Akari Therapeutics, Plc (AKTX) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Akari Therapeutics KOL Event. [Operator Instructions] This call is being recorded, and a replay will be made available on the Akari website following the conclusion of the event. I'd now like to turn the call over to Rachelle Jacques, President and Chief Executive Officer of Akari Therapeutics. Please go ahead, Rachelle.

Thanks, Tara, and welcome, everybody. As Tara mentioned, I'm Rachelle Jacques, CEO of Akari Therapeutics and really pleased to have you all here today. Thank you for joining our Key Opinion Leader Event, and we're going to focus today on geographic atrophy and the potential of long-acting PAS-nomacopan to address significant needs in the area. So today's webinar is going to be featuring Dr. Elias Reichel. Of course, we are going to be making forward-looking statements. So just take note there, please. Let me now introduce Dr. Reichel, who is going to give us a brief overview of geographic atrophy. He's going to talk about the GA landscape in terms of treatment and treatment evolution, very exciting time. And then followed by that, I'll make some comments about the Akari PAS-nomacopan program in GA. And then we'll have a Q&A session at the end where we'll be joined by Dr. Miles Nunn, our Chief Scientific Officer at Akari to take your questions, and I think you have an opportunity to put those into the Q&A section anytime during today's presentation. So I'm very pleased to be able to introduce Dr. Reichel, who is a Professor of Ophthalmology at Tufts University School of Medicine. He is an expert in vitreoretinal disorders with over 30 years of experience. Dr. Reichel's research interests include macular degeneration, diabetic retinopathy and inherited retinal disorders. He is a principal investigator of multiple clinical trials and the author of over 130 peer-reviewed publications. So Dr. Reichel, thank you so much for taking the time to be with us here today. And I'll turn it over to you to take us through a bit about geographic atrophy, symptoms, the diagnosis, the progression over time as well as, of course, importantly, the current treatment landscape as a clinician who obviously sees many patients with a condition. It's also very helpful to hear your input on experiences, concerns and unmet needs with patients who are suffering from GA. So with that, I'd like to turn it over to you and take us away.

Thank you, Rachelle, for that wonderful introduction. Good afternoon, everyone. And as Rachelle said, I'm going to be talking about geographic atrophy, which is a leading cause of blindness related to age-related macular degeneration. How do we define geographic atrophy? Geographic atrophy is the advanced atrophic form of age-related macular degeneration. It is a form of dry AMD, and it's characterized by progressive loss of photoreceptors, loss of the retinal pigment epithelium and loss of the choroidal blood vessels, the choriocapillaris. This schematic shows geographic atrophy, and you can see that there's a loss of blood vessels underneath the retina. Bruch's membrane, which separates the choriocapillaris from the neurosensory retina is thickened with age-related macular degeneration. The yellow deposits represent drusen. And you can see that there's loss of the retinal pigment epithelium and photoreceptors. This schematic shows the sequence and the pathophysiology of geographic atrophy. So geographic atrophy is a multifactorial condition. You can see on the left-hand side, the normal retina. You can see that the choriocapillaris has a full complement of blood vessels. And we can see Bruch's membrane is thin. That's that gray flat area that's right over the choriocapillaris blood vessels. Above that, the orange cells are retinal pigment epithelium. And above that, the gray, purple cells are photoreceptors. Over time, chronic oxidative stress, accumulation of visual cytotoxic byproducts and impaired lipid metabolism causes an unhealthy macular and an unhealthy retinal pigment epithelium that ultimately affects the choriocapillaris and photoreceptors. We know that complement pathway is dysregulated in age-related macular degeneration. And that's another factor in leading to atrophic AMD characterized by geographic atrophy or neovascular AMD as well. There's a breakdown of the blood/retinal barrier and there's also a capillary dropout. The blue cells you see there are inflammatory cells and inflammation is a key component in the pathogenesis of geographic atrophy. Finally, you've seen this picture already, but there's RPE, that's retinal pigment epithelial cell loss and photoreceptor cell death related to these changes. It's important to define neovascular age-related macular degeneration or NV AMD, which is the equivalent of wet age-related macular degeneration. This is important in that, this is part