD. And I'd like to talk to you about two trials on AMD using gene therapy. The first is the phase one optic trial by Adverum Biotechnologies, looking at ADVM-022. This is a two year multi-center perspective trial. This is an intravitural injection of AAV-7 with Aflibercept, or we know it more with the name ILEA, in patients with wet AMD. And these patients were previously treated with anti-vegeth injections. They have enrolled six patients for the study and the 24 up to 34 week data was presented in AAO just in October, 2019. And interestingly, these patients prior to enrollment of the study were getting almost monthly injections of ILEA and after one injection, maintained visual acuity without having any rescue injections for this study. And so really gene therapy for AMD has a prospect for sustained anti-vegeth release without need for monthly injections. The second trial is Regenex Biotrial and in contrast to the last trial, this is subretinal injection of AAV-8 with an anti-vegeth FAB protein, also for wet AMD. Phase one and two results were also released in October, 2019. This is a dose dependent response trial and the highest concentration led to almost a quarter of the patients being injection free at five or six months. So kind of a similar conclusion to the first study. And they're gearing up for a phase two B for wet AMD as well as also targeting for diabetic retinopathy. Chris will mention a little bit, but there's also other strategies for delivery of viral of genes to the retina. And one such delivery is suprachroidal delivery that can be done in clinic. So in summary, since the approval of viridogene and parvovec, many clinical trials are underway to treat IRDs with gene therapy. AAV vectors are improving and gives us different platforms for gene delivery, including subretinal and intravitual. Gene therapy and AMD is promising to be able to decrease the burden of injections in clinic. Some of the future perspectives and knowledge gaps that I just like to leave you with, it's a very exciting field, but there's still a lot of work that needs to be done for epidemiological studies. We still really, as I've mentioned, we don't know the visual burden of IRDs and people think that it's really grossly underreported. And one of the ways it could be for a population screening using handheld fulfilled ERGs. In genetics, there is still a 30% negative rate for suspected people with genetic eye disease. So we haven't found all the mutations, we haven't found all the gene set. So still a lot of work that needs to be done in that field. And then lastly, molecular mechanisms for inherited diseases. We still need to understand pathways to better understand the role of modifier genes that modulate the clinical phenotype. So what do I really mean by that? What I mean by that is that these are all photos of what we would have called Stargard disease. They all have ABCA for associated retinal dystrophy. But as you can see, the clinical phenotype can go from very mild to very severe to the right. The other thing is, you know, similar phenotypes and this is Stargard disease as well. Very, very similar, but can have different mutations. This is an ABCA for mutation and ELOVL for mutation. So we need to really start thinking about this diseases, not kind of how we think about traditional phenotypic diagnosis but we really need to think about these molecular diseases. Thank you. Any questions? We're gonna, any quick questions while Chris is setting up? I just have one, AAB7? I'm not sure. I know that there's some non-specificity for these things, but in their trial, there's animal models that basically show that, but it's hard to show that for human trials. Yes. I wonder if one of the, replicating or they're lasting a lifetime, what is the cycle there? Yeah, so these retinal cells are terminated fully differentiated so they're not replicating and so the thought is you introduce gene therapy inside these photoreceptors and stay there. We don't know how long they could last and that's why it looks sort of trial shows that it can last up to, its effects may last up to four years. Okay, we're gonna move on to the next one. If there are more questions, if we have time, we'll go through them. Eqa will be available. Chris will talk about surgical approaches to gene therapy. Thanks Nika for that. Great. So to start it off, does anyone know how many surgeons were involved in the initial phase three clinical trial that led to FDA approval of L'Uxterna? I'll give you options two, five, 10 or 20. Two. So when I was asked to talk about this, something that's very technical and not a lot of people have done, I had to rack my brain of how best to approach it and I went with the theory of fine people with white hair, no hair or white hair and no hair and there was this article that was published last, I don't know, a few months ago that is a really good review and I'll be citing it heavily. So for the residents, what's the first step in sub-retinal gene therapy with a patient? Yeah, so preoperative eval, great. So what they recommend is that we first select candidates by phenotype. You then confirm that by genetic testing. So we don't just do genetic testing and if you have a genetic mutation, even if it's not the right feed if I don't treat that with gene therapy. You're gonna do multimodal imaging. You're gonna assess with micropermitry to find the favorite fixation point for the patient and then you're gonna have a very detailed informed consent and it's notable to say that if they do gene therapy now in a trial, they might not be able to be in any other trials later on so you might be closing the door for them in certain