Good morning, and thank you for joining us today for the fourth and final session of our Explorer Series, featuring our clinical program for the treatment of geographic atrophy, NGM621. My name is Brian Schoelkopf, Head of Investor Relations at NGM Bio. We will be making forward-looking statements during today's presentation, including statements about anticipated timing of events and the potential benefit of our product candidates. We refer you to our most recent 10-K, which identifies factors that could cause actual results to differ materially from today's forward-looking statements. I encourage you to read the full language on this slide and all of the slides that will be presented today. They will be posted to the Investors and Media section of our website. With that, I will hand it over to David Woodhouse, Ph.D. and Chief Executive Officer at NGM Bio. David? Thank you, Brian. It's my pleasure to welcome you today to the fourth and final installment in our multi-episode R&D Day we call the Explorer Series. We've covered a lot of ground in the first three episodes in the series. We started by discussing our discovery engine, the foundation of NGM Bio, in the first episode, and then covered two stromal checkpoint inhibitor programs for oncology, NGM831 and NGM438 in our second episode. Our third episode focused on NGM707, our dual ILT2 and ILT4 antagonist, and its potential as a potent myeloid checkpoint inhibitor for the treatment of solid tumors. If you missed those earlier episodes, I encourage you to tune into the replays available on our website under the Investor Relations tab. We're dedicating the final segment of the series today to NGM621, a program that we think could be a category leader for the treatment of a leading cause of blindness called geographic atrophy, and a program for which we have an important clinical readout later this year. Our objective with the Explorer Series is to give you a sense of our science-driven approach to drug development and the rationale that underlies certain of our newer additions to the pipeline. What it doesn't provide, though, is a view of our entire pipeline. Beyond the programs we are featuring in the Explorer Series, we have three additional programs in active development, each of which are currently in phase II clinical trials. In brief, they are as follows. NGM120 is an anti-GFRAL receptor antagonist we're developing for the treatment of cancer. We plan to share more data from an ongoing phase I-B in metastatic pancreatic cancer later this year, while we near completion of enrollment in an ongoing phase II in the same setting. We also plan to initiate a new phase II cohort in prostate cancer for the program shortly. Next, aldafermin is our FGF19 analog, for which we expect to have phase II results in cirrhotic NASH in the first half of next year. Finally, MK-3655 is a FGFR1c agonist antibody in a program that Merck has already licensed from us, for which they are enrolling and fully funding a global phase II-B study in the F2/F3 NASH population. Overall, with seven programs in total in the clinic and four of them in phase II studies, our pipeline is poised to deliver multiple proof of concept clinical data readouts across each of our programs over the next 12-18 months. Our most proximate top-line clinical data readout is for the program we'll be highlighting today, NGM621. The profile of this product candidate is particularly exciting. First, it's directed towards a clinically validated target for a very large and unserved patient population. Second, the program is part of our collaboration with Merck, and if they choose to license the program after our data readout later this year, we'll be able to leverage their late-stage development commercial expertise while retaining meaningful backend economics. I think that's a particularly important advantage considering the size of the patient population globally. Third, NGM621 has attributes that we believe can support a preferred product profile for providers and patients in this setting. As you'll hear in more depth in a moment, NGM621 is a high-affinity monoclonal antibody we have designed to block Complement C3. We believe NGM621 can help prevent the progression of an advanced form of dry age-related macular degeneration, known as geographic atrophy, that is a leading cause of blindness globally and currently has no approved treatments. We completed enrollment in a 320-patient phase II study we call CATALINA last year. We're on track to reporting out the top-line results from the study in the fourth quarter of this year. While we initially targeted Complement C3 based on genetic evidence suggesting the complement system plays a role in developing geographic atrophy, we now also have clinical validation of the target from development work done by our industry peers that has shown an ability to slow disease progression by blocking Complement C3. Beyond the target it binds, however, NGM621 has some important features that we believe can distinguish it as a preferred product profile for patients and physicians. The potential differentiation spans three areas, improved efficacy, less frequent dosing, and an improved safety profile. You'll hear in the presentation today the experience and history of the wet AMD class of drugs, which we believe is an instructive analog to how retinal specialists adopt new treatments that can inform how the dry AMD and geographic atrophy landscape will unfold. It supports the idea that the areas of differentiation we believe NGM621 can have can translate to a clinical benefit that is quickly recognized by retinal specialists seeking the optimal treatment for their patients. We are thrilled to be approaching the completion of CATALINA, a trial that we upsized enrollment for due to strong patient enrollment demand, as well as the potential opportunity for the study to be counted as a pivotal trial. We're pleased with the integrity of the study to date across all metrics and remain on target for a top-line data readout in the fourth quarter. With that brief overview, let's now turn to how we have organized the time today. First, Erin Henry, NGM's Head of Ophthalmology Clinical Development at NGM Bio, will provide an overview of geographic atrophy and the urgent need it represents for therapeutic intervention. Next, Mark Soloway, our lead scientist for NGM621. We'll walk through the complement hypothesis for treating GA, as well as highlight some important molecular attributes of NGM621. You'll hear from Dr. Charlie Wykoff, a board-certified medical and surgical retina specialist and ophthalmologist who serves as Director of Research at the Retina Consultants of Texas and the Texas Retina Research Foundation. We're very pleased to have Dr. Wykoff join us today to share his perspectives on the current state of play in the geographic atrophy treatment landscape. We'll then bring Erin back to discuss the key areas of differentiation of NGM621 and our clinical development activity for the program. Finally, before we open it up for Q&A, you'll hear from Siobhan Nolan Mangini, our Chief Financial Officer, on the opportunity in geographic atrophy and the collaboration terms we have with Merck around NGM621. I'll now invite Dr. Erin Henry, who as I mentioned, is our Head of Ophthalmology Clinical Development and Project Team Leader for NGM621, to introduce herself and then kick off the agenda with an overview of geographic atrophy and our therapeutic hypothesis with NGM621. Erin? Hello, my name is Erin Henry, and I head the NGM621 Clinical Development Program. I joined NGM after 13 years at Genentech, working in their ophthalmology franchise on a number of retinal disease programs. In particular, I had the privilege to work on the lampalizumab pipeline program for geographic atrophy, secondary to age-related macular degeneration, or AMD. While ultimately not successful, the large clinical development program helped to advance our collective understanding of GA and how best to monitor and measure progression over time. We collaborated with leading retinal experts, and the articles shown here represent a sample of that output. Now at NGM, the learnings from those published reports have been instrumental to the decisions our team makes on the NGM621 program. The successful completion of the phase I study and the rapid progress of our ongoing phase II trial gives us a lot of confidence that we're on the right track in our exploration of the clinical utility of this molecule. Let's take a step back to talk about geographic atrophy. GA is a debilitating, progressive retinal degenerative disease associated with irreversible loss of central vision. The image on the right gives you a sense of what the field of view looks like for somebody struggling with GA. We know from natural history studies that over time, GA can rob patients of their central vision, which can lead to a loss of independence, social isolation, depression, and an increased risk of falls and fractures. GA has no approved treatments, making it a leading cause of blindness in the developed world, with an estimated 1 million patients suffering with GA in the U.S. and over 5 million worldwide. In the U.S., the prevalence of GA is similar to the other advanced form of AMD called wet or neovascular AMD, and the risk of developing either of these conditions rises exponentially as one ages. With the aging of our worldwide population, the burden of both wet AMD and GA is estimated to affect over 19 million people by the year 2040. AMD affects the macula, a portion of the retina which is located in the back of the eye. The retina is a structure of highly organized cells which convert light into visual information that is processed