of the disease spectrum associated with age-related macular degeneration. Neovascular AMD, or wet AMD is characterized by leakage or bleeding from abnormal blood vessels due to age-related macular degeneration. And the blood vessels that causes our choroidal neovascularization, or CNV, if you look at the color picture on the right-hand side, this is a case of wet age-related macular degeneration. The arrow is pointing to the neovascular complex. That gray green area is the abnormal blood vessels. And you can see a retinal hemorrhage, which is characteristic of wet age-related macular degeneration. There's also an area of yellow there, and that area of yellow is lipid exudate from the leakage of these blood vessels. We all know that anti-VEGFs are the mainstay of therapy for wet age-related macular degeneration. But it's important to remember that neovascular age-related macular degeneration can occur in the setting of geographic atrophy. And we're going to talk more about this with the therapies that are now available for geographic atrophy, we do see an increased risk of choroidal neovascularization. The black and white photograph shows a frond or an arborizing choroidal neovascular membrane. And so this image was taken with OCT angiography. So just to put the 2 images together, we can see the abnormal frond of blood vessels there that cause leakage and bleeding underneath the retina with severe loss of vision, typically associated with choroidal neovascularization. The epidemiology of geographic atrophy is a worldwide problem. Approximately 5 million people worldwide are affected with geographic atrophy. In the United States, that number is about 1.5 million. And what's very interesting is that in individuals over the age of 90 greater than 20% have geographic atrophy. So this is a condition of the very old. When we're talking about geographic atrophy, we're talking about 80 and 90-year-olds as opposed to choroidal neovascularization or wet AMD tends to be a little bit younger patients in their late 60s and their 70s, although it can affect people in their 80s and 90s as well. But geographic atrophy is a disease of the very aged. And this is an important point because as we'll discuss, the older the patients are, the more difficult it is to have these patients be compliant and show up for their visits. Geographic atrophy accounts for 10% to 20% of legal blindness due to age-related macro degeneration with the vast majority of legal blindness being caused by wet age-related macular degeneration. How do we diagnose geographic atrophy? Well, it's basically on clinical examination, we can take a look at the patient's retina in the office and determine whether they have geographic atrophy. We can also use color photographs, fundus autofluorescence or optical coherent tomography to document these changes, and I'll show examples of that. This is a set of images, and we can see that the colored photograph shows an area of loss of the pigment, which is consistent with the loss of the retinal pigment epithelium which is consistent with geographic atrophy. So that -- and we can also see these large blood vessels, those are the large choroidal blood vessels, but we're not seeing any of the smaller choroidal blood vessels, which is consistent with geographic atrophy. The black and white panel to the right of the colored photograph is fundus autofluorescence. And the rental fundus can auto fluoresce due to chromophores such as lipofuscin that are deposited in the retina. But the black spots that we're seeing are geographic atrophy. So all those black spots, except for the optic nerve are consistent with geographic atrophy. The set of images below the 2 top images are from optical coherence tomography, or OCT. And we can see on the left panel that there's round, light gray or white scallop lesions, which is consistent with the geographic atrophy and coincides with what we're seeing on the fundus autofluorescence. So with OCT, we see them as white or pale gray lesions and in fundus autofluorescence, we're seeing them as dark lesions. And then there's a blind scan right next to the [ en face ] image that is consistent with geographic atrophy, you can see thinning of the retina and loss of the retinal pigment epithelia in that line scan that is a cross-section of the retina. Next slide, please. So geographic atrophy causes loss of central vision. And in these 2 photos, you can see how this trial compares to someone who's normally sighted. And then if you look at the other image, there are blind spots seen. So the image of the face is poorly ascertained by the patient with geographic atrophy in the macula. The symptoms and presentation of geographic atrophy are consistent with loss of central vision, especially when the fovea is involved. When the fovea is involved, this can result in severe loss of vision with vision