ways. In terms of what you start before you're actually doing the procedure is they recommend treatment with oral corticosteroids at one milligram per kilogram for three days and then they're gonna be on a postoperative taper of them. You have to have the vector prepared for you. So this isn't something like an ILEA that sits just in the refrigerator. This is something that is prepared by the company and then sent to you. Once it arrives in your office or in your pharmacy, there is a viable use period. So there's a lot of coordination that needs to happen between the pharmacist, the surgeon and the patient to make sure that the time line is all set up correctly. The pharmacist needs to be involved early and it needs to have a appropriate protocol set up and you need to inspect the vector not just for contamination but they had even examples of the wrong vector being mailed and so you wanna make sure that you're putting the correct vector in the correct patient and you wanna note the expiration time. I'm gonna go through this real quickly but notably there's a lot of stuff you need which this is my favorite slide because as Dr. Shakorn knows, I'm a gear junkie but in terms of what's specific for this is you need intraoperative OCT. Doing sub-retinal gene therapy without it is not gonna be very successful and they recommend with the ZEISS system using Callisto. Callisto allows the assistant to control the focus and the position of the OCT. If not, you have to toggle back and forth as the surgeon on the scope and when you toggle onto the OCT focus, you're not controlling the microscope focus anymore. And the other interesting thing is using sub-retinal needles. It's a 23 gauge outer lumen and then the inner lumens of 41 gauge sub-retinal needle and they have different ones for different points of the procedure. You wanna select an injection site. This is a normal picture but these patients aren't gonna be normal. They're gonna have areas of excessive atrophy. They're gonna have areas of severe retinal thinning and you will want to try to steer clear of those areas. You also wanna be at least two millimeters from the center of the fovea and most of the time is you're gonna select somewhere on the arcade somewhere back here or here and that's where your needle's gonna go through. Beyond that, you need a plan where your bled is gonna go. So where is that sub-retinal space going to be formed and go to and realize that you might need to have multiple injections to cover your entire area. Don't think that you have to do all of that desired treatment area with one bled. Also, you need to make sure that you decide beforehand if you wanna detach the fovea or not. So now we're to the procedure. First, you start with a cord retractomy which is the first step in most of retinal surgery. They highly recommend injecting that lute-trimed sewn to show the cortical vitreous and aid in creating a PVD. Many of these patients are young and have very adherent PVDs to atrophics in retina. And so we'll look at some videos showing that. This is also a normal step. They recommend using the soft tip or a membrane scraper or the flex loop. Oftentimes here, we just use the protractor. So this is one of their videos and that's the tri-essence going in. They're doing their cord retractomy and now they've jumped forward and they're using the flex loop to open a little opening in that cortical vitreous. Then they'll engage the side of it with the flex loop and very gently elevate the cortical vitreous off the macula and you see it propagate through the nerve. They continue to move it nasally and then they'll switch to the protractor and clean up the gel. So the next video is one from the Moran. This is actually a retinal detachment in a 22-year-old and we just use the tri-essence to stain and using the cutter to elevate and induce the PVD. All right, so interrupt, you've induced the PVD. Now you need to prepare to make the pre-blob and what you're gonna use is a 10-CC VFC syringe filled with VSS and it's really important not to have air bubbles. You're gonna mount an extendable 23-gauge, 41-gauge sub-retinal needle and then manually prime it to get any air out of the system. You'll then connect the tubing to the protractor and you're gonna adjust the VFC infusion pressure to 20 millimeters of mercury and then you're gonna engage it with the foot pedal, push out any dead space and you'll get a jet of fluid coming out of the needle. But you actually don't want a jet of fluid, you want a steady drip and so you'll lower the pressure to 10 or 12 and then slowly increase that pressure until you have a very slow and steady drip from the tip of the 41-gauge needle. You don't want any jetting because any turbulent flow in the sub-retinal space can be problematic. You saw briefly before, they cut the tip of the needle at 45 degrees to give it a little bit of sharpness and then they switch out the 25-gauge trocar for a 23-gauge valve or valveless and they typically use a valveless trocar because you're infusing enough fluid, they want there to be egress through the cannula. Retract the tip, insert it and reprime in the mid vitreous making sure there's no air bubbles. So then you're gonna go back to your treatment plan, make sure you know exactly what you're trying to detach and where you wanna put the needle. You're gonna position the intraoperative OCT and there's two line scans. There's a horizontal line scan and a vertical line scan. The horizontal line scan needs to be going through the horizontal plane where the needle's gonna go into the sub-retinal space. The vertical line scan needs to be adjusted so that the slice is going through