Hello, welcome to Annexon's conference call. At this time, all participants are in a listen-only mode. There will be a question and answer session after the prepared remarks. Please be advised that this call is being recorded at Annexon's request. I would now like to turn the call over to Jennifer Lew, Chief Financial Officer. You may begin. Thank you, good afternoon. Yesterday, we issued a press release outlining results from our ARCHER phase II clinical trial, evaluating ANX007 in patients with geographic atrophy, that were presented during an oral presentation at the ASRS 2023 annual meeting. The press release, podium presentation, and slides used for this conference call are available under the Events and Presentations page within the Investor section of our website. Today's discussion will include forward-looking statements related to Annexon's current plans and expectations, which are subject to certain risks and uncertainties. Actual results may differ materially due to various important factors, including those described in the Risk Factors section of our most recent Form 10-Q and other SEC filings. These forward-looking statements represent our views as of this call and should not be relied upon as representing our views as of any subsequent date. We undertake no obligation to publicly update these statements. Now let me turn the call over to Annexon's CEO, Doug Love. Thank you, Jen. Thank you all for joining us today. On the heels of the top-line ARCHER results that we shared in May, we presented these phase II data for the first time at a medical meeting, ASRS, this past weekend in Seattle. The data presented included additional analysis supporting ANX007's protection against vision loss in patients with geographic atrophy, and we're excited to share the data more broadly today. Joining me on the call is our Chief Innovation Officer, Dr. Ted Yednock, who will walk us through anti-C1q's neuroprotective mechanism of action in GA. Importantly, and distinct from downstream complement approaches, our upstream approach is designed to preserve the function of photoreceptor synapses and cells to protect against vision loss. Our Vice President and Head of Ophthalmology, Dr. Donald Fong is also joining us to provide an overview of ARCHER, including the study's endpoints, patient demographics, and ANX007's well-designed drug candidate properties. Finally, we are delighted to be joined by Dr. Jeff Heier, the Director of Retinal Service and Retinal Research at Ophthalmic Consultants of Boston and an investigator in the ARCHER study. Dr. Heier will review ARCHER's efficacy and safety data, including the trial's protection against vision loss, as demonstrated by several analyses. At the end, we will open the call for Q&A with Dr. Heier and our team. As many of you know, at Annexon, our bold mission is to free the body, the brain, and the eye from complement-mediated diseases. Indeed, our aim is to enable every person impacted by complement-mediated diseases to live out their dreams and talents without being robbed of their physical and cognitive health due to disease. To do so, we're sharply focused on stopping classical complement's aggressive inflammatory cascade, where it starts on diseased tissue, to provide the most complete protection against harmful classical pathway inflammation and resulting functional loss. Our steadfast pursuit of our mission has led us here today to discuss the promising results from our GA program. As described on slide 5, our broad portfolio was built on the understanding that not all complement inhibitors are the same, and that upstream C1q inhibition can drive powerful functional benefits. This differentiated approach has now been demonstrated in the clinic, with robust functional improvement shown in Guillain-Barré syndrome, Huntington's disease, and now geographic atrophy, and puts us on the path to potentially helping millions of patients through our programs. While the focus today is on our GA program, we have multiple additional value-creating catalysts expected across our broad complement portfolio throughout the remainder of 2023 and into 2024, which are shown on slide 6. More to come on these readouts, but needless to say, we're quite encouraged by the data we've generated to date, clinically and pre-clinically, in support of each of these programs. Before I turn the call over to the team to review the ARCHER trial, I want to quickly highlight the key learnings from our in-depth analysis of the study. As outlined on slide 7, there are four key takeaways from ARCHER. First, the findings support our founding neuroprotective hypothesis that blocking C1q to preserve photoreceptor synapses and cells to protect vision loss is quite distinct from inhibiting downstream complement, such as C3 and C5. Second, ARCHER is the first study to demonstrate consistent visual function benefit in GA. With ANX007 treatment, there was statistically significant dose and time-dependent protection against vision loss on 2 pre-specified clinical measures, BCVA and LLVD. BCVA is a well-established endpoint to assess visual acuity and will be important for future development. These findings are strengthened by a host of related analyses, adding breadth and depth to the veracity of the vision protection data demonstrated in the general GA population. Third, while the primary endpoint of rate of lesion growth did not reach statistical significance, evaluating the first and second 6 months of treatment showed greater effect on lesion size with time. This suggests that lesion growth may slow