being worse than 20/200 or legal blindness. I showed the picture with the blind spots and the scotomas that are consistent with wearing the way of the central macula. These individuals who are affected with geographic atrophy have reduced reading speed. They find it very difficult to read. And what's also interesting is that many of these patients have difficulty with light and dark. So they have night vision deficiency and they have adaptation issues. And what this means is that many of these patients going from a light environment to a dark environment take a while to acclimate with their vision. And that can happen also going from a dark environment to a light environment. So these adaptation issues relate to dysfunction of the retina and its ability to perceive images. Geographic atrophy is a progressive condition, and the average growth rate of lesions is about 2 millimeters squared per year. 50% of the time patients are presented with bilateral disease, so both eyes are affected. And the progressive nature can be variable. There may be genetic components that caused it to be variable where there may be acceleration relative to the average patient with geographic atrophy, and there are environmental factors, such as smoking that may accelerate the progression of geographic atrophy. The images at the bottom of the slide show geographic atrophy changes over time. So this is the same patient, the color photographs are at the top, and I hope everyone realizes that the images at the bottom are fundus autofluorescence. You're getting a tutorial here in retinal imaging. If you look at the left side, there's a small yellowish lesion. And if you look at the panels, over time, it gets larger. And not only does that lesion get larger, but there are more lesions showing up. So this is coming from unifocal disease in the panel to the left to multifocal disease in the rightward panels. And ultimately, you can see that the center of the macula is -- has all this geographic atrophy involving it and surrounding it. And this is true both in the colored photographs and the fundus autofluorescence. Remember, I said that the dark areas in fundus autofluorescence are geographic atrophy. And it's pretty pronounced that you can see that almost the entire central macula is wiped out from geographic atrophy. A patient with these findings would probably have pretty poor vision of 20/200 or worse. Genes that may play a significant role in geographic atrophy includes complement factor H, complement factor B, complement component 2, complement component 3 and the complement ARMS2 gene. There are 6 complement genes that have polymorphisms that account for almost 60% of the AMD genetic risk. These include CFH. It's a complement factor I, component 2, complement factor B, C3 and C9. So we know that genetics plays a role in age-related macular degeneration. How much of a role for each of these genes is still being studied at this point. We're going to switch topics here, and I'm going to talk about patient experience and the geographic atrophy treatment landscape in the United States. So up until the recent approval of pegcetacoplan, there is no treatment for geographic atrophy. AREDS 2 vitamins really have no role for the treatment of geographic atrophy. And patients would come in and they'd be told that they have dry age-related macro degeneration, it is characterized as geographic atrophy, but the patients were frustrated that there's no therapy for this. Patients come in very concerned about loss of vision and difficulty with reading. And the patients were very aware of progression of their -- progressive loss of their vision over time. The other thing is that, that patients really did not see great value in being followed since no -- there was no treatment being done. So typically, the patients with geographic atrophy were seeing -- were being seen every year. We've talked about imaging, and we do monitor patients with the clinical examination, color fundus photos or fundus autofluorescence or optical coherence tomography. So that's what we were offering patients prior to the approval of pegcetacoplan. But now there's an FDA-approved treatment, and we'll be discussing this. Pegcetacoplan was FDA approved February 17, 2023, and this is a remarkable achievement. This was the first drug approved for geographic atrophy. It was developed by Apellis Pharmaceuticals. Pegcetacoplan blocks C3 and C3b. The indication is for geographic atrophy. And the dosage is that you can treat every 25 to 60 days or once a month or every other month. There's a very broad label attributed to pegcetacoplan. And so it's something that's easily accessible for us to use in our patients who have geographic atrophy. Pegcetacoplan block C3, and it's important to understand this, with blockage of C3 and C3b, C5 is reduced in being produced. And if C5 is being