the phobia because the phobia is the most likely place that when you're doing this injection, there's gonna be a traumatic whole formation. And so you want the assistant and yourself to be very aware of what's happening. If that starts to become eccentric or extend, you need to stop injecting. We'll show you what happens when you don't do that. And you're then gonna engage the tip into the retina while you're watching OCT. You're gonna pay attention to see if you see curvil blanching in the microscope and also to see on the OCT if you're indenting the RP layer. If you're indenting the RP layer, you've gone too deep and you need to back up. You're then gonna slowly inject. Normally it takes about five to seven seconds to create a bleb. And you're gonna confirm this all with OCT. So let's look at some of these pictures. This is just a photo, intraoperatively showing where the needle is. In the top scan, it actually looks like the needle is in an appropriate position and they're shadowing. However, you can see in the vertical scan that there's a depression in the RP. If they were to inject right now, this would cause coroidal hydration and not sub-nurse sensory retinal hydration. This is what you're trying to do. This is a perfect bled that was formed after seven seconds. And this is gonna be the spot, and this is with BSS, not the viral vector to clarify. But this doesn't always happen. If you go too deep, you get coroidal hydration. So this is super coroidal injection and this is sub-retinal injection. They say it's very common, don't get too upset, go find a new place and find your sub-retinal space. This is just a cool footage showing where the needle had gone through into that sub-retinal space. And again, coroidal hydration, sub-retinal hydration. These are all too deep. Now, if you look, if you were not deep enough, you can get intra-retinal hydration, which is the cyst that would have been formed. But they went back and they made an appropriate sub-retinal injection here. So this is them showing how it's a little bit challenging. They're manipulating the OCT so that they can get the vertical scan, which is on the bottom, through the phobia. You can see the phobia. And the horizontal scan's gonna be in the plane where they're gonna do the injection. Right now, there's still this inspecting. Needle's in the eye and primed ready to go. They're gonna slowly lower the needle down. And you'll see it come into the OCT pretty soon. And what they're saying is, it really ought to pay attention to phobia because as it detaches, it will stretch and you don't want to overstretch that or you'll cause a macular hole. So the fluid's about to start injecting. There's some hydration and there's the blood formation. Again, this is BSS, not the viral vector. They're just creating a space for the viral vector to be injected. You see the phobia, it looks pretty thin to me, but they're saying that's what it normally looks like when you're doing this stuff. If you inject too quickly, or if bubbles come in at the wrong time, bad things can happen. Like a hole through the phobia, look right here. You can see all the sub-retinal fluid coming out through the phobia. And the problem with this is not just that you have macular hole, we fix those regularly. The problem is, once there's a hole of that size, you can't inject the viral vector because if you were to inject the viral vector, it's just gonna egress out through that hole and you're not gonna achieve the gene therapy you desired. And you can see that the problem was these air bubbles. All right, and as we talked about, you go with more blebs, not a bigger blood. So if you're having trouble getting the spaces you want, go and get more blebs. Now, I'm gonna go through as quick as I know we're getting low on time. When you prepare the vector, it's very similar to what we talked about with the BSS and the 10CC, but it's a one CC syringe with an adapter that also can be controlled by the BFC pedal with the bit tractor. So essentially the same thing. And now we'll talk about actually injecting the viral vector into the sub-retinal space. There is the option to do a straight sub-retinal injection without the BSS step. The people that publish this article recommend against that because you have a very limited volume of viral vector and that it's not always straightforward to get the blood created. And so you can actually run out of viral vector before you've actually achieved the treatment that you want. And so using BSS first is the preferred way to go. And this will be the first injection. So there's a bleb, you can see that on the CT. And the needle will come in, you can see it shadowing right now. We're gonna enter that space and here it goes. And what's gonna happen is it's gonna fail to progress to the phobia and they wanted to get a sub-phobia treatment. And that's probably because you'll see in just a second when they go to inject again, boom, here comes an air bubble. So once the air bubble's in, they thought it was too risky to keep injecting and they actually decided to just go make another bleb along the inferior arcade and then connect those two blebs. So we'll skip where they go and do the second bleb and just show you what it looks like once they start injecting the second bleb. So now they're all on the inferior arcade. They have this nice big bleb that's adjacent to the phobia and they'll go into that space. Needle's going into the sub-retinal space and then they're gonna inject and they're gonna deliver the viral vector. They recommend that 0.3 milliliters be injected into the sub-retinal space. Do not inject that much simply to do it if you're seeing