by the brain. macula is particularly important real estate because it's what we use for discerning fine central vision. The vision that we use to drive, to read, to recognize the faces of our friends and loved ones. Multiple factors are thought to contribute to the pathogenesis of AMD, including a person's genetic risk, coupled with their lifelong exposure to environmental stressors. These factors, coupled with time, can damage the photoreceptor cells in the macula, illustrated in this central insert showing the photoreceptor outer segments nestled against the retinal pigment epithelium and choroid, which provide support and nourishment to the photoreceptor cells. The damage from AMD often begins in a patient's fifties or sixties and is usually diagnosed by an eye doctor when retinal deposits called drusen begin to appear in the macula. Drusen can increase in size and number over time and can lead to either advanced form of the disease, neovascular AMD or geographic atrophy. At NGM, we're focused on GA, which is essentially patches of dead retinal cells that grow over time as the neighboring cells also get sick and perish. You can see that depicted here on the right side of the slide as that C-shaped area where the photoreceptor cells and RPE cells are absent. GA lesions relentlessly grow and expand over time. The figure on the right shows that well. The upper panel shows color fundus photographs of a GA lesion. The lower panel is that same lesion imaged with fundus autofluorescence. This is an example of GA progression observed over a four-year period of time. You can see the GA lesions, which are yellow in the upper panels and black in the lower panels, grow in size and develop new islands of atrophy over time, coalescing and involving the fovea by the end of this period. GA is characterized by that progressive loss of photoreceptors, retinal pigment epithelium, and choriocapillaris, which can lead to irreversible loss of vision. Unfortunately, GA typically impacts both eyes, often with one eye developing symptoms a few years ahead of the other, leaving patients with the knowledge of what's coming as the second eye becomes involved and deteriorates. Most clinical trials currently ongoing are testing potential therapeutics that aim to reduce progression of GA lesion enlargement and preserve the retinal tissue for as long as possible. We've learned from natural history studies that the fovea is actually resistant to atrophy in the earlier stages of the disease. GA will grow faster towards the periphery of the retina than it will towards the fovea, which means that for treatments that reduce disease progression, the goal is to reduce the overall size of atrophy as well as preserve the foveal island, which is seen below on the left panel as the center of that donut shape GA lesion for as long as possible. Both objectives will provide the patient with functional vision for longer. This is illustrated nicely in the graphic below on the right, which depicts the natural history of GA progression over time as two red lines, with the overall GA area getting larger and the foveal region getting smaller until it's completely involved. One can imagine that a treatment that reduces GA growth will essentially reduce the slopes of both these lines, and that is depicted by the blue lines on the graph, giving the patient more time with functional vision and an intact fovea. Once the foveal island is lost, central vision, as measured by the visual acuity chart, will drop dramatically even though the patient represented here probably already has visual dysfunction prior to that final event. Now let's shift to learning a bit more about what's being done to combat this disease process. Mark, our head of research for NGM621, will take it from here. Thanks, Erin. As Erin mentioned, I'm Mark Soloway, and I lead the biology teams for NGM621 and our ophthalmology program. We're excited to bring NGM621 into the clinic, not only because of the significant unmet medical need in GA, but also because this program highlights how we first used strong biological insights from the study of human genetics to help define a tractable drug target. Our biologics colleagues leveraged their expertise at tailoring proteins to design the best drug that we can make. As you will see on the next slide, the argument for targeting the complement pathway, and especially the C3 protein in AMD, is especially compelling. In this process, we first analyzed the ClinVar database, a public archive of reports of the relationships among disease phenotypes in greater than 130,000 variants in 5,000 genes. We selected 200 genes of potential interest, and these were systematically curated and evaluated for further study, again, with an emphasis on compelling genetic data. The plot on the left demonstrates exactly why we became interested in the complement pathway and eye disease. Scientists use genome-wide association studies to search in an unbiased way for genetic changes that are associated with certain traits or diseases. This Manhattan plot is from one of these studies and graphically illustrates the association of various SNPs, or single nucleotide polymorphisms, with the disease age-related macular degeneration. Samples were taken from over 17,000 patients with advanced AMD and 60,000 healthy controls, and SNPs were measured across all the chromosomes, which you can see labeled across the bottom. The Y-axis shows the strength of these associations. 52 genes associated with AMD, and it is striking that several of the most significant hits are in genes associated with the complement pathway. These are complement factor H, C9, C2, complement factor B, and C3, highlighted with the red arrows. Gene variants in the complement pathway account for over 60% of the total genetic risk of AMD. Right off the bat, we can see that this pathway is critical, but several key points are still missing. Is this pathway upregulated or downregulated with disease? And among these genes, which is the primary driver or best target for modulation? The figure on the right demonstrates one of the reasons we believe C3 to be the most promising part of the complement cascade to target for GA. This is a section through the retina of an elderly human donor who was diagnosed with GA two years previously. In this retina, the GA lesion is on the right-hand side. If we focus on the leftmost box, which is taken from a relatively healthy part of the eye, you can see abnormal deposition of C3 in pink that is adjacent to the photoreceptors highlighted in yellow. This deposition was not seen in eyes from healthy donors. In other studies, C3 was also found to be associated with drusen, the abnormal protein deposits which are the hallmarks of AMD. C3 is abnormally upregulated in disease and is present in the regions of the diseased eye that are headed for disaster. This genetic and histopathological evidence both point to C3 as a promising target to prevent the advancement of geographic atrophy and address this significant unmet medical need. Now let's dig a bit deeper into the complement pathway on the next slide. This pathway is a part of the innate immune system that complements the activity of antibodies and phagocytic immune cells. Complement factors circulate in our blood like a small army held in reserve that is always on the alert, scanning for engagement with the immune system or cellular debris. Once activated, these troops initiate a proteolytic cascade where a protease becomes activated, cleaves its target, which is also a protease, which in turn gets activated and cleaves its target, et cetera, et cetera. This culminates in local inflammation, the clearance of dead cells, and a coordinated attack against pathogens. This hierarchical activation is schematized to the left. As I mentioned previously, complement can be activated in a number of ways. These include classical activation by antibody antigen complexes, as well as alternative activation directly by viruses, bacteria, and parasites. It is notable that each of these stimuli leads to the formation of a C3 convertase, which drives the formation of C3a and the active protease C3b. These factors then further activate the complement cascade, as well as mediating immune cell responses and the process of opsonization, which prepares cells and debris for clearance. C3b can also itself activate C3 convertase and thus further propagates the complement activation response. Unlike other targets in the complement pathway, including C5, none have the power of C3 in terms of blocking all downstream effector activity. C3 integrates multiple different activation signals and acts as the first gatekeeper for this pathway. Having identified C3 as the optimal target to pursue to counteract the disease biology of GA, we then challenged our protein engineering group to produce the best molecule to modulate this target with high therapeutic potential. We designed NGM621 to effectively block C3 using tried and tested antibody engineering technology. The precursor for NGM621 stood out as a candidate molecule among other antibodies from multiple antibody campaigns based on its exceptional picomolar binding affinity for intact C3. It was subsequently screened for its ability to completely block C3 cleavage and prevent release of C3a and the active protease form C3b. Finally, this molecule was shown to effectively block both classical and alternative hemolytic cascades, which measure complement's ability to lyse red blood cells. This antibody was clearly our most promising target for further development and eventually became NGM621. NGM621 is a humanized IgG1 monoclonal antibody with an Fc domain engineered to eliminate effector functions that potently