reduced in being produced, it leads to a diminution or a reduction in membrane attack complex. Just as a reminder, membrane attack complex includes C5, C6, C7, C8 and C9. But if C5 is reduced, then membrane attack complex is not formed. And if membrane attack complex is not formed, then it causes less cell death and less dysregulation. In other words, membrane attack complex is bad. It's implicated in both dry and wet age-related macular degeneration. And if there's a way of reducing the amount of membrane attack complex being formed by blocking C3 and subsequently blocking C5 then this is real positive for the -- reducing the risk of geographic atrophy in these patients. Pegcetacoplan shows a 17% to 22% reduction in the mean rate of geographic atrophy lesion growth. And monthly dosing showed greater reduction than every other month. So the graphic here shows sham, which is the open circles at the top with the dotted line. And relative to sham, patients who were treated every month had a 22% reduction in the lesion growth rate. And those who were treated every other month had an 18% reduction in lesion growth rate. So there's a small benefit in monthly therapy and clinicians are balancing that out with the potential risks of these drugs as to whether patients should be treated monthly or every other month with pegcetacoplan. I'd also like to point out that pegcetacoplan's brand name is SYFOVRE. Avacincaptad pegol or ACP, blocks C5 and this is being developed by Iveric. They've completed Phase III clinical trials. Iveric was just acquired by Astellas Pharmaceutical on April 30, 2023. ACP blocks C5. And again, this is -- should be familiar since we've discussed C3 before, you can see that C5 is blocked. If C5 is blocked, then membrane attack complex and the inflammasomes are reduced in number. And by inhibiting C5, it slows inflammation and cell death associated with the development and progression of geographic atrophy. Ultimately, this all relates to reducing membrane attack complex as was shown with SYFOVRE. There were 2 pivotal clinical trials. The second pivotal trial was called GATHER2, and this showed a 14% reduction relative to sham of the mean rate of change of geographic atrophy growth. It's important to point out that ACP is a monthly treatment it's other -- the brand name is Zimura for ACP and the PDUFA date is expected August 19, 2023. So again, this drug shows a statistically significant reduction in GA growth rate relative to sham. It's important to realize that there's an increased risk of development of choroidal neovascularization in the setting of C3 and C5 blockage related to pegcetacoplan and ACP. Over 24 months, pegcetacoplan showed a 12% risk of choroidal neovascularization with monthly dosing with every other month dosing, it was a 7% risk and compared to sham, which was only 3% risk over 24 months. With ACP or Zimura, over a 12-month period, there's a 7% risk with monthly dosing, and there's a 3.6% risk with sham treatment. So it was almost double what you see with Sham. So this is important to remember because if we're treating patients with geographic atrophy, they're going to be getting one set of injections for that. And for wet AMD, they may be -- or they will be needing an anti-VEGF therapy for those who developed choroidal neovascularization. So there are other treatments for geographic atrophy in development. We're going to be discussing Akari's intravitreal therapy that blocks C5 and leukotriene B4. But just to point out the landscape, and this is by no means totally complete, but these are drugs that are in humans now, safe for Akari's drug at this point. But Gyroscope is working on C5 -- complement factor I as a gene therapy. Janssen is using CD59 as a gene therapy. Annexon is blocking C1q with intravitreal injections. Alexion has an oral drug for complement Factor D. Ionis has a subcutaneous drug for complement Factor B. By and large, most of what is being done is manipulation of the complement system for geographic atrophy. There are some other approaches and people are looking at transplantation of stem cells that is being done by Lineage Cell Therapeutics and by Luxa. And then visual cycle modulation is being done with deuterated vitamin A by Alkeus. And this is an oral drug. But by and large, most drugs in development relate to the complement pathway. And I think a lot of this is been done because of the enthusiasm related to Apellis' drug and Iveric's drug being efficacious. So what are the unmet needs in treating geographic atrophy? It's important that we reduce the frequency of therapy. In addition, treating geographic atrophy and preventing choroidal neovascularization from developing is another important unmet need. There is a significant treatment burden associated with intravitreal injections as we've learned with anti-VEGFs for the treatment of wet age-related