with longer than 12 months treatment with ANX007. Finally, ANX007 was generally well-tolerated as monthly and every other month treatment through 12 months, with no increase in CNV rates between the treated arms and sham, and no reported cases of retinal vasculitis. As you know, GA is a devastating disease of aging that greatly limits a person's ability to read, perform activities of daily living, and even to see the faces of their loved ones. To be clear, protecting against vision loss for patients with GA is our seminal goal, and it is of the utmost importance for healthcare professionals and patients. Based on the strength of ARCHER's data, we believe that ANX007 has the potential to be a new and distinct treatment option for patients with GA, marking an important step toward achieving our mission of delivering game-changing therapies to patients living with classical complement-mediated diseases. We look forward to discussing next steps for ANX007 with regulators later this year. We'll update after we've done so. With that, I'll turn the call over to Ted to walk us through our anti-C1Q neuroprotective mechanism of action. Ted? Thank you, Doug. Turning to slide 9, Annexon was founded based on the work of Dr. Ben Barres, the former Chair of Neurobiology at Stanford. Dr. Barres made the discovery that C1Q, the initiating molecule of the classical complement cascade, recognizes synapses in neurodegenerative disease, triggering aberrant synapse removal. This pathway causes neuroinflammation and damage to become a key driver in the neurodegenerative process and was the founding technology of Annexon over a decade ago. Dr. Barres' work spawned an entire field that has been validated in multiple laboratories and neurodegenerative models, including neurodegenerative diseases of the eye, brain, as well as acute brain injury. A consistent finding in these studies is that synapses loss, synapse loss precedes loss of neurons and correlates with functional decline. Protecting synapses with anti-C1q is a novel neuroprotective approach that starts by protecting function. Slide 10 describes C1Q and the role of the classical cascade in neurodegeneration. The left diagram shows how C1Q triggers activation of downstream C4 and C2, which then activates C3 and C5 within the classical pathway. Inhibition of C1Q at the top blocks all downstream components of the classical cascade, including C3 and C5, within the classical pathway. However, it leaves the lectin and alternative complement pathways in place, retaining normal homeostatic and immune functions of both C3 and C5 within those pathways. The diagram on the right shows how the classical cascade contributes to pathology in GA. The diagram represents a photoreceptor cell with a synapse on top that connects the photoreceptor cells to the rest of the retina. C1Q localizes on the photoreceptor cell synapses in GA, where it anchors classical cascade activation on the synapse surface. Each of the activated complement components plays a specific role in driving aberrant synapse removal by microglial cells, causing loss of visible function, neuroinflammation, and photoreceptor cell loss. Inhibiting C1Q blocks all of these downstream components to protect synapses and provide a unique neuroprotective mechanism. This process has been validated in animal models, as shown on slide 11, where anti-C1Q is protective against photoreceptor cell damage. In the left panel, photoreceptor synapses are labeled in red, and C1Q is green. After exposure to damaging bright light, C1Q binds to the synapses of photoreceptor cells within three days, triggering classical cascade activation and synapse removal. On the right of the slide, in a published study with light-induced damage, intravitreal administration of anti-C1Q, shown in the maroon bars, protected against photoreceptor cell loss and protected photoreceptor cell function. Slide 12 is a key slide because it shows how this process relates to geographic atrophy and importantly, illustrates how measurement of visible function is distinct from lesion growth. The image shows a cross-section of retina or retinal tissue taken from a patient with geographic atrophy at the edge of a GA lesion. The green labeled cells on the bottom are retinal pigment epithelial cells, or RPE. The GA lesion is on the right, where the RPE cells have already died and are missing in the orange box. Above the RPE are the photoreceptor cells in blue, and directly above those are photoreceptor synapses, which appear as red dots highlighted by the green and white arrows. These dots are physical structures that connect the photoreceptors to the rest of the retina and so are critical to visual function. The photoreceptor synapses are very dense on the left side of the image, away from the lesion and outside of the white box. Moving toward the lesion on the right, within the white box, the synapses become sparse and are entirely absent in many places. Every loss of a synapse represents a loss of visual function since they are the only connection for the photoreceptors to the rest of the retina. Anti-C1q is designed to protect synapses and their function, as demonstrated in multiple animal models of neurodegeneration. Anti-C1q would have the potential to protect visible function nearly across this entire image. In contrast, lesion growth is shown by the orange arrow on the right, illustrating the average growth of a lesion in a year. This growth, as measured by FAF, only tracks loss of the green RPE cells, such as those above the orange arrow. This occurs in a region