binds and inhibits human C3 with picomolar range affinity. Specifically, NGM621 inhibits the enzymatic cleavage of C3 by multiple C3 convertases, prevents downstream activation of the complement cascade, and stops this disease-promoting pathway in its tracks. Given the potential role of complement activation in the pathogenesis of GA, intravitreal NGM621 may reduce the rate of retinal tissue damage and atrophy associated with this aberrant complement response. Now it is my great pleasure to introduce you to our next speaker. Dr. Charles Wykoff is a board-certified medical and surgical retina specialist and ophthalmologist who serves as Director of Research at the Retina Consultants of Texas and the Greater Houston Retina Research Foundation, and as Chairman of the Research and Clinical Trial Subcommittee for the Retina Consultants of America. We are fortunate to have Charles with us today to discuss the current state of play in the treatment of geographic atrophy. Charles? Hi, I'm Charles Wykoff, Medical and Surgical Retina Specialist from Houston, Texas, where I'm the Director of Research at Retina Consultants of Texas, and it's a privilege to be here with you virtually today to talk about the treatment of geographic atrophy. In particular, over the next 15-20 minutes, we will talk about the current state of play for the development of treatments for geographic atrophy from my perspective. In particular, I'd like to go over three major topics. The first, we'll talk about the development in context. What I mean by that is, where have we been from a development perspective with treatments for geographic atrophy? What's the historical landscape look like that's led up to where we are today? Second, we'll talk about the ongoing programs, developing treatments for geographic atrophy, where we are today and where we might go in the future. Then finally, we'll talk about the patient perspective, right? When we have treatments that are available, hopefully in the not-too-distant future, who's going to be treated, what's compliance gonna look like, and what's clinical adoption broadly across the United States gonna look like today and moving into the future. Let's jump in. First topic is the development in context. There have certainly been many failures in the field of developing a treatment for geographic atrophy or advanced dry age-related macular degeneration. The most prominent failure, of course, was the lampalizumab program. Here's the paper. It was published in 2018, the top-line results of the CHROMA and SPECTRI phase III randomized clinical trials. While these were ultimately a failure because the drug was not successful in slowing the development, progression really of geographic atrophy, these were extremely well-designed, very well-controlled and executed global phase III trials. This was a top-notch program. Because of that, it really was sort of hurtful, if you will, from a personal perspective for those of us that do clinical trials and drug development, because we all thought we might have a treatment with this drug lampalizumab that ultimately failed. Unfortunately, this isn't the only failure in the past of developing treatments for GA. There's another reference here, but there's many other that litter our historical past. All of this is in the context with quite robust data that continues to indicate that complement really is a core component and critically important to the development and progression of geographic atrophy. I've always been a believer that complement is critical to the development of GA and its progression, and it's been really challenging to find a treatment for that. This is a complicated disease. There's intrinsic factors, there's extrinsic factors, extremely complicated neurodegenerative process. Looking back, maybe it's not unsurprising that it's been so challenging to find the right treatments for this disease. I want to again highlight the data that clearly indicates that complement is critically important. None of this is new data, but it's always worth revisiting. The first is genetics, right? We know that this is largely a genetic disease process. There have been dozens, over 40 of genetic loci implicated in the development and progression of age-related macular degeneration, identified across more than a dozen human chromosomes. My genetic profile and your profile probably account for over 50% of our risk of developing age-related macular degeneration. Many of these components, although importantly, not all of them, are within complement components. Here I've listed a few of these that are particularly strongly associated with AMD. Overall, these complement component haplotypes, if you will, are predicted to increase the activation or decrease the inactivation of the complement cascade, theoretically leading to an increased inflammatory state long-term over the course of a patient's life. That may be what increases the risk of breakdown and ultimately death of multiple layers of the retina and choroid that account for age-related macular degeneration and geographic atrophy. Genetics is not the only component that indicates complement in the pathogenesis and progression of AMD and geographic atrophy, specifically. We have very elegant human histopathologic analyses that have directly identified accumulation of multiple complement components. Here are some well-published images showing C3 and C5 deposition and accumulation in drusen and in the sub RPE space. Most importantly, implicating complement is, of course, the recent clinical trial successes. When I say success, I mean that there has been clearly evidence from my perspective that inhibition of C3 and C5 through the pegcetacoplan and avacincaptad program prospectively have clearly slowed the progression of geographic atrophy. Now we can talk at length about the percent reduction in progression of geographic atrophy, and that's a really important topic, happy to get into later. I'm going to leave that discussion for later because I think the point from these trials, the overarching point is that we are repeatedly seeing signs of efficacy with C3 and C5 inhibition across two, very well-constructed clinical trial programs to date. With that background into our second chapter for discussion, let's talk squarely about the ongoing clinical trial programs that exist. I put together this slide because there is a lot of movement in this space. It's incredibly exciting to see this much activity from a patient perspective, first and foremost, but also from someone that does a lot of clinical trials. Here is a simplistic overview of the complement cascade, which I'm sure all of you are now intimately familiar with, showing the core activation pathways leading to C3 cleavage, which then leads to C5 cleavage and ultimately to the MAC, Membrane Attack Complex formation and cell death. Multiple, you know, breakdown products along the way are also probably very important to AMD pathophysiology. The reason I put together this simplistic slide was to be able to overlay many of the ongoing programs. This is not an exhaustive list, but is pretty comprehensive of most of the programs that have been completed in the past and many of the ongoing programs. You can see there are many shots on goal, if you will. All of these products labeled with the red background and the white letters are molecules that are trying to inhibit pathway at different steps. On top of that, you can see that there are multiple products trying to actually increase the expression of down regulators of the pathway. Very elegant approaches here in many instances. Again, many of these are in human clinical trials currently. Let's not forget that complement is not the only approach to treating geographic atrophy that's being explored currently. There are multiple non-complement targets being explored. Many of these are preclinical, but some of these are also in humans currently. The two that I find may be most interesting here currently are modulating Fas signaling, which is a mediator of cell-mediated cell death. Then the second one here, which is HTRA1 activity. Both of these, I think, are fascinating shots on goal with more data to come in the future. When I look forward in time to our sort of development programs and how we are going to move the ball forward, I'd like to put forward some of my thoughts here. This is predicting a space in the not-too-distant future where we have FDA products to slow the progression of geographic atrophy. Namely, let's take a theoretical future where both avacincaptad and pegcetacoplan are FDA approved for the treatment of geographic atrophy. How are we going to move this space forward at that time? I'll give you my sort of five thoughts here, some of them detailed and some of them bigger picture. Well, the first is to improve efficacy. Now, what do I mean by that? Well, before we define what that means, we need to define what our current generation therapeutics are doing. Remember, we're taking place now in a futuristic world where avacincaptad and pegcetacoplan are FDA approved. In that context, we know that the natural history of geographic atrophy, as indicated by the red lines here, is that the area of geographic atrophy is simply enlarging over time. We have to remember that this is an unforgiving, progressive, irreversible blinding process. In conjunction with that increase in geographic atrophy growth over time, the red trajectory on the top of this graph, there is a parallel, mirror image red trajectory that's going down. That negative slope represents decline in visual function, which becomes extremely obvious when you talk to any patient that has geographic atrophy over time. We'll look at some patient-specific