macular degeneration as well as anti-VEGFs for the treatment of diabetic retinopathy and diabetic macular edema as well as the treatment of retinal venous obstruction. So these treatments involve frequent visits to the retina specialist. It can be monthly visits in the first year of many of these therapies with anti-VEGFs. And not only are there frequent visits, but there are frequent injections, especially in the first year of therapy. It's important to remember that most of these patients rely on others for transportation or help in getting to their retina specialists. And so it's a significant treatment burden not only for the patients, but for family members and friends who may be bringing these patients in for treatment and evaluation. As far as compliance with intravitreal injections, there have been a couple of studies looking at this. And most neovascular AMD patients, wet AMD patients are highly motivated to return, but 1 out of 9 to 1 out of 5 patients are lost to follow-up. One out of 7 patients don't have follow-up within 6 months of their last injection. And as the age increases, so after the age of 80, the risk of loss to follow-up increases over time. So these older patients may drop out of therapy because it's just too hard for them to continue with it. There are other complications that increase the treatment burden of therapy. And these are complications related to intravitreal injection. Endophthalmitis is the one that we're most concerned about and it's caused by a bacterial infection. It's typically treated with intravitreal injections of antibiotics. Endophthalmitis can lead to severe loss of vision. The risk of endophthalmitis is 1 out of 5,000 per injection. So it means that the more you treat the higher the likelihood per patient. So if you treat the patient 10 times in year 1, there's 1 out of 500 risk that, that individual would actually develop endophthalmitis. There's a risk of inflammation. This is uncommon. It occurs less than 1% of the time. But it is something that increases our treatment burden as we have to treat these patients with corticosteroids and make sure that they get better over time with their inflammation inside the eye. IOP is intraocular pressure and glaucoma and many intravitreal injections over time may increase the risk of glaucoma. Intraocular pressure spikes are not uncommon immediately after injection. And this warrants careful follow-up in the immediate post injection period of these patients. And so all these things add up to concerns and increases in attention treatment burden for patients with intravitreal injections. So what are the strategies for reducing the treatment burden? Well, we can lengthen the dosing interval with the anti-VEGFs and we can also develop longer-acting anti-VEGF drugs. So we're focusing on anti-VEGFs as a model for what we can expect for other treatments that are intravitreal injections. So some of the things that we've learned from anti-VEGFs is that we can lengthen the dosing interval. And there are treat-and-extend use of anti-VEGFs, particularly for wet age-related macular degeneration. This requires a longer dose interval between therapies and treat-and-extend reduces the number of visits relative to monthly and PRN approaches, and PRN is pro re nata, or as needed, and it also reduces the treatments relative to monthly therapy. With PRN and use of anti-VEGFs, it reduces the number of treatments, but it doesn't necessarily reduce the number of visits. So we're treating the patient if they have fluid or not, but these patients still require fairly frequent visits to determine if they are dry or if they are wet with their neovascular age-related macular degeneration. So some of the lessons that we've learned is that longer-acting agents may improve compliance and by reducing the visit and treatment burden. And it also likely reduces discontinuation of therapy if you have a longer-acting agent. The enthusiasm for a longer-acting agents is great. And there have been 3 drugs that have been approved for wet AMD that displayed longer acting use. Brolucizumab; SUSVIMO, which is the port delivery system; and faricimab have slightly longer durations of therapy relative to the older anti-VEGFs, meaning ranibizumab, bevacizumab and aflibercept. High dose aflibercept is being developed by Regeneron, and that should be approved in June of this year. And the high dose aflibercept gives prolonged duration of therapy. And then there are 2 other drugs that are being developed for longer duration therapy, vorolanib and axitinib. And so I think this just shows you the enthusiasm with trying to get longer-acting agents to try to reduce the treatment burden of anti-VEGF therapy, particularly in wet age-related macular degeneration. We've seen this slide before. I just want to emphasize that there is this increased risk of development of