signs that there might be thinning of the retina or you're gonna induce a whole stop injecting. This is a video just showing the direct injection of the viral vector which kind of looks like just doing the BSS. It also highlights something. Without the OCT as it wasn't provided with this video, it's really hard to know where that needle is. So if you're in the carotidal space or you're in the intra-retinal space or you're in the pre-retinal space, it's just very difficult. But you'll start to see there's really low elevation right now and that low elevation will progress to the macula. But without intraoperative OCT, this would be exceedingly difficult to do reliably. Now you're really starting to see that bubble form and the edge is gonna progress to the phobia. So final steps, you do the sclerotopressed exam. Make sure there's no tears, treat it with laser if you need to. And then all the trials so far they've done an air fluid exchange. They're not sure this is absolutely necessary, but that was part of the protocol. For postoperative care, you position them supine for two to 24 hours, even if the eye is air filled. You continue to roll prednisone for 21 to 60 days and you're gonna taper after the first two weeks. You're just gonna prescribe routine topical antibiotics and then you're gonna get a macular OCT as soon as you can see the macula so once the air is gone. And you're gonna assess for resolution in that fluid. You're gonna perform your multimodal imaging and your normal visual acuity in addition to micropermetry and ERG to see how the patient's responding. And you'll see how they do. So putting it all together, this is gonna be a video from Dr. Davis that is on AAO's website and it's just everything in sequence. So triascent, stain to gel, core, lift to PVD. And while this is a pretty common step that we do all the time in retina surgery and these patients is not always straightforward. All right, they got their PVD. Now they're gonna move to their BSS blood. They're just explaining that it's optional and you don't have to do this step. And here comes the viral vector and you can see that it's now underneath the fovea and that was their treatment goal. All right, and so with that we can have a couple of quick questions and then we'll hand it over to Eric to take us home. So just one comment I just wanted to make is that right now is we're starting to participate in recruit patients for gene therapy. They are being done generally at centers of excellence. So our patients would have to be referred elsewhere. When we start with Greg Hageman and Stephanie and the other people here, we will probably, and the intention is to do these gene therapies here. And, but we're also part of trials. The trials that will happen this year are gonna be for vitriol and we're gonna be part of phase one and two. We're gonna be one of the first two sites in the world to be doing that for carotid remand, actually, darmahee. Any quick questions here? Well, we will go to Eric next. He's going to cost an ethical considerations. All right, so, all right, so I'm Eric Hansen. I'm also one of the NFLs. I think most people know me right now. I can't leave. So we've kind of zoomed in. We've done all the, both looked at how we make the viral vectors, what the gene therapies that are kind of coming down the pipeline that are already here. And so I'm gonna zoom out and take kind of a societal perspective on what these mean. Cause there are some special considerations, both from an economic, but also maybe some ethical considerations as we deliver cares as physicians that are important to at least discussed amongst us. And I've already been kind of discussed in the literature already. I think they will continue to be. So I have no financial disclosures or connection to these drugs. So I think that, if you've been paying attention at all to the new cycles, especially related to the upcoming primaries and elections, healthcare costs are kind of becoming, not becoming, they have become a really important talking point and something that's affecting a lot of people. Insurance premiums are continuing to rise and healthcare costs have continued to grow pretty steadily, both as a percentage of the GDP, but also just as a raw number. And it is something that people feel is necessary to rein in and address. I don't have a graphic up here, but one way of looking at the rise of insurance premiums is about 10 years ago or 12 years ago, there's only a few states that the insurance premium was 10% of someone's income. And now pretty much every state that people's, when you look across the country, that that's true, that is the above the average. And so this is just to kind of focus us into gene therapy, which the first FDA approved gene therapy was Luxterna. And so people were really eager to see how it would enter the market and its pricing. And it entered the market with a really high cost. Does anybody know the cost off the top of their head? Yeah, so almost, so 425 is about 850 for both eyes and both eyes are done as part of the protocol. So about $850,000 price tag for the one time treatment. And around the same time, the US Institute for Clinical and Economic Review, which is supposedly a non-bias organization kind of came out with a cost analysis that said that this probably wasn't cost effective. The reason this was important is because as I kind of just mentioned, there's a lot of gene therapies that are coming down into the phase three and we're also being released shortly thereafter. And they were looking to Luxterna and what the reaction was to determine what pricing would be, because this is a very expensive therapy