images in a few slides. On this graph, I've put in what's called a severe impairment dotted line. At some point, we get to a point that's severe impairment. Now how are we defining that? Well, that's up to the patient, the physician, and the sponsor designing a trial. Is that foveal involvement? Is that 20/200 or worse visual acuity? Is that counting fingers vision? You could define that in different ways, but the point is that as the area of geographic atrophy gets larger, which it does inexorably in all patients with a certain size lesion or larger, they will eventually develop severe impairment of visual function. The goal of our current therapeutics is going to be to decrease that progression of geographic atrophy area, and that's indicated here by the blue trajectory. That will translate, I believe firmly, into a slowing of the rate at which patients are going to develop visual decline and ultimately delay the time to severe visual impairment. Now, fascinatingly, we as a field are still trying to learn how to best quantify visual function. Is it microperimetry? Is it low luminance visual acuity? Is it reading speed? Is it microperimetry? There's many ways to assess visual function, and we're still learning the best way to assess it globally across the macula. But I think over time, we will be better at quantifying this on a population and an individual basis. Back to the point of this slide, which is I do think next generation therapeutics and geographic atrophy need to emphasize improved efficacy. In other words, can we achieve a greater percentage reduction in the slowing of geographic atrophy? In other words, our current generation therapeutics are gonna reduce geographic atrophy growth by X%, and can we make that percentage larger with new therapeutics over time? The second way that we are going to improve therapeutics over time, I believe, is to improve durability and or improve delivery mechanisms. What I mean by this is, let's say our current generation therapeutics that are FDA-approved again in the near future will be dosed mostly once a month to get maximal efficacy. Over time, can we develop products that are reliably able to be dosed at every eight weeks, at every 12 weeks or three months, and even every six months? Those would be meaningful step forwards for the field. Along that line, can we develop one and done therapeutics, right? We have multiple shots on goal looking at gene therapies that may be able to be a one and done for the treatment of geographic atrophy to slow its progression. These are being looked at by multiple routes of delivery, including intravitreal, subretinal, and then theoretically even suprachoroidal. Also, can we develop a sustained drug delivery system? Can we use cell therapy, cell technology to produce therapeutics inside of the eye that are not gene therapies? I think the answer to all of this is yes, and programs are ongoing. Then finally, from a delivery perspective, for number two here, can we get away from a direct intraocular injection ultimately? Can we develop a pill, drops, a subcutaneous treatment? Obviously, all of these would be beneficial because they would lower the risk profile of an injection inside the eye, it would be easier uptake from a patient perspective, there may be compliance benefits here. Then also for the systemic therapies, you have the value of treating both eyes. Third, how can we move the space forward? Well, this focuses on safety. In particular, I bring this up because I think both of the C3 and C5 inhibition programs that we're looking at currently have an increased rate of exudative AMD development with ongoing therapy. I think this is fascinating. This was unexpected, at the beginning before these trials began to have data. It's clearly consistently being seen in each of these clinical trial programs in each of the different studies. I think we have a long way to go to understand why these eyes are developing exudative AMD. Who are the eyes that are developing exudative AMD? Some develop it, some don't. Are there baseline characteristics that are predisposing to that development? How do we move forward to improve the safety here? Well, maybe most interestingly would be, can we harness this somehow, right? There's a theory that AMD itself may develop because of local hypoxia and breakdown and loss of the choriocapillaris, where you get decreased blood flow to the retina because of loss of the choriocapillaris. Can we harness this development of exudative AMD? For example, there's data now suggesting that if you have non-exudative quiescent type one CNV membranes that are under an intact RPE, that may recapitulate a dysfunctional choriocapillaris and actually bring nutrients to the outer retina that may be helpful. I think that would be challenging, and in the short term, I think is unlikely, but I think we do need to continue to consider that. I think more likely it would be very interesting if there was a way to develop a strategy to avoid the development of exudative AMD with new therapeutics, looking down the road for either C3 or C5 inhibition. Fourth, this is sort of a big, big picture item, but I thought I would put it in here 'cause this is really what patients want, which is, can we get towards a situation where we're not slowing or stopping the progression of geographic atrophy, but can we actually replace damaged or lost or dead tissue? The way I see that moving forward is, of course, some type of cell-based therapy, either regenerative or a paracrine effect, where you, use some type of stem cells to repopulate the lost tissue in geographic atrophy. I think this is possible. Multiple programs are looking at this and are in humans. I think we have a long way to go to understand this and certainly a long way to go before this is clinically viable. The final perspective I would bring from how do we move forward is. Is there an endpoint evolution that we can, use to move this space forward? On the right here, I have listed what I think are most of the approvable endpoints from an FDA regulatory perspective today, vision being paramount. Multiple imaging endpoints, multiple physical exam findings, mobility testing have all been used from an FDA perspective or are currently in phase III clinical trials and anticipated to lead to approval, hopefully in the near future. It's clear the FDA is willing to take imaging-based biomarkers, and I think the field needs to move forward with really validating and then hopefully utilizing the EZ area or the ellipsoid zone area as a potentially approvable endpoint as we expand our clinical trial programs in AMD, potentially the earlier stages of the disease than frank geographic atrophy. Let's get into our last chapter here, which is the patient perspective and what I think clinical adoption is going to look like as we have new FDA-approved therapeutics coming. Again, hopefully both pegcetacoplan and Avacincaptad. We must always come back to the patient in these discussions. Here are a couple images of patients of mine that I have treated for many years, both of them actually with wet macular degeneration as well as macular atrophy or geographic atrophy. Both of them 100 and 103, respectively, right? We have many, many patients that are elderly that are suffering from geographic atrophy. It's important to put the faces with the numbers. At the bottom here, this is a patient of mine that was really completely asymptomatic in 2010. Then by 2019, as you can see on these near-infrared images, had extensive geographic atrophy enveloping most of their macula. They could no longer read a book, they couldn't write checks, they couldn't drive. Of interest, they were still 20/20 at each of these time points. This is the challenge with geographic atrophy. There is a problem where you get foveal sparing in many cases, but significant visual dysfunction. It's this sort of disconnect between best-corrected visual acuity and visual decline that again, we are still struggling with as a field to how best to quantify visual decline in these patients. 'Cause there's no question that the eye on the right here with significant geographic atrophy is much more impaired than the eye on the left, but the absolute normal luminance visual acuity is exactly the same. We know on average that these patients will lose about one line of visual acuity each year that we follow them. Here's data from the Proxima AMD datasets. This is published prospective observational natural history data from multiple different cohorts of patients with geographic atrophy of different sizes. This has been reproduced in multiple datasets over time that on average, patients lose about one line of visual acuity annually, until they are at approximately the 2,200 to 2,400 range, where they often will stabilize the geographic atrophy. The correlation here with functional decline is striking. This is probably one of the best papers that addresses this. This is from Usha Chakravarthy out of the United Kingdom, looking at patients with bilateral geographic atrophy at presentation. What she showed was, again, a loss of about one line of visual acuity each year cumulatively, such that over two years, patients lost about 10 letters of visual acuity. Then from a functional perspective, within that two-year timeframe, about 2/3 of patients had lost the ability to legally drive, one of the real markers of independence in our often car-based society across the United States. My last slide here, clinical adoption. What is this going to look like when we have agents that can be used monthly and maybe every other month with pegcetacoplan, depending on what that FDA-approved package insert looks like? Again, assuming these get FDA approved, which