CNV with C3 and C5 blockage. So there is a significant intravitreal injection treatment burden with complement inhibition. Pegcetacoplan requires monthly to every-other-month therapy. And there's really no room for PRN or treat-and-extend approaches as per anti-VEGF used. You have to use it at what is recommended for the indication. ACP is a monthly therapy. It's not yet approved, but likely will be this summer. And that's going to be a significant treatment burden with monthly therapy. We have to remember that these geographic atopy patients are older patients, and they have more of a likelihood to discontinue therapy as we've learned with the anti-VEGFs. With the treatment with the complement inhibitors, there's no dramatic improvements in vision as we see with anti-VEGF and wet AMD. There's continued slowing -- there's continued loss of vision, although it may be slowed with the complement inhibitors but the patients may not recognize this and therefore, patient motivation to be treated or continue to be treated may be low. So these are things that we have to think about. So if a patient has geographic atrophy and they develop CNV, it could mean that they get 20 or more injections in their first year of therapy. It could be that they're getting monthly anti-VEGF and then they get another 6 to 12 injections of complement inhibition. So the treatment burden is quite significant with these patients. So there is a combined need for complement in anti-VEGF therapy. And what do we do in the office? Well, we can administer both therapies on the same day, but we need to wait for the intraocular pressure being reduced. So typically, you wait half an hour and the intraocular pressure is reduced, and then you can treat with your complement inhibitor after you've treated with your anti-VEGF therapy. This is likely going to cause significant issues with patient logistics and flow in the office, an alternative approach to treating a patient who has both choroidal neovascularization and geographic atrophy is you can treat the day the patient presents with the choroidal neovascular membrane with anti-VEGF and then have them come back in a week or 2 for treatment with the complement inhibitor. This will likely affect patient compliance. And it's important to realize that you're adding visits and dramatically increasing the treatment burden. So there's a combined need for inhibition of complement and VEGF overexpression. And so what about patients who present with significant risk of choroidal neovascularization and geographic atrophy. This hasn't been studied, but it would be great to have a drug that reduces choroidal neovascularization risk and also treats geographic atrophy. This would be something that would be ideal. So as PAS-nomacopan is a dual inhibitory drug, and it binds both C5 and leukotriene B4, it sequesters leukotriene B4. The C5 works in preventing C5 activation. And we'll get into a little bit of the mechanism of leukotriene B4, but it actually increases VEGF-A. So if you can block leukotriene B4, that would inhibit the production of VEGF-A. What's also exciting about PAS-nomacopan is that the early studies of PK and PD suggests that it can be dosed 4 or fewer doses per year relative to SYFOVRE, Zimura or Annexon's drug. You can see here that with SYFOVRE, you can do monthly or every-other-month treatment. Zimura is monthly, and Annexon is exploring monthly or every-other-month treatment with their drug. Whereas with PAS-nomacopan, we are optimistic that it could be done with 4 fewer doses per year, which would be a significant advantage. So this is the description of PAS-nomacopan and leukotriene B4 inhibition that may reduce the risk of development of choroidal neovascularization in geographic atrophy patients. Leukotriene B4 can upregulate the production of VEGF-A, which is a key driver of choroidal neovascularization. And PAS-nomacopan is a bispecific molecule. It inhibits complement C5 and LTB4. And as I said, LTB4 inhibition may help reduce the risk of CNV and geographic atrophy. It's actually fairly well characterized and straightforward. Choroidal neovascularization starts with inflammation in the choroid and retinal pigment epithelium. And the damaged retinal pigment epithelium releases leukotrienes, including leukotriene B4. Activation of leukotriene B4 can lead to overexpression of VEGF-A. And we know VEGF-A is important for the development and normal expression of VEGF-A in the retina to form the inner layer of the blood vessels. However, overexpression of VEGF-A is not a good thing and drives choroidal neovascularization. So the hope here is that this drug not only treats geographic atrophy with C5 inhibition, but with leukotriene B4 inhibition, it reduces the drive for development of choroidal neovascularization. So with that, this concludes this section, and we will go on with Rachelle.