of the retina where there are very few functional synapses remaining. Therefore, it's not surprising that lesion growth, as measured by FAF, correlates poorly with visible function. We anticipate that by protecting photoreceptor cell integrity and visible function across a broad region of the retina, anti-C1q will slow lesion growth over time, rather than just saving RPE cells at the very edge of the lesion. To summarize, anti-C1q provides a unique approach for protecting vision by preserving functional synapses. This was the founding technology of Annexon and is distinct from downstream complement processes. This mechanism has been validated in multiple animal models of neurodegeneration, including models of photoreceptor cell loss. In geographic atrophy, anti-C1q offers the potential to protect photoreceptor synapses, cells, and visual function across a broad region of the retina for lasting benefit. Thank you for your attention, and with that, I will turn the mic over to Don to talk about the ARCHER trial. Thank you, Ted. By way of background on slide 14, GA is an advanced form of age-related macular degeneration, or AMD. It's chronic, progressive, and neurodegenerative disease that can lead to blindness for about 1 million people in the U.S. and another 4 million worldwide. In the early stages of GA, patients have trouble reading or seeing in low light conditions. This is because the light-sensitive cells or the photoreceptors start to break down. As the photoreceptors start to die, patients will lose vision and the associated independence that comes with that. Slide 15 describes our drug, ANX007. I want to spend some time highlighting the key attributes. ANX007 is a 50 kilodalton Fab antibody modeled after standard Fabs, like Lucentis. It is not PEGylated. The formulation is low viscosity. ANX007 fully inhibits the classical pathway. Importantly, it doesn't affect the alternate and lectin pathway and leaves in place their normal immune and homeostatic functions. In summary, ANX007 is designed for intravitreal injection. Moving to the trial design on slide 16. The ARCHER trial is pivotal design and is a randomized, multicenter, double-masked, sham-controlled study comparing the safety and efficacy of ANX007 to sham in patients with GA. The study enrolled 270 patients, stratified by GA lesion size, location, and fellow eye CNV to minimize biases or imbalances in the data. Patients were randomized to receive 5 milligrams intravitreally, either monthly or every other month, or sham, for a total of 12 months, followed by a 6-month off treatment period. The primary endpoint of the study was the rate of GA area change, measured by fundus autofluorescence from baseline through 12 months. Importantly, the ARCHER trial included multiple pre-specified endpoints to assess visual function. These are Best Corrected Visual Acuity, referred to as BCVA, Low Luminance Visual Acuity or LLVA, and Low Luminance Visual Deficit or LLVD. These endpoints are important because prevention of vision loss is what we, as ophthalmologists, want and what our patients demand. Turning to slide 17, patient demographics and study eye characteristics were generally well-balanced across groups. In total, 270 patients were enrolled across three arms: 89 in ANX007 monthly, 92 in the every other month group, and 89 in the sham group. The trial was predominantly conducted in the United States, with approximately 95% of study patients in the U.S. The overall demographics of the population is consistent with other GA studies, including age, gender, and ethnicity. The average age in the study was 80 years old. I mention this because, at this age, patients do not have a lot of time to wait for vision preservation. Best Corrected Visual Acuity was the same across all three arms. Patients were split almost equally between foveal and non-foveal. As background, foveal patients are those whose disease has not involved the central macula, which is responsible for central vision. Non-foveal patients are those whose lesions are not yet affecting the central macula. Taking a look at patient discontinuations on slide 18, between 11% and 15% of patients discontinued from ARCHER, which is consistent with previous GA studies. Slide 19. BCVA is a measure of visual function and has been a widely accepted functional endpoint for FDA-approved ophthalmology products. The assessment of BCVA 15 letter loss is considered clinically meaningful because it represents a 50% loss of a patient's visual acuity and is the gold standard for assessing efficacy in many retinal diseases. For veracity in our study, we defined vision loss as losing 15 or more letters on two consecutive visits or if the loss occurred at the end of study. This approach is designed to reduce variability in vision testing between visits, adding confidence to our data set. We are honored today to be joined by Dr. Jeff Heier, an investigator in our ARCHER phase II trial. I'd like to turn the call over to Dr. Heier now to walk us through the ARCHER phase II results. Thank you, Don. It's my privilege to present the ARCHER results now. If we go to slide 21, we see the ARCHER primary endpoint. As Doug mentioned before, ANX007 did not meet its primary endpoint, a reduction in GA lesion area change from baseline to month 12 versus sham injection. It slowed lesion area change by roughly 6% from baseline to month 12 versus sham injection. However, if we look at slide 22, showing the effect on lesion size over time, we see that looking at the first 6 months relative to the second 6 months, the separation