is again, an assumption still at this point. All right, who are the patients that are going to be treated? Right, we've heard a lot of discussion of fovea versus non-foveal lesions. What's interesting if you look at the data is that clearly patients with non-foveal lesions, so geographic atrophy that has not involved the center point of the fovea, those lesions tend to have a more rapid progression as a natural history background. If you have a medication that slows progression, you're naturally going to see a greater reduction in the progression among eyes that naturally have a faster rate of progression. That's why the percentages overall, when you look at non-foveal eyes, in both the pegcetacoplan population, that subpopulation with non-foveal eyes, as well as the avacincaptad population, which is all non-foveal eyes, you see a greater reduction in geographic atrophy progression than you do when you look at eyes with foveal involvement. That's a critical sort of key understanding of why we're seeing those differences. It might be natural to think, well, we're going to use this in patients with non-foveal involved geographic atrophy. That does make sense because you're going to get the greatest benefit for slowing geographic atrophy among those patients. The challenge is there are many, many, many patients with foveal involvement who are still noticing visual decline. Literally, these patients will tell you every day, every week, every month, it's getting worse. I think it's a little bit overly simplistic to think that we're only going to treat non-foveal patients. If the package insert allows foveal involvement and the payers reimburse for it, I do think there will be a lot of patients with foveal involvement that do want to receive treatment. In fact, I think this is going to be a patient selection process, not really a doctor selection process. Some patients are going to think, "Yeah, I want to get treated." I think essentially all patients with geographic atrophy will be interested in hearing about what it means to be treated, and I think many will want to initiate therapy. This is a blinding, irreversible disease. The challenge is, of course, not going to be to get patients interested. It's going to be long-term adherence, right? Because the challenge is both of these products are going to slow the development of geographic atrophy, I believe, but are not going to stop it. At least with 18-month data that we have now from the OAKS and DERBY program as well as the GATHER1 program. We are clearly consistently slowing the progression through 18 months, but we're not stopping it yet at that point. Patients are going to continue to notice visual decline, but hopefully at a slower rate than they would if they were not being treated. It's going to take a lot of patient education to maximize long-term adherence. Again, it's going to take us as a field to really kind of begin to understand how to quantify these correlations between anatomy and function in a way that patients can understand that and believe that they are receiving benefit, which I think they will. The very last point I would like to make is that I think as our field looks forward, we will and need to continue to think about ways to move earlier in this disease process, right? Many of the therapeutics in late-stage human clinical trials now, and most of them in early-stage trials, are still focused on eyes with frank areas of geographic atrophy. How do we shift earlier, right? We really need to better understand the early pathophysiologic changes from drusen to early areas of geographic atrophy, and where can we intervene to slow that progression or even stop that progression. To do that, we need to better understand phenotypes such as iRORA and then early geographic atrophy with cRORA and that transition. We need better natural history data. Also, we need to continue to prioritize an understanding of how these different phenotypes correlate with visual function and visual function decline over time. With that, thank you for your attention. I hope that was helpful. It's an incredibly exciting time in this space. We've learned a tremendous amount over the last 10 years, and we still have a long way to go for the benefit of our patients. There are many exciting programs that are going to have data over the next many months to years. In particular, in the fall, I look forward to the NGM621 data and the well-designed, very large phase II CATALINA program. It'll be very interesting to see how that inhibitor of C3 cleavage may be able to differentiate itself in this space. With that, I'm going to pass this back over to Erin Henry. I'd be happy to engage any questions about any of this stuff that I've talked about later in the program. Thank you. NGM621 is an exciting investigational molecule, and it's all the more exciting to evaluate its potential to treat GA after having seen other complement inhibitor programs demonstrate proof of concept efficacy. It feels like we're on the cusp of having treatment options available for patients. Yet the data available to date from the other programs still leaves an opportunity for NGM621 to show improvements upon the outcomes we've seen. We have multiple opportunities for potential differentiation that we are exploring in the CATALINA phase II study, and these could include reductions in the rate of GA lesion enlargement, extended dosing, and a better safety profile, one where perhaps we don't see the convergence to wet AMD and choroidal neovascularization. When it is available, our phase II data will speak for itself. Based on the results of our preclinical studies, we believe NGM621 may have certain favorable attributes that could translate to better clinical results. The preclinical data I'm showing here, it's part of what makes me so excited about NGM621's potential. These are the results from our preclinical hemolysis experiments designed to quantify the inhibitory concentration of drug needed to reduce or eliminate complement activity via either the classical or the alternative pathway activation. This is represented as a percentage of hemolysis on the Y-axis, essentially complement-mediated cell membrane rupture. On the x-axis, we plot drug concentration. NGM621 inhibits complement-driven hemolysis more potently than APL-1, a Compstatin-derived cyclic peptide targeting C3 that we made in-house at NGM for the purpose of exploring preclinical comparability. We do not believe that pegylation impacts binding, and since APL-1 and APL-2 have the same binding site, APL-1 is a reasonable comparator for this assay. Comparing NGM621 to APL-1, we see smaller IC50s for NGM621, showing it is approximately 100-fold greater potency to inhibit classical or alternative complement activity. This means that in the study, less NGM621 was needed to inhibit complement activity, and we believe this may translate to an advantage clinically. In preclinical experiments, we also compared NGM621's affinity for C3 and C3b to that of the Compstatin derivative cyclic peptide targeting C3. We found high-affinity binding of NGM621 to both C3 and C3b. In comparative binding assays, we see that NGM621 binds much better to C3 than the cyclic peptide did. The affinity to C3b is similar for both these molecules. We believe that intravitreal-administered NGM621 should be able to neutralize all C3 and C3b present in GA patient eyes, and the clinical translation is being explored in the ongoing CATALINA phase II study. Our collaborators at Merck helped us to model the expected durability of NGM621 post-intravitreal injection. Using an ocular pharmacokinetic pharmacodynamic model. Assuming a dose of 15 mg given intravitreal, the model predicts that there will be a greater than 90% target engagement with C3 in the eye for a duration of approximately 60 days. In other words, this model supports a dosing interval of up to eight weeks, which is what we're exploring in the ongoing CATALINA trial, along with every four-week dosing. We also believe that NGM621, which is a monoclonal antibody, may lead to less choroidal neovascularization development than what has been seen in other investigational complement inhibitor studies as a result of its lack of pegylation. This belief is driven by the results of the experiment shown below, which is a rodent model of CNV, where laser is used to induce neovascularization and vascular leakage. When you administer an anti-C3 monoclonal antibody, you see a reduction in vascular leakage and angiogenesis as compared to control. This is shown in the lower left panels. Conversely, on the right side, you see that in the same model, injecting 40 kDa of PEG, not associated with any targeting molecule, just the PEG by itself, elicits an exacerbation of the vascular leakage and angiogenesis, suggesting that PEG alone may enhance the damage. While we do not know how this might translate into the safety in our clinical trials, it suggests that treating GA with an unpegylated complement inhibitor like NGM621 may reduce the risk of CNV development. One of the potential benefits of using a monoclonal antibody for retinal therapy is that its size provides favorable ocular pharmacokinetics, allowing it to remain in the eye for weeks after intravitreal injection. The size of the molecule doesn't prevent penetration through the retina to the photoreceptors, retinal pigment epithelium, Bruch's membrane, as well as choriocapillaris and choroid. This is elegantly demonstrated in the figure of bevacizumab immunostaining after intravitreal injection in a non-human primate. We see that bevacizumab labeled as the red or pink areas on these retinal cross-sections. The bottom of the images are the inner retinal layers closer to