to produce. The viral vectors are much more expensive than other kind of molecular therapies that we're used to. And so in the next couple of years, a few more gene therapies came out. Two of them in the European markets were actually so expensive they were taken off the market, the markets and the government decided they weren't worth it. And then a $2.1 million drug came out not for an ophthalmology disease, it's for spinal muscular atrophy. And that's a $2.1 million one time treatment. So all that to say is there's a valid question of are these treatments worth, this kind of cost to society for orphan disease, being rare diseases in this case that affect a small number of people? And are the data for the clinical trials showing that the effect of the gene, that the efficacy of the gene therapy is high enough to warrant it as well? So how do you answer this question? Well, one way to do it is through a public health analysis and I won't get too much in the leads with public health theory, but I think most people will know these terms, I just wanted to kind of go through some terms that are important for the rest of my talk. So when you look at public health and the cost effectiveness of something, of a therapy, all often it's termed in relation to quality adjusted life years. So quality adjusted life years is just a multiplication of the number of years that something affects or the lifespan if it's a lifelong effect, times a health related quality of life, which is kind of set by validated metrics. The Markov model is what has been used in a lot of these studies and all that says is basically that the transition from one state to another is only dependent on the state year end. So for example, in this one, which is looking at Neovascular wet AMD, the wet AMD Neovascular macular degeneration, if somebody has a stroke, for example, in the study then therefore they're from there on, it only depends on the stroke or if you've created health states or transition states for vision, once they go from one vision, it'll state to another. It only depends on them being in that state. It's only important for how it's a model that doesn't really come into play much more. And then cost effectiveness is the idea that we're trying to budget limited resources in our healthcare system. And so we're trying to pick things that are both not too costly, but also very effective. And when if anything is in balance on one of those two scales, they might not be the best choice for a society in treating a disease. And then the incremental cost effectiveness ratio is the idea that for one therapy versus another, if you get one more quality adjusted life years, how much did that one additional quality adjusted life year cost you? So that's the incremental. All right, so to look at kind of where eye disease or visual impairment is how it's valued from a public health perspective, I have this table. And it's actually quite striking if you look at it. So this comes from a study that's later presented about cataract surgery. But when you see someone that bilateral cataract surgery, their utility, so health related utility is from one to basically a zero scale, one being the perfect life, zero being death. So it's near one, 0.97. What's interesting is you look like someone to just have one eye done, unilateral cataract surgery. And it's raked below a mild stroke, below treated HIV, below impotence. I might argue with that. But you then go down to somebody who hasn't yet had cataract surgery and they're 2080 in both eyes. 2088 for retina is people we see quite commonly. And for these therapies would be quite applicable as some of the cut off vision was 2060 in some of these studies. So they are still ranked as less than having to have dialysis at home, having A's with a CD4 count of less than 50, having MI with moderate effect. Point being to sum it up, visual impairment or visual function is very heavily weighted in these cost effective analysis because we know what basically what it's saying is if you have 2080 vision, your whole life will in some way be affected, your whole lens of how you perceive or interact with your life is affected by your vision. Whereas everything else has kind of a more of a seesaw pattern. And that's why it's rated that way. So as Luxterna was coming out last year, they, somebody took the US Institute of Clinical and Economic Review statement and they actually published a study on it with the modeling and they concluded that overall that this, that Luxterna or Vortigine was unlikely to be cost effective compared with the standard of care at the current price and a commonly used cost effectiveness thresholds that being usually around 100,000 to 150,000 quality adjusted life years per, sorry, dollars per quality adjusted life years. And what they showed is that when you look at the, they're modeling and any time you do a modeling like this you're doing this basically a number of simulations, it's called Monte Carlo simulations so that you catch the fact that you're modeling obviously as bias so you try to simulate a number of times and then you can get probabilities through that. So if you look at this, what it's showing is that at the willingness to pay threshold, so as I say in like 100,000, 150,000 is generally commonly accepted, the probability from either a US healthcare perspective which means you're just dealing with direct costs and then a modified societal perspective which is you include things like lost productivity, government program costs, those kind of indirect costs that the probability that it'll be cost effective doesn't even reach 10% until you're getting into well over 200,000 and