between the sham and in treated groups increases after month 6. This suggests that lesion growth may slow with longer treatment with ANX007. However, if we go to slide 23, we see that ANX007 treatment did result in a dose-dependent protection against vision loss in this pre-specified endpoint. Persistent vision loss was defined as 15 letter or greater loss at two consecutive monthly visits or at the 12-month visit. Again, we see a dose-dependent effect here. Slide 24 is a Kaplan-Meier analysis that shows that 15 letter loss occurred quicker and in much greater numbers in sham-treated patients versus monthly ANX007-treated patients. ANX007 treatment resulted in a 72% risk reduction with monthly therapy and a 48% risk reduction with every other month therapy. If we look at slide 25, this is an even more stringent definition of persistent vision loss. 15 letter loss at two consecutive months and eliminating the patients with a 15 letter loss at only their last visit. We see a similar significant dose-dependent reduction in risk of visual loss was maintained, with the risk of 15 letter loss reduced by 66% relative to sham with monthly dosing. The completeness of the data, the consistency of the data, is really highlighted on slide 26. We see that the reduction in risk of visual loss was not influenced by baseline demographics. When adjusted for a range of baseline characteristics, the risk reduction was maintained in both the monthly and every other month treatment groups, with all point estimates to the left of 1, thus favoring treatment. Slide 27 shows a consistent protection for vision loss was further supported by. Excuse me 1 second, didn't show a slide. By elements in the fellow eye. In the fellow untreated eye. 15 letter Best Corrected Visual Acuity loss at month 12 was evaluated in patients with GA in both their study eye and fellow eye. Among patients in the sham group, the rate of 15 letter loss was consistent in the sham and fellow eye. Among the treated patients with bilateral GA, again, we see a dose-dependent protective effect of ANX007 treatment in the study eye relative to the fellow eye that did not receive treatment. The risk of 15 letter loss was reduced by 74% and 47% with monthly and every other month treatment, respectively. Again, highlighting the theme that we're seeing in all of these outcomes. If we look at slide 28, a similar dose-dependent result with other cutoffs of Best Corrected Visual loss is shown. A dose-dependent trend was seen in 10 letter loss, which is considered noisier, 10 letter loss, with 15.7% of patients treated monthly with ANX007 experienced a persistent 10 letter loss, compared to 5.8% of patients in sham. A significant dose-dependent change in persistent 20 letter loss, again, less noisy with higher criteria here, were demonstrated, with 4.5% of every other month treated patients compared to 16.9% in the sham group. If we look at slide 29, we see a trend in mean change in Best Corrected Visual Acuity at 12 months were also consistent with the dose-dependent effect of ANX007 treatment on vision protection in GA patients. At month 12. the sham group had lost a mean of 4.1 letters, which was consistent with previous GA trials, while the every month and every other month groups lost a mean of 1.8 and 2.7 letters, respectively. Looking at Slide 30, we see ANX007 treatment protected against vision loss even after adjusting for baseline lesion location. Among patients with foveal and non-foveal disease, both monthly and every other month treated groups showed a significant treatment effect compared to sham. Slide 31 looks at a classification of retinal health, which is classified by low luminance visual deficit. We chose low luminance visual deficit of less than 30 letters as healthier and greater than or equal to 30 as less healthy. ANX007 treatment compared to sham, stratified by healthy and less healthy retina, reduced 15 letter Best Corrected Visual Acuity letter loss in both the monthly and every other month group. If you look just at the healthier eyes, 0% of monthly treated eyes suffered 15 letter loss. In Slide 32, the protection from vision loss seen with ANX007 is further supported by looking at early data from the off-treatment period. This is from 12 to 18 months where patients are off treatment. During treatment, there is a steady separation between the sham and treatment arms, showing protection against vision loss. However, during the off-treatment period, the drug arms progress at a rate similar to sham. These results, showing a change on and off treatment, strongly support the beneficial impact of ANX007. We plan to present the full data set from the off-treatment period later this year, given that these data represent approximately 50%-85% of subjects who will ultimately complete the study, we do not expect to see that these results will change. Looking at Slide 33, visual function protection was evident on other measures of visual function as well. There was a trend in reduction of 15 letter loss as measured by Low Luminance Visual Acuity, there was significant protection from 15 letter loss in Low Luminance Visual Deficit with monthly ANX007 treatment. I hate to keep harping on it, but what we're looking at is a remarkable consistency of the visual function data. Slide 34 addresses safety. ANX007 was generally well tolerated with monthly or every other month dosing. There is no apparent difference in the incidence of CNV across the three arms. 3 cases of endophthalmitis were observed. There was only 1 case of retinal vascular