Super. Thank you, Dr. Reichel. Thank you for your good overview as well as the tutorial on retinal imaging. Thank you very much. And really exciting to start to see how you're thinking about the landscape as now there are, luckily, GA treatments coming to the fore. And I think we really view this, at Akari, as an exciting time. Geographic atrophy has certainly been an area that's been underserved. And we're excited about the promise of complement inhibition, specifically the 2 programs that you've pointed out that have seen some positive efficacy and one of those progressing to an FDA approval, both were complement inhibitors intravitreally injected. And so I think that we are, here at Akari, really looking to build on that promise of that efficacy, but also to try to close some of the gaps that you outlined. So the PAS-nomacopan program here at Akari is really focused on just that, and it is on delivering on the efficacy benefits in C5 complement inhibition and trying to address 2 really important things that we think are challenges for these new therapies. And I think it's pretty typical in an area where there's not been a therapeutic that sometimes the first therapeutics have -- they're a great step forward, but they do have challenges, and we see this here. And the 2 areas that we're focused on are the frequency of intravitreal injections and the safety risk around increased risk of CNV. So for our PAS-nomacopan program, we are looking at intravitreal injections of 4 or fewer per year. Again, delivering on the efficacy promise of C5 inhibition and then doing that while not increasing the risk of CNV for these patients, and it seems a bit counterintuitive to be addressing a site-threatening GA and at the same time, introducing site-threatening CNV. And so what we're really focused on here on the CNV piece is , again, to the dual mechanism of action of nomacopan and our PASylated, which is our long-acting version of nomacopan. LTB4 inhibition, as Dr. Reichel has pointed out, can be a driver of overexpression of VEGF-A. And as we know, VEGF-A can drive CNV. And so we believe that by inhibiting LTB4, we may be able to deliver on the benefits of C5 in efficacy case, but not do so at risk of introducing CNV. So really eliminating this increased risk of CNV. A couple of kind of, I say [ snacks ] here around the different pieces of data that we have been really coming to with our pre-IND work that we're doing, our preclinical studies that we're doing, really focusing on answering these questions around can we deliver on this extended dosing interval, what does it look like in particular. And so what you can see here is for our PAS-nomacopan, we have looked at, in this case, in a rabbit model the dose of 20 mg per ml and a dose of 60 mg per mL. And in particular, we followed them the PAS-nomacopan concentration, in vitreous, in retina and in choroid retinal pigment epithelium. And we've done that for 28 days and evaluated through mass spec. And what you can see, a couple of things to point out here. What you can see over to the left are the 2 blue lines, you can see the half-life is roughly the same for the 2 PAS-nomacopan doses, but you also can see a nice dose response of the higher 60 mg ml delivering on a longer duration. Those are about 8 days, half-life. And then on the right-hand side, just to point out that when we look at all of the data points in the 28 days postinjection, we're at about 20% to 30% of drug concentration in vitreous, in the retina and [ again ] choroid RPE, which those are relevant tissues anatomically for dry AMD. And so you can also see that this is plotted against in this case, Eylea, which is used in wet AMD just to have a view of how that stacks up. So when we're looking at this data as well as other data that we've generated through our preclinical work, we are increasingly confident in PAS-nomacopan ability to deliver on a dosing interval that is 3-plus months in duration. And we think this is important. I think there are several things that Dr. Reichel pointed out, there's obviously frequency of dosing introduces risk. When we think about the actual -- whether or not patients are going to show back up for these doses and are they going to be compliant. but I think there's another piece of it and that is when we're thinking about balancing risks and benefits of these early treatments, some patients just probably will not be treated at all. And so for those patients, we hope that we'll be able to provide something that is really fitting in the cost benefit that is relevant for them and then be able to reach more patients with treatment for GA and, of course, addressing the sight-threatening nature of that. Now when we look at again the CNV question and look at some of our early data on CNV, and how we're evaluating that, again, preclinically. What you can see here is building on this concept of LTB4 can drive overexpression of VEGF-A which then can drive CNV, then can we, by inhibiting the LTB4 can we then address the VEGF levels. And what does that look like compared to other and for example, VEGF inhibition. So in this case, what you see is a preclinical model in severe uveitis. We've looked at long-acting PAS-nomacopan and what it does to the intravitreal VEGF concentration. And you can see here that it's as effective as an anti-VEGF antibody treatment. So for again, kind of looking at this as one piece of the puzzle and putting it together with the other work that we've been doing in our preclinical program, we are increasingly confident in our ability to address as well the CNV issue that we've highlighted today. So importantly, though, as I think you all know, it is critical work. The IND-enabling studies is preclinical work. But really where we're headed is, of course, into the clinic, and that's incredibly important to see how these things play out in the clinic. So our IND-enabling studies are underway. They continue to be underway. We are on track, and we'll be initiating clinical supply later this year. And as we've announced previously, we expect to file our IND in the first half of 2024. And assuming the success of the IND, then we will be moving into clinical studies in 2024, which I think is incredibly important again in really proving out the potential benefits of PAS-nomacopan. So we're very excited about the program. We think that the target product profile is very well suited here for patients, and we look forward to keeping you all updated on the program. With that, I would love to jump into some Q&A. And for the Q&A session, as I mentioned previously, we're going to welcome back Dr. Reichel and we'll welcome for the first time into today's discussion, Miles Nunn. Dr. Miles Nunn our Chief Scientific Officer at Akari and is, in fact, the person who discovered nomacopan. So clearly, the world's expert. And I'm very happy now to be joined by Dr. Reichel and Dr. Nunn and jump into Q&A.