then you can kind of read the graph from there. And there are numbers which will be important for the next study I'm gonna talk about show this that the additional quality adjusted life years for the gene therapy was only 1.3 more than standard of care. How do they determine that? They used, and this would be some controversy surrounding this is they used kind of standard visual, vision related metrics that were validated for other cost effectiveness models that have been used for AMD and other ophthalmic diseases. The question being is that the best for these particular diseases where there's visual field loss, where vision, visual acuity might not be the most important thing that you're seeing decline, nectolopia, other things and it's a pediatric disease. And then you can also see so with the US direct costs about 650 and when you include the societal perspective which includes indirect costs, it's about 480,000 per quality adjusted life year is what these therapies cost from a public health standpoint. So then just a few months ago in JAMA there was another study published kind of in response which also looked at the cost effectiveness. It changes economic and model on some of the assumptions. So one of the most important things it did was looking at how do you determine the health utility of this gene therapy for RPE 65 mediated disease. And so they said, well, I don't think the normal valid ways of doing it is the best way for this. So they use vignettes. They created six health or vision states which were kind of like moderate, severe visual impairment and like hand motion, no light perception. They use an expert panel and they basically came up with their own health utility is essentially what they did. And they also then changed one thing I didn't address in the previous one is they used their model for duration or durability of treatment was that after three years you started to have a 10% decline in the effect or the durability of the treatment. So people started, they started losing effect after three years. They did that because that was kind of the timeframe of the studies at the time. Here they assume the lifetime horizon for their study that based on the theoretical implication that these viral vectors and the delivery of these genes in the sub-retinal space should continue to have effect for basically indefinitely and there's we don't know yet the durability. So that was the basis for their assumption. And then they use a much broader calculation that indirect costs. So the things that really kind of stuck out was their inclusion of government programs for the blind from a pediatric population onward were much higher. And with that, and I want you to pay attention just quickly so they show that the indirect costs were so different that the incremental value if you include indirect cost was actually negative. This means there's a return on investment for society, it's quite a different finding. And with direct cost, the, sorry. Oh, it was about 79,000. Sorry, that was the number, 79,000. The major points of difference though comes to how they value the health utility where you see there's a 10, 9.4 actually, incremental value of health utility compared to 1.3. And then the other major point was the indirect cost. So what do we do with all this? Well, one criticism of this is that the valid, the health utility is not validated. How do we know it that the duration of treatment it might not be lifetime? I think that even in the studies they discussed whether this is gonna, whether you need re-treatment, whether this, how long is this gonna last? We don't know yet. We have some reliance on animal models. The indirect cost is probably overstated. And then there's no adjustment for the second eye and actually there's no adjustment in either study where if you get one eye, is this, do you get an equal, exactly equal value for the second eye? Probably not, but we don't know. Really how to value that yet because it's not the same as cataract surgery. These people are probably more reliant on their bilateral vision than somebody who has a cataract on one eye and got cataract surgery in the other eye. And then these, the people who study, or published this study are employees of Spark which was also vaguely problematic, perhaps. So, all that to say I have about five minutes. I want this to be semi-interactive in the last five minutes. How many people think about cost on a regular basis when they're treating patients and cost effectiveness of what they're using to treat? Okay, if I say only cost effectiveness from a public health standpoint, how many people would say they regularly consider that? So, ophthalmology actually, we're a little bit fortunate in that a lot of our treatments are very cost effective. This is something that I encountered a lot when I was doing the Global Fellowship and out there. The cost effectiveness from a public health standpoint of cataract surgery is among the best of anything that's offered in medicine. When you talk about SICS and high volume cataract surgery in Nepal and India, it gets to the point of like four to five dollars per additional quality adjusted life year which is comparable to immunizations and almost as good as vitamin A supplementation which is incredibly effective. Within, well, with fake emulsification and with modern cataract surgery here in the United States even, the numbers range from anywhere from a thousand to there's actually a new study that was published in 2012 that shows that if you include indirect costs much like that last study of the luxterna gene therapy that the return on investment is something like 4,000% for society for