occlusion, which is listed as a branch retinal artery occlusion under serious adverse reactions. There were no cases of retinal vasculitis or any cases of ischemic optic neuropathy. In terms of serious adverse reactions, there was 1 case of iritis, there was 1 case of vitritis, and 1 case of vitreous debris, as well as the same case of retinal artery occlusion. Based on the totality, totality of these data, the consistency of the visual function benefits, I continue to be excited by the opportunity of ANX007 to treat this devastating disease, and I look forward to seeing its continued development. I'll now turn the call back to Doug to close us out. Thank you, Dr. Heier. Really nice job, also Ted and Don. Well, in summary, the novel neuroprotective mechanism of ANX007 translated into consistent and clinically meaningful protection of visual function in the ARCHER trial, as you just heard. This effect was significant, dose and time-dependent, and robustly demonstrated across multiple measures and patient subtypes, and was not dependent upon a significant change in lesion growth. Moreover, ANX007 was well tolerated throughout the study, which is important for this aging patient population. As a result, we believe ANX007 has the potential to fundamentally change the treatment paradigm for geographic atrophy, offering a chance to preserve vision in a broad population of patients. We're planning to engage quickly with regulators to discuss next steps and determine the optimal path to advance ANX007 toward patients. Our work at Annexon is only made possible by the passion, commitment, and know-how of many. We sincerely thank our employees, collaborators, and advisors who have greatly contributed to this milestone. We also thank the scores of physicians, medical teams, and most importantly, the patients, families, and caregivers who participated in our clinical trial. We are grateful and humbled by your support and contributions, and we are intent on bringing a new therapy to help solve this devastating disease. With that, we're happy to take your questions. Operator? If you'd like to ask a question at this time, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Andrew Tsai with Jefferies. Hi, good afternoon, and thanks for taking my questions. Appreciate all these analyses. Clearly, based on this presentation, there's some consistent functional signals here to warrant further evaluation. As we think about next steps, when can we expect you specifically to meet with the FDA? When can we expect to hear the outcome around your phase III plans? Secondly to that is, what would be the ideal outcome in terms of the phase III program strategy as well as the phase III design itself? Thanks. Thank you, Andrew. Appreciate you joining today. We are actively working up a plan for discussions with the regulators. We anticipate speaking with them by the end of the year. We'll certainly update the market shortly after we have done so. With regard to the discussions there, we really want to, you know, we will be discussing the phase III study design with an emphasis on BCVA 15 letter loss as the primary endpoint in that study. Again, we will update after we've had concrete discussions with regulators on that this year. Great. Then maybe just a quick follow-up, for both you guys and the doctor. You know, another industry player has, unfortunately disclosed some, you know, retinal vasculitis. So maybe talk about, your own views around that safety. A, what's your hypothesis why that, other drug is seeing vasculitis, and why, ANX007 is different and should not show, any cases, especially since both of your drugs are both, complement inhibitors? Thank you. Yeah, well, we only have the public information that you all have, and so we will not speculate on what the potential drivers are for, for the safety events you are referring to. What we will say is that we are encouraged by the profile of ANX007. This study in geographic atrophy is the second study that's been used with this therapy in a ophthalmic patient population. The first population was glaucoma on top of IOP-lowering drops, where it demonstrated a robust safety profile, and we're seeing very well tolerability here in this geographic atrophy study. We do think, as you've heard over the course of this discussion, that targeting upstream C1Q and the classical pathway specifically, does have the potential to be differentiated, both on the efficacy side as well as on the safety side. On the safety side, by blocking only C1Q and the classical pathway down through C3 and C5 and allowing the lectin and alternative pathways to remain intact for their immune function, that has the potential over time, chronically, to perhaps be a well-tolerated therapy. So that's our approach, a-and that's what we know today. I'll open it up to the team members to see if they'd like to co-comment further, whether it's Dr. Heier or Don. Sure. This, this is Jeff- Oh, sorry, go ahead. Sorry, Jeff. Go ahead, please. Jeffrey Heier. You know, I think just to focus on ANX007, as Doug pointed out there, we're very happy with the safety profile that we saw in the study. With respect to any other programs, I defer to the work that's going on with those programs and prefer to just focus on ANX007. Makes sense. Thank you. Our next question comes from the line of Pete Stavropoulos with Cantor Fitzgerald. Hi, Doug and team. Congratulations on the ASRS presentation. First question I have is, you know, when you look at the data for, for patients with foveal involvement, you know, do you believe the difference