So for those of you who might want to ask a question, there is an active question kind of chat available. So feel free to put those into the queue, and we'll take those there. So great. I see Miles. Miles. All right. Great. We can hear you. Super. So let's jump right in here. I am going to start with a question here, and this is for Dr. Reichel looks like -- so let me just read it to you. The drug potency is of importance to GA, which translates into the percent of GA reduction at a given time frame compared to current standard of care. So do you anticipate this new drug to move the needle to improve the current efficacy of 20% reduction at 12 to 24 months. And have you thought about studying the intermediate AMD population since this dual MOA may be more potent. So I'll open it up.

Yes, it's hard to predict efficacy without having data [ in man ]. So I think all bets are off. I would -- hopefully, it will be better. But there's nothing that says that it would be. As far as intermediate AMD, I think that's a great idea, and it's something that should be looked at. Indeed, it may be that by inhibiting C5 and LTB4, you may prevent the development of choroidal neovascularization and geographic atrophy in high-risk intermediate AMD.

Yes. Great. Great. Continue to think about that path to the clinic, which is incredibly important. Next, question here then is for Miles. Miles, any concerns about development of uveitis and potential IOP spikes postinjection.

Thanks, Rachelle. So uveitis, I can't see the reason why that the -- this biologic will be any more likely to induce the uveitis than any other biological. I guess the dosing frequency will be longer, so that may reduce the risk of uveitis. And we actually have some preclinical data in a model of experimental autoimmune uveitis, which shows that nomacopan, PAS-nomacopan is beneficial, actually reducing clinical scores and structural damage that occurs in induced uveitis. And in terms of the IOP, we've been careful to -- as we've been developing as PAS-nomacopan preclinically to ensure that the dose is going to be a small volume, so it's going to be less than 100 microliters. And indeed, in the preclinical work we've done so far, we haven't seen any spikes in IOP. So I think that's not going to be a risk for us.

Great. Great. Thank you. So I think Dr. Reichel, one of the areas that is clearly rapidly evolving is just how to think about patients and the treatment with the earliest first therapeutic SYFOVRE and then potentially ACP in the future. And thinking about that kind of decision that you would need to make and others in your shoes will need to make around how to think about the right patients, how to have that dialogue with patients about the trade-offs. And we certainly see the efficacy has increased in the monthly dosing regimen. And as you pointed out, there's risk associated with monthly dosing as well as CNV risk. How are you thinking about maybe already, how are you having those discussions in the clinic with patients about who will be treated and what that will look like and what those trade-offs are.

Yes. So I mean, If you have a patient with geographic atrophy and it's threatening the center of the macula, the phobia, we're going to want to aggressively treat those patients, particularly if the patient is monocular, meaning that they already have significant geographic atrophy in one eye with loss of significant central vision, you're going to want to be fairly aggressive in treating those patients. The -- we can discuss SYFOVRE best because that is now out and you have an option with SYFOVRE to treat once a month or every other month. And I believe that every other month balances risk and benefits better, meaning that you have close to the same benefit as monthly treatment, but you avoid more of the potential complications by going to every other month therapy. As I outlined, there's a reduced risk of choroidal neovascularization, you reduce the potential for issues with IOP, you reduce the risk of endophthalmitis by going to an every other month approach. Some of these patients also develop ischemic optic neuropathy, which is a observed in the monthly treatment but not in the -- as great in the every other month treatment. So these are things to remember is what's the patient is doing with their other eye. If the vision in the other eye is excellent, they don't have geographic atrophy. And it's an extrafoveal lesion something that's far away from the fovea, you may actually want to just watch that patient. So those are the kind of things that we're thinking about.