the front of the eye, and the upper part of the images are the outer retinal layers, including the RPE and choroid. As early as day one, bevacizumab can be seen in the photoreceptor outer segments, RPE, and choroid. The concentration of bevacizumab increases over time, demonstrating clear retinal penetration and transport to the outer retinal and subretinal structures. This is one of the many reasons why we believe antibodies are a smart molecule framework for retinal therapies, along with their relatively good safety profiles. In summary, we believe NGM621 is potentially an optimized complement inhibitor for the treatment of GA. It has selective high-affinity binding for both C3 and C3b. It has favorable biophysical properties like high solubility, relatively low viscosity, and excellent long-term stability. As an antibody, we believe NGM621 will be well-tolerated in the eye and will fully penetrate the retina to reach the target tissue. We look forward to seeing how these unique attributes will translate into clinical trial outcomes. The NGM621 development program is rapidly advancing. We completed our phase I safety and tolerability of single and multiple injections of NGM621 in 2020, showing that NGM621 was well-tolerated at all dose levels evaluated with no drug-related adverse events, no serious adverse events. Safety looked really encouraging in this first in-human study with no ocular safety signals, no CNV, no endophthalmitis, no inflammation. Those results paved the way for us to bring forward the 15-mg NGM621 dose into the ongoing proof of concept phase II-B study called CATALINA, which is fully enrolled in 65 U.S. sites. Also of note, we received Fast Track designation from the FDA for NGM621 in February, giving us additional access to FDA for advice on our development program planning. To provide more details on the ongoing CATALINA study, CATALINA is a multicenter, double-masked, phase II study in which 320 patients were randomly assigned two to one to intravitreal NGM621 or sham with dosing every four or eight weeks. The efficacy and safety will be assessed after 52 weeks, and the final study visit is week 56. Our primary endpoint is evaluating the rate of change in GA lesion area as measured by fundus autofluorescence over 52 weeks of treatment. We have engaged the FDA multiple times on our primary analysis approach, and we are following their guidance and will be performing a slope analysis over the three GA area time points collected. Enrollment completed in July 2021, and we look forward to the results being available in the fourth quarter of 2022. It has been heartening to see the commitment of our study sites, investigators, and patients that have managed through the COVID pandemic to help us evaluate the potential of NGM621. In particular, we see really good dosing compliance, well over 90%, for patients who have already completed the study as well as for those that are still on study. We know this adherence to protocol takes effort and commitment for all involved, and we are hopeful that NGM621 will show the differentiation clinically that the data have suggested preclinically. We look forward to sharing those results with you later this year. Thank you so much, and I'll be happy to take your questions during our Q&A session. Thank you, Erin, and thank you for joining us today to learn more about NGM621 for the treatment of geographic atrophy. My name is Siobhan Nolan Mangini, and I'm NGM's Chief Financial Officer. I'm looking forward to giving you an overview of the opportunity we have for NGM621, given the substantial unmet need in geographic atrophy, and to also highlight key features and economic terms of our collaboration with Merck as it relates to the program. We think there's an opportunity for NGM621 to be a leading geographic atrophy therapy that can truly transform the lives of many patients who are impacted by the effects of this debilitating disease, which has no approved therapies today. I'm excited to share with you the important elements that we think may drive that outcome. First, I will touch on our partnership with Merck for this program. Merck and NGM have had a long and positive history working together, with our collaboration dating back nearly seven years to 2015. From 2015 to 2021, NGM received $75 million a year in R&D reimbursement from Merck in exchange for the rights to the output of our discovery engine in the form of a license to option at clinical proof of concept. For the first six years of the collaboration, we could work in any therapeutic area that we chose. To date, we have received over $500 million in R&D funding from Merck as part of this relationship, and we've generated many of the programs that we've discussed in the Explorer Series. In 2018, Merck optioned a program that was part of this collaboration, NGM313, which is now called MK-3655 for NASH, which David mentioned earlier is currently in a global phase II-B study for F2 and F3 NASH patients. In 2021, NGM and Merck worked together to restructure the agreement to address both companies' evolving objectives. We focused our collaboration work on ophthalmology, which I will dive in more detail about shortly, as well as early-stage cardiovascular metabolic disease target discovery with a focus on heart failure. At NGM, our primary focus was to regain full rights to our oncology portfolio, an area where clinical development suits our scale and corporate strategy. The revised agreement achieved those objectives. Most relevant for today's Explorer Series is Merck's option to license NGM621. In our partnership with Merck, we have a clear focus on ophthalmology, as it has the potential to be a new therapeutic area for Merck, and our discovery engine is working to produce a portfolio of molecules available to them. NGM621 is our lead ophthalmology asset, and Merck has an option to license the program after CATALINA data expected in the fourth quarter of 2022, as well as to also license two undisclosed preclinical retinal programs at the same time. We're excited to have Merck as a partner, particularly for a large opportunity like GA. Both companies share a deep science-driven philosophy to drug development that allows the two companies to complement each other's strengths for the benefit of the program. In fact, for NGM621, we've been working closely together across a variety of functions to anticipate the potential handoff from our organization to theirs for late-stage development and commercialization that could be enabled by CATALINA data if Merck exercises its option. I'll describe the general structure of the option, and you can find details in our SEC filings. Following CATALINA top-line data readout in the fourth quarter of this year, Merck will have roughly one quarter to make their option decision for an exclusive worldwide license to NGM621 for an upfront $20 million option fee. If Merck chooses, NGM621 bundled with the two undisclosed preclinical retinal programs for up to $45 million option fee. As you can see in more detail on this slide, if Merck does option NGM621, NGM will have an option around the time of Merck's completion of their phase III design to either participate in a 50/50 development cost profit split, with Merck advancing up to 25% of the cost to be repaid with any future profits at 8% annual interest, or an option to decide not to co-fund development and instead receive development and commercialization milestones and tiered low double-digit to mid-teen royalties on worldwide net sales. Additionally, NGM has co-detail option in the United States that we may elect prior to the U.S. commercial launch independent of our co-profit or milestone and royalty option. Given the significant unmet need for geographic atrophy, we are thrilled to potentially have the opportunity to work with one of the world's premier pharma companies to help bring a differentiated therapy to patients and hopefully beneficially impact the lives of the millions of people who have geographic atrophy. Today, there are over 5 million people globally and over 1 million patients in the United States facing this debilitating disease with possible irreversible loss of vision. Due to the aging population of the world, the incidence of advanced AMD in North America is anticipated to grow and nearly double in the next 20 years. At NGM, we have tremendous conviction around NGM621's potential. While we've seen exciting developments in the GA space in recent years, with certain complement inhibition therapies demonstrating proof of concept, we also believe that the results thus far leave ample room for NGM621 to demonstrate an improved overall profile, including the three areas that Erin highlighted. We think that the evolution of the wet AMD treatment landscape over the past 20 years offers an instructive case study of how we may be able to successfully bring a differentiated therapy to patients, even if it's not the first approved product for GA. Delivering therapies to wet AMD patients began with the approval in 2000 of Visudyne. The adoption of Visudyne was limited, likely due to limited efficacy, complications of administration, and notably 4.4% of patients experiencing a severe decrease in vision. The first Anti-VEGF was then approved in 2004. Macugen, developed by Eyetech, was the first anti-VEGF that offered some efficacy improvements as well as improved safety compared to Visudyne. What really shifted the paradigm for the treatment of wet AMD was the approval of Genentech's Lucentis in 2006, also an anti-VEGF, but one for the first time that pushed efficacy even further by demonstrating vision gains as well as further improving the safety profile. Finally, five years later, Eylea, another