observed for, for every month versus every other month was due to not having enough drugs on board, for the every other month group, or is there some other explanation? Does the data for the foveal, non-foveal involvement, you know, suggest to you that there's an opportunity for a different treatment paradigm or dosing regimen for the two groups of patients? Yeah, really good question. I'm going to turn that over to the experts. Don and Dr. Heier, please, weigh in on that. Jeff, do you want to start, or do you want me to respond to you? I'll let you start, Don. I'll let you go. That's fine. We did demonstrate an effect with foveal patients. This has not been seen previously, prospectively. What's really interesting is that we know now, this year and an earlier analysis from lampalizumab, that foveal patients often have eccentric fixation, and this eccentric fixation is very susceptible to synaptic loss and photoreceptor loss. Our mechanism is shown to be effective in the foveal patients as well as the non-foveal patients. In terms of whether our lack of effect is due to a mechanism, mechanistic difference, I think that you can sort of see that with our non-foveal patients, there are just not enough events. I think that, with longer studies and, with our phase III study, we, we will see an effect without every other month treatment as well. Yeah, that's, those are excellent points, Don. One other thing to add is that we think of foveal patients as potentially not having viable tissue or good vision. It's important to remember that there are many patients who have foveal disease who actually do have good vision and do have preserved foveal photoreceptors and synapses. So the effects can be similar in, in some of these patients between foveal and non-foveal patients. Thank you for that color. Just 1 follow-up question, if you don't mind. You know, so the data for LLVA and LLVD, you know, Dr. Heier, can you help us understand what those 2 measures mean in terms of predictive value or prognosis for a clinical course and outcomes in general? Can you provide us with your interpretation of these data with respect to a reduction observed in the zero zero seven arm versus sham? Thank you. Take my questions. Yeah. So low lumin- I'm sorry, go. Do you want to say something, Don? No. No, No, please go ahead. Yeah. Low Luminance VA and Low Luminance Visual Deficits are other means of measuring different types of visual function, and they, the patients, both in terms of aging and with age-related macular degeneration, have decreases in, in each of these. This is another means of measuring visual function. And in, in many advanced GA patients, it's hard to pick up a difference here. But what we're seeing is the, the consistency here of being able to see a difference, both in terms of Low Luminance Visual Acuity and the Low Luminance Visual Deficit, just highlights more that we're having a consistent effect on visual function. We also spoke to the Low Luminance Visual Deficit. The, the differences between regular visual acuity and Low Luminance Visual Acuity often speaks to the health of the eye. The closer those numbers are together, overall, the healthier the eye is, the healthier the tissue. When you're seeing these very different, you're looking at eyes that are considered healthy versus eyes that are considered not as healthy. Don, you may want to have some comments about this as well. Yeah, I'm happy to add to that. One of the ways to assess sort of the functioning of the retina is to look at how the photoreceptors and the synapses work in different luminance conditions. In a low luminance condition, where the, where the light is lower, the photoreceptors have to work harder. That difference tells you whether the photoreceptors are able to work hard or not. If there is a big difference between what a eye or a patient can read in a normal light versus low light, that tells you that the photoreceptors aren't working as well and that it's less healthy. Okay? That deficit gives us a way to assess photoreceptor and synaptic function, by looking at low luminance VA and VD. Thank you, and congratulations once again. Thanks, Pete. Our next question comes from the line of Tazeen Ahmad with Bank of America. Hi, can you guys hear me? Yes. Hi, Tazeen. Okay, great. Hi, Doug. Thanks for the presentation, congrats on the updated data. I wanted to get your thoughts about dosing frequency. You know, the most intriguing or one of the intriguing parts of your data was that you did show some early signs of potential benefit for visual acuity. Now, if it's the case that you continue to see that benefit, but it's limited to, for whatever reason, needing to have a monthly dose, I wanted to ask what you thought the commercial attractiveness of dosing monthly might be, maybe that's also a good question for Dr. Heier. I had a follow-up. Yeah, definitely Dr. Heier should weigh in on that. My early thought on that, however, is that as you think about the import of vision in a person's life, particularly a person who's aging, to maintain independence, they will do a lot of things. I think it's a, a benefit analysis and the strength of your data in being able to protect against vision loss. We see that patients are coming in monthly where benefit is less than that. We would anticipate that this is likely to expand the market opportunity. I think coupled with that, when you see the data on the impact of ANX007 on the healthier eye, these are patients who may sit on the sidelines a bit longer before they get some type of therapy. This is