cataract surgery, bilateral cataract surgery. And the metrics there are a little bit more validated and a little bit more robust as far as how they evaluate it but even when you just take direct cost it's about $1,600 for cataract surgery. It's very good. Now let's take something that us retina folks do a little bit more and that's treat a new vascular AMD with intracutral injection. So $50,000 here on this published paper but it's a little bit more complex. And I wanna give this because as I come away from the gene therapy which I think maybe is one way of interpreting what I said is that maybe we're not gonna have a great bang for a buck I wanna kinda show you another thing we do very commonly we don't think too much about should we be changing on a regular basis and that's Avastin versus some of the brand name anti-diagef therapies. So if you look at this, this was a comparison of Betasysmab versus Ranibismab for cost effectiveness for wet AMD newly diagnosed and basically this is the same thing the probability and just to sum it up, there's basically very little chance, very little chance that unless you lower the cost of Ranibismab or substantially that it will ever be more cost effective or as cost effective as giving Avastin either monthly or as needed. And even when you look at outcomes as needed Betasysmab is actually more cost effective than monthly or more regular treatment. Is that what we do is that how we interpret it not really and then you look at this this is including the Flibersep and you look that the incremental value so the same metric that was used for the gene therapy is in the 600,000, 800,000, 500,000 range for using the brand name anti-diagef, Lucentis and Iliya versus Avastin from a public health perspective. Yet we all kind of have also have the data that it's more efficacious, at least in the short term and we use that and our patients know about it, they know about these drugs as well and we do see anecdotally better effect and so we still continue to treat in that way but I offer that as a way of I guess framing the gene therapy and so I wanna get to some questions. All right, so do we have a more obligation to consider cost to the patient? Would everybody say yes? I think so. To society, do we have a moral obligation to these stewards of cost and how this affects societal costs? No, why would you say no? Well I think because we're not making societal decisions and so we're not driving that, I think our responsibility is to the patient in front of us. Yeah, and I'm glad you said no because that allows me to then say so if we are not and I think there is a valid argument there, there's a lot, there's very interesting literature on this dichotomy or opposition is how then do we determine these decisions? So should this be a democratic process? For example, if you're enrolled in a health insurance plan, should there be some kind of democratic process amongst people who are enrolled in it that they determine whether they're gonna accept a high cost therapy or not? Should we do it as a society? I think theoretically we think we'd do that but pretty clearly we do not because we're voting on so many such a fragmented and complex healthcare market that's all tied up in other policies that are not healthcare related. But maybe is there some way we could do it democratically? What about like a writer on your health insurance? So you have to buy into a writer before you have the disease that you for high cost therapies. For example, cancer medications for metastatic disease are very high cost medications as well, often in the order of a few hundred thousand dollars. Should patients have to have a writer so that those insurance plans will cover that in the case they need it? That way it's not passed on to everybody in the plan. And the other question I ask is in cases where these costs are passed onto the patient this might not be as applicable to patients with these particular diseases because I honestly just don't know we haven't dealt with this but are the cases where insurance besides they won't pay for it, right? And now that you have a patient who has a million dollar bill for something is a patient often the parent in these situations in a rational or is that a just position for them to be making that decision that they could be burdened with a million dollar bill and then how that might affect their life going forward. And people who have actually dealt with the insurance implications this would no better know how to discuss that. So quickly there's about a thousand to two thousand and one thousand to three half thousand depending on the study of RP 65 mutation or patients with this mutation in the US. It would cost a billion and a billion and a half dollars to deliver this therapy to everybody just a small percentage of the total healthcare expenditures which is in the trillions of dollars. Not everybody would actually be a candidate but just as theoretical. However, if gene therapy or as gene therapy becomes more and more prevalent and more and more available for other orphan diseases for other genetic diseases, where does that cost in the blossoming to or blooming or bloating to depending on how you're looking at it. And I think that's what you have to consider and when you're talking from a societal perspective is we could probably do this, it would be a blip in the radar to deliver it to everybody but this sets the paradigm for how we're delivering care down the road 10, 20 years down the road and there are opportunities cost associated with it. So on the basis of time I'll let that go but hopefully it was some fodder for thought. You guys have a great Wednesday.