anti-VEGF therapy developed by Regeneron, was approved and launched for patients with wet AMD. Prior to approval, Eylea's sponsor ran a head-to-head study with Lucentis. This study demonstrated what became a critical differentiator between the programs. Whereas Lucentis was approved as a once-monthly intravitreal injection, the head-to-head study showed that at every four weeks, as well as at every eight weeks, Eylea had nearly the same efficacy related to vision for its primary endpoint, which enabled less frequent dosing and fewer injections for patients. This differentiation was further enhanced with modest secondary outcome advantages. All of this led to a telling evolution of the wet AMD field. Here we have a graph depicting revenues over the past 20 years from each of the four FDA-approved therapies for wet AMD that I just discussed. Revenues are depicted in millions. As you can see, Visudyne and Macugen both had limited uptake. When Lucentis launched for wet AMD patients in 2006, it saw very quick uptake due to its superior efficacy and safety. However, once Eylea was approved and launched in 2011, as a reminder, with its primary differentiation around convenience of dosing frequency, we find it fascinating to see how quickly retina specialists were to adopt Eylea, and ultimately, Eylea uptake surpassed Lucentis' after three years. Eylea grew the overall treated wet AMD patient population that it served as well. Geographic atrophy is an enormous problem, and we believe that there can be multiple therapies which succeed in treating patients with the disease. However, we share this case study as an example of how overall product profile, not timing of market entry, ultimately dictates category leadership. We think if we can demonstrate areas of differentiation in efficacy, frequency administration, or safety, NGM621 could be adopted by patients and providers quickly. At NGM, we believe NGM621 has the potential to be a powerful therapy for geographic atrophy patients. As you heard from both Mark and Erin today, our approach is to target complement C3 specifically and block its activity with a high-affinity antibody. We are the only therapy in the clinic with a monoclonal antibody inhibiting complement C3, and we believe this may allow NGM621 to demonstrate improved efficacy. Additionally, by virtue of NGM621 being an antibody, we think that NGM621 has the potential for every other month rather than monthly dosing based on PK modeling we've done in collaboration with Merck. With intravitreal injections, this would be a significant advantage for both patients and providers, as demonstrated in the wet AMD case study I just shared. We also hope to see lower levels of CNV conversion based off our preclinical modeling by virtue of the fact that NGM621 is not pegylated. We believe that this could also provide us with safety differentiation, and with that feature alone could be a meaningful reason why retina specialists might prefer NGM621. Finally, as I shared with you today, if Merck options NGM621, we would have a large pharma partner to support us in the development of a new treatment for geographic atrophy. We believe that a partner can really help us with some of the heavy lifting required to establish new therapies in a new field. In particular, we believe that this can help us set a foundation to partner closely with the motivated and highly evidence-driven retina specialist prescriber base. 2022 is poised to be an event-filled year for us at NGM, with multiple catalysts on deck across our deep pipeline of clinical stage assets. We expect to share new data from three of our programs in the second half of 2022. Top-line data from our phase II study with NGM621 in geographic atrophy and interim phase I clinical data from two of our oncology programs, NGM707 and NGM120. We've already advanced two of our immuno-oncology programs into the clinic, NGM831 and NGM438, earlier this year, and we completed enrollment in Alpine 4, our phase II-B trial with aldafermin in cirrhotic NASH to tee us up for data in the first half of next year with that program. All this while Merck continues to make progress advancing MK-3655 through phase II-B development in non-cirrhotic NASH. We look forward to sharing these updates with you as we continue to drive our pipeline of therapeutic candidates forward with the goal of providing meaningful therapeutics for the benefit of patients. With that, thank you for joining us for our fourth and final Explorer Series at NGM. As a reminder, in the first segment of this series, we shared with you details behind our discovery engine that has produced our entire pipeline from scratch. In the second episode, we gave an introduction to two of our myeloid reprogramming portfolio programs, NGM831 and NGM438, that we think can demonstrate the power of overcoming stromal checkpoints that underpin immune resistance in certain solid tumors. Our third Explorer Series focused on NGM707, our ILT2 ILT4 dual antagonist antibody, and our most advanced myeloid reprogramming candidate. If you didn't have a chance to catch those earlier segments, replays are available on our website. Given the depth and breadth of our pipeline, we hope that these R&D Day modules serve as a resource to learn more about NGM and our diverse pipeline. While this is the final session in our Explorer Series, we look forward to seeing you back here again in the future to discuss new discoveries we are working on at NGM Bio as explorers on the frontier of life-changing science. Thank you. With that, I'd like to open up our Q&A session. Good morning, and thank you again for joining us today for the fourth and final session of our Explorer series. This is Brian Schoelkopf, Head of Investor Relations at NGM Bio. In the room with me are David Woodhouse, our CEO; Siobhan Nolan Mangini, our CFO; Erin Henry, Head of Ophthalmology; and Mark Soloway, Principal Scientist, Biology, and Research Lead for NGM621. Joining us on the phone today is Dr. Charles Wykoff, Director of Research at Retina Consultants of Texas and Chairman of Research for the Retina Consultants of America. I invite you to submit your questions through the Q&A box in the webcast platform at this time. We'll start with a question from Mayank Mamtani at B. Riley. A two-part question. First part is, what have you heard from ophthalmologists regarding their desire to adopt new GA therapies? How do they view clinical meaningfulness of a therapy in GA for their patients recognizing the incremental risks? Great. Thanks for the question, Mayank. It's David Woodhouse here. Yeah, we've been doing quite a bit of work understanding that. I'll let Erin start on describing some of that work, but then, I think it'll be interesting to hear Dr. Wykoff's thoughts on that as well. Hi. Yeah. In terms of what we've done, I would say both anecdotally as well as with some of our recent market research, we hear high enthusiasm for the potential of a GA therapy. There is an acknowledgment of the high unmet need and the fact that this is very difficult right now to manage patients where there isn't any sort of effective therapy to provide to them. We see this in the enthusiasm for clinical trials right now, as well as in our qualitative market research. You just hear this desire for anything, and certainly the more effective, the better. Really more than anything, needing options and tools in their armamentarium to treat this disease. Dr. Wykoff, do you want to comment on that as well? Yeah, absolutely. Thank you. I completely support Erin's great points here. I think we as physicians really are looking for some option to treat patients with. I would say a high enthusiasm, certainly. I mean, there are so many patients. You saw the numbers. I think that that's overall an underrepresentation of the true potential value here for patients across the U.S. There are a lot of patients that are asking for something, quote, anything for patients. I also echo the point, you know, more efficacious is better. What does that mean? Where do you draw those lines? It's hard to know. I think the phase II and the phase III trials that we've seen so far are sufficient to make a meaningful impact clinically, and anything building on that would be even better. There's high enthusiasm across the space for therapeutics for GA. Great. Thank you, Dr. Wykoff. The second part of the question here, based on your ongoing strategic collaboration, if Merck decides to opt-in for NGM621, how might procedural decisions be made regarding phase III program scope, design, et cetera? What's the level of strategic involvement we would anticipate to have from NGM and Merck's long-term aspiration in this relatively new therapeutic category for the larger biopharma? Sure. Yeah. I'll let Siobhan address these questions. I think just generally, we're really pleased with the collaboration with Merck, particularly in this area, and we've been working very close together. Siobhan, why don't you expand on that in addressing the question? Absolutely. Sure. Maybe just a reminder, you know, we've been working with Merck for over seven years now, and we've actually done this before. You know, NGM has acted as a sponsor going into new therapeutic areas. I mentioned in my prepared remarks, there's MK-3655. It's in a global phase II-B study for NASH. That was a new therapeutic area. I think we've learned a lot in terms of how we can work together and what best practices are in these handoffs. Currently, in the run-up to phase III, NGM's taking the lead on things like, CMC manufacturing. That being said, Merck is working side by side, coming to site visits with us, so that we can try to have as quick of a handoff as possible if Merck were to