encouraging and suggests that the earlier you treat, the better, particularly in the monthly group, where you saw 0 out of 51 lost 15 letter loss, lost 15 letters in vision. I think this has a real opportunity to expand the market, both in those patients who would come in to get treated earlier and those patients who are having meaningful vision loss and really want to slow that activity. I'll, I'll turn it over to Dr. Heier to, to weigh in. Sure. I think that a lot of that answer will depend on individual patients. Let's assume that we replicate these findings in the phase III program, and perhaps with larger numbers, these even are statistically significant just in terms of Best Corrected Visual Acuity. I think where the patients, where they're in. ... visual function, what their vision is, where their disease is at that time, may dictate whether they go with monthly therapy or less often than monthly. I agree entirely with Doug that patients will do a great deal to preserve vision. If you're a patient who has poor vision in one eye, say, from GA, then your second eye has an analysis that shows you have damage very close to what is your central vision, and now I'm talking about analyses of the photoreceptors and the synapses, and there are different ways to potentially assess that. If you're close, you may say, "I want monthly therapy there." If you're farther away, if you're a bilateral patient, you may say, "I'm more comfortable with less frequent therapy." Again, it's really early to sort of determine those guidelines. Okay- This is Ted. I'll just add a few things, one thing as well. Uh-huh. That is obviously dose response is very encouraging with respect to the efficacy of the drug. This is a very well-behaved drug from a formulation perspective. I think we have a lot of different opportunities going forward to extend that dose, you know, given its continued efficacy. I'm sorry, that's all I wanted to add. Thanks so much. Maybe just a quick follow-up. Dr. Heier, if you were, you know, advising Annexon on what the best phase III trial design would look like, just based on what we've learned about the potential for safety events to, to happen in clinical-- not in a clinical trial, but in, in commercial use. What do you think is the right number of potential injections to, to need to observe in a, in a, in a big Phase III program in order to, to really truly rule out the potential for safety concerns? Thanks. Yeah, it's, it's a good question, one which everybody always puts a lot of time thinking into. It's, it's hard to say. It depends a lot on your dosing. It depends a lot on what the safety profile looks like in the clinical trial as you go forward. You know, it's very hard in even very large phase III programs to pick up everything, and rare events often aren't seen until you're in clinical practice. It's, it's hard to make that statement right now, and I think a lot of that depends upon what you see in your, in your phase III program. Okay, thank you. Our next question comes from the line of Anupam Rama with JPMorgan. Hey, guys. Thanks so much for taking the question. Is your base case assumption that ARCHER would count as one of the pivotal trials here in GA? Is your base case assumption that the next study would be placebo-controlled versus having an active comparator? Then for Dr. Heier, how does the concept of sort of vision loss or vision preservation versus, say, vision gain with a VEGF resonate with patients? Maybe how does it change your risk-benefit profile assessment in an elderly aging population? Yeah, maybe I'll go quickly, Jeff, and then, then turn it over to you. Just with regard to our base case, we certainly have designed and executed the ARCHER study as a pivotal study, so it's double sham control, of course, with stratifications and all the bells and whistles that we learned from prior GA programs, which we're thankful for in the conduct of that. That'll be the discussion we'll have with the regulators, as we move forward. I'll turn it over to you, Dr. Heier, to answer the question on- Sure. Hi, Anupam. As always, a great question. It's... You know, there's, there's no question when you have a treatment like anti-VEGF therapy, and you have immediate gratification, it's very easy for patients to appreciate the benefit and to see the benefits when they look at the OCT, and many of our patients have become, master readers of the OCT. Having said that, patients are more and more appreciative and understanding of how devastating this disease is, to the point that many patients come in the clinic, and when they hear they have advanced dry AMD, they're extremely disappointed and said: "Oh, I was hoping this was wet because I know there's a treatment for wet." So now, as we start seeing an environment where there are treatments and potential treatments for dry, many patients are highly motivated to do whatever they can to, to arrest progression and preserve what vision they have. There, there's no question that if we could improve vision, and I'm sure down the road, we'll be looking for ways to do that, but right now, patients are highly motivated in many cases, to do whatever they can to preserve vision. Instances of that are patients who have family members that they've cared for or know of, who've lost all their central vision to GA. Perhaps it's patients whose fellow eye has lost vision to GA or even exudative disease, and they, they appreciate how they're progressing. We, we followed for years patients who would have vision, and they'd come in and tell you that they're really