option. If Merck does option NGM621, they do have a worldwide license for the program. They're gonna drive development for the program, and we think that's a positive given the size of the opportunity to have their late-stage expertise. As I shared, NGM does have an option for up to 50/50 cost profit split or the milestone and royalty split. We feel really fortunate to have such a great pharma partner for this, potential development of this program, given the large unmet need. Great. Thanks, Siobhan. We'll now move to a question from Paul Choi at Goldman Sachs, and this question is for Dr. Wykoff. With DERBY and OAKS results now out, what would you consider a good result for NGM621 in the CATALINA trial? Yeah. Thanks, Brian. I'll turn it over to you. Oh, thanks. Appreciate that. Yeah. You know, the way I interpret DERBY/OAKS is that this is strong, positive proof of concept that inhibiting C3 is going to have a meaningful impact. Building on that, of course, I think the entire community would like to see NGM621 differentiate in some way. You heard some great discussion here today from all the presentations about how that might manifest. From a clinically relevant perspective, that could take one of three forms, either more efficacious, second would be improved safety, and third would be increased durability. All of those could be meaningful contributions in a clinical world where there is one or two previous anti-C3 or anti-C5 agents available. Just to take one of those in a little more detail, let's talk about safety. You know, when we first saw the phase II FILLY data with pegcetacoplan, no one expected there to be an increased rate of accelerated AMD development. We've now seen that across both of the late-stage programs out there. Why are we seeing this? We're still a little unclear. I think we're gonna learn a lot with the CATALINA data, why we might be seeing this. For example, if CATALINA were to show a meaningfully reduced rate of CNV development, I think that would be a meaningful step forward. I think differentiation in any of those three categories would be useful. It's not to say that all of them look the same, that it couldn't still be a useful drug. I think we've learned a lot in the past about how comparing efficacy and safety between clinical trials is useful, but you only really learn how a drug is gonna perform once it's out in the real world. We still, of course, don't have that for any GA drug. Great. Thank you, Dr. Wykoff. The next question here: Have you done analysis on NGM621's ability to traffic to the back of the eye similar to what you showed for Avastin? If so, what did the analysis show? It would be great to hear Dr. Wykoff's perspective on the ability of mAb to traffic to target tissue as well. Great. Yeah. The short answer is yes. I'll let Mark describe that, and then Mark, why don't you hand it over to Dr. Wykoff to give his thoughts as well? Yeah. Yes. The answer to the question is yes, we have run similar biodistribution studies in non-human primates. We like the Avastin example because of the temporal nature of that analysis. But we have done similar studies and see the expected biodistribution in various tissues, including the retina. Additionally, the study was run in healthy animals, and it's thought that in disease, that will only increase the access of these tissues to therapeutics. Charlie? Yeah. Certainly no concern from my perspective. I think clinicians in general that a monoclonal antibody can very adequately and meaningfully penetrate the entire full thickness of the retina and then get into the choroid. We've obviously seen that clinically with bevacizumab as shown in the images, but more importantly clinically for the last 15 years. Also with aflibercept and faricimab, which are monoclonal antibodies or monoclonal-like antibody structures that obviously do extremely well clinically, and we know penetrate the entire retina and choroid. Really no concern from my perspective about full penetration of NGM621. Great. Thanks, Dr. Wykoff. The next question here is from Anvita Gupta at Cowen on for Boris. Could you provide some color on why the top line results from CATALINA are in the fourth quarter this year when the enrollment completed in July of 2021? Sure. Thanks for the question, Anvita. The answer's pretty simple. While the treatment period for the trial is 52 weeks, there's a four-week safety follow-up off drug. Given the fact that this trial may be considered a pivotal trial, we wanted to make sure to maintain the integrity of the trial. When you add that up with database lock, it takes us into the fourth quarter. Great. Next question here. You showed APL-1 in the binding assay. How does that compare to APL-2? Would you expect any difference in the outcomes? Yeah. We worked with APL-1. We've our understanding is that's the active moiety that binds C3. APL-2 is a PEG-modified version of APL-1. We didn't manufacture APL-2, but we think the binding is basically the same. Great. Thanks. The next question here from Swapnil Malekar at Piper Sandler. What are the factors that NGM is considering when deciding between a 50/50 partnership with Merck or opting for the royalty and milestone structure? That's the first part of the question. Yeah. Siobhan, why don't you weigh in on this one? Obviously, we need to sort of see the complete package, what the CATALINA data and, then what the phase III design looks like, which is an advantage we'll be able to see all of that before we have to make that decision. Siobhan, you might wanna touch on some of the financing mechanisms embedded in the deal that I think are helpful. Absolutely. Yeah, just building on what David was sharing, I think, you know, it is a compelling investment. We're a very data-driven company, though, and we're gonna wanna see our results and understand the differentiation that we were just talking about, and then ultimately what the costs are for development and then run our analysis. I think one thing that is important in the 50/50 is that up to half of that, so 25% of the full cost of development can be financed by Merck and paid for in future profits at an 8% interest rate. Really what we're thinking about is the initial cash outlay of potentially 25% of the cost, and then ultimately gaining 50/50 on the other side. Ultimately, we wanna see the data and then make a decision from there. Great. Thank you, Siobhan. The next part of Swapnil's question: What lessons have you learned from previous trials from programs targeting complement to the treatment of GA? Yeah. I think there's a lot to be learned. As Erin introduced in her opening comments, she actually worked on the lampalizumab trial, but she's obviously familiar with a whole bunch of different trials in this area. I think we've been benefiting from learning from that. Erin, do you wanna expand? Sure. I mean, I think that the field has learned from all of the efforts to date, but recently, you know, when we think about complement inhibition and try and hone in on the most appropriate approach, I think being at NGM, one of the things that really was enticing to me was the idea of working on a C3 inhibitor because I think there is concern about whether or not selective inhibition of just part of the complement pathway is sufficient. You know, what we've seen from the recent DERBY and OAKS study is, I think, proof of concept on that. I think that NGM621 being able to inhibit at that first point of kind of convergence of the three pathways and being able to prevent any of those downstream effects is one of the things that may set it apart. You know, the other thing we've learned through all of these trial programs is that there is high interest in participation. It really speaks to the unmet need. You know, we have to acknowledge that CATALINA was going on in the middle of a pandemic, and yet we saw really strong enrollment and compliance to date from patients. It really speaks to you know how desperate they are for treatment options and being part of the research process until there is you know potentially commercially available therapies. All of those are things that I think are reinforcing that we're on the right path and that this research is really important to both clinicians and the patients. Great. Thank you, Erin. Then the last question here from Steve Seedhouse at Raymond James. Do you have any data or modeling specific to NGM621 that suggests its bioavailability will be sufficient for GA treatment? Yeah, thanks for the question, Steve. I'd point to two things. One is, you know, we've shared our PK/PD modeling that we did with Merck coming out of our phase I trial, that was effectively measuring in our phase I patients peripheral amounts of NGM621, so the 621 that leaks from the eye into the periphery, and then comparing that to our non-human primate studies where we had both intravitreal and systemic measurements. And so we think that's pretty good evidence of what we can tie together in humans. You tie that together with our data that Mark was just referencing as it relates to our non-human primate studies of where does the antibody go in the eye. The fact that we, while we don't have as pretty pictures as was shown with Avastin, we do measure the drug in those different regions, and that demonstrates that the antibody can get where it needs. Now, what we don't have in this disease is a good preclinical model. That's sort of the missing piece, and that's why CATALINA and the clinical data will be important to confirm all of that is translating. Great. Thanks, David. Thank you again to Dr. Wykoff for joining us today. With that, we will conclude the Q&A session in the final module of our Explorer Series. Thank you, and have a great day.