worsening, and you check their vision, and it looks their scan looks roughly the same, and their vision looks roughly the same.... I think we're appreciating more and more now that there are components of their retina, their findings that are beyond our conventional OCT, that if we were to track, we would understand better why they're experiencing that vision loss. I think the image that Ted showed at the beginning of his or towards the end of his talk, where you see the RPE intact until you get to the atrophy, but you see overlying photoreceptor damage and photoreceptor synapse damage. I think that helps to explain a great deal why patients understand they're losing vision, but we're not often able to detect it. I think patients will be very motivated to try to preserve that. Not all of them, but many will. Well, and certainly, just to, to close, close out on that, that is certainly the standard for neurodegenerative diseases. Slowing of disease worsening, whether you're in Alzheimer's or ALS, and pick the neurodegenerative disease, very unusual to find a therapy that enhances benefit. That is kind of the standard neurodegenerative approach, and, and that seems to have worked for patients across the board. Thanks for taking our questions. Thanks, Anupam. Our next question comes from the line of Joseph Stringer with Needham & Company. Hi, thanks for taking our question. We understand the importance of the 15 plus BCVA letter loss data, given its potential use as a registration at 1 point. Just curious if you did a sensitivity analysis or have a Kaplan-Meier curve across groups for both the 10 plus and the 20 plus BCVA letter loss when you sort of excluded those patients with vision loss only at month 12 or the last visit. Did you see similar dose-dependent trends as you did in the 15 plus letter BCVA loss analysis? I guess I'm referring to slide 24 and 25 for the 15 plus group. Just curious if you saw that with the, with the 10 and the 20 plus. Yeah. Yeah, Don, do you know that answer? Yeah, I can comment on that. We did repeat slide 24 with the 10 and 20 loss, and the, the trends support ANX007's effect on visual function. Yes, we did do that. What's the, the second part of the question? No, I think you got it. Yeah, that was it. I just, the question was, did you see similar dose-dependent trends, as, as you show on slide 25? You, you answered it. Thank you. Yep. Thanks, Joey. Our next question comes from the line of Ernesto Rodriguez‑Dumont with Cowen. Hi, team. Thank you for the additional analysis and for taking our question. We wonder if you're aware of or planning to use any other biomarker that would correlate with the benefits in visual acuity and perhaps corroborate the mechanism underlying the clinical benefit, yeah, the clinical effect seen. Yeah. Also, we were wondering, what, what type of feedback do you receive from physicians at ASRS? You know, how are they reconsidering the, the, the failed primary endpoint, but the clinical benefit observed in the, in the second, functional benefit observed in the secondary endpoint? Thanks. Yeah, we're, we're assessing. Thank you, Ernesto. Thank you for calling in. We appreciate that. The first part of this analysis has been deeply focused on the function, really around BCVA 15 letter and all of the additional analyses that you see around that. We will be assessing various biomarkers over time, and so we'll come back and update as we do that. We have not done any of that yet, and so we will look at, look to do that, kind of in our next wave of analyses of this data. Just with regard to physician perspective or views on the data, maybe I'll turn that over to Dr. Heier and Don to weigh in on that. Sure. I thought, I thought there was a comment after my presentation was on the panel at the ASRS, which was highly relevant to your question, and that was, one of the members said this was the most exciting failed study, failed, phase II study he'd ever seen. I think it's important to recognize that phase II studies are, are really designed to help highlight and clarify what the strength is and what the benefits are of your investigational agent. We use, the anatomic outcome, and we have to realize that really is a biomarker for visual function. It was because to date, we had not been able to achieve the visual function benefits that we went to the biomarker. Many of you have heard the discussions with the FDA, where the anatomic outcome was acceptable as a regulatory endpoint because the assumption is that if you're preserving retinal tissue or losing less tissue, that ultimately that will translate into a functional outcome. In this case, the functional outcome has already been achieved. That's. These are actually the outcomes that we ultimately want to achieve, which is true preservation of visual function. I think, there's a recognition that these are the outcomes you want. The anatomic outcomes are good, and they're important because they're hopefully leading to these outcomes. Very helpful. Thank you again for taking our question. Thank you. That concludes today's question and answer session. I'd like to turn the call back to Doug Love for closing remarks. Yes. Well, thank you all for joining us today. We're really, this is an exciting time for Annexon and the field. We're very much focused on bringing this therapy forward to the next stage, with more details to follow latter part of the year. Thank you again for joining us, we wish you well. Take care. This concludes today's conference call. Thank you for participating. You may now disconnect.