Annexon Inc Aktie

Good morning, everyone. Thank you for joining us on day 2 of the Goldman Sachs Healthcare Conference. It's my pleasure to introduce the Annexon team. With us, we have Doug Love, Chief Executive Officer and President; and Lloyd Clark, SVP, Ophthalmology Strategy. Thanks so much for being here.

Thanks for having us.

And to start here, perhaps a snapshot of how to think about the second half of '26 and beyond. This is a potentially transformational year for the company with pivotal data in geographic atrophy that was expected in the fourth quarter of this year. Describe maybe to start here, your asset, how it's differentiated from the other geographic atrophy assets and your confidence in the Phase III study success?

Yes, happy to do so. And thanks again for having us. It's delightful to be out here in Miami with you all. So look, we're really excited about the Phase III asset vonaprument for the treatment of geographic atrophy.

I would say it's differentiated from the first-generation assets in 3 principal ways. First and foremost, recognizing that GA is a neurodegenerative disease, we're targeting exactly that, providing a neuroprotective approach to preserve vision with vonaprument in this disease, which is very different from the prior drugs that are approved, targeting a surrogate biomarker for vision.

Secondly, the drug candidate itself is quite differentiated. So this is a small antibody fab fragment. It's 50 kD, no PEGylation with really low viscosity. So the ease of administration is really important for us. Importantly, it's a really small microliter, 25 microliters, which is about 1/4 of the size of the currently approved therapies.

What that means is when you administer the drug, you don't experience the floaters or temporary blindness that you do with these drugs with higher concentration that resulted in ocular pressure. So really excited by that. And then finally, we're really excited about the data we've demonstrated already in the Phase II and which we're looking to replicate with the Phase III.

Vonaprument is the only program that demonstrate significant preservation of the photoreceptor retina neurons that are responsible for visual acuity, that had an even more pronounced impact in the central macula of the eye, which is principally responsible for the vision loss in geographic atrophy. And that translated to significant preservation of vision on all of the measurements in our Phase II study, importantly, best corrected visual acuity, 15 letter loss, which is the gold standard. So a really differentiated outlook from the prior therapies, and we're excited about where we are in the Phase III program.

Maybe to jump a little deeper here into the Phase II data. With regard to the -- what we saw, the study did not meet the primary endpoint of GA lesion growth, which showed vision preservation for BCVA, as you mentioned. How do we reconcile the benefit on vision preservation with the lack of impact on anatomical markers?

Yes, really good question. So first and foremost, we did have an impact on the anatomical markers, photoreceptor neurons, which is, again, the structure in the eye that is responsible for vision, as you alluded to, did not have a significant impact on the RPE sales or lesion growth. And the reason for that is you actually now -- it's now known you lose photoreceptors prior to your RPE sales. And so that is what we're targeting principally. Maybe I'll invite Lloyd to talk about all of that.

Yes. So as Doug said, it is well -- we know from our work as well as other groups that photoreceptors are lost first in dry AMD with geographic atrophy. RPE atrophy is a lagging indicator of disease activity. And so it's important to -- it's critical to protect photoreceptors first. And that's another key differentiator of our drug as a C1q inhibitor. C1q is known to localize on photoreceptors that are lost in geographic atrophy.

So by inhibiting the function of C1q, we protect photoreceptors first, which then protects RPE cells down the line. And from our data in the Phase II, we did not show a statistically significant benefit in RPE lesion growth, but we saw a 10.5% reduction in the final 6 months of our Phase II program. We expect to see further protection of RPE in our Phase III program out to 2 years as we protect photoreceptors first, which then leads to protection of RPE cells later.

And how do you address the elevated BCVA 15-letter loss in the sham arm? And then what's playing out in the fellow eye data between the treated and sham arms in that context?

So you're talking about our sham event rate in the Phase II, right? So our -- the data that we've pulled forward is our definition was confirmed 15-letter loss at 2 visits. That number in our Phase II was 16.9%. That compares -- it's very comparable to other studies in the medical literature. Probably the best comparator for our program is the lampalizumab natural history cohort, which is somewhere between 12% and 14% at a year. So these are very similar numbers.

Now -- we've done a good bit of internal analysis of this data to feel very, very comfortable with where we are with our sham event rates. So we're comfortable with that number and understand that our study really was recruited for a functional outcome. That's the other important difference between our study and really all the others that have been evaluating patients with geographic atrophy is that their specific patient population was to study RPE lesion growth.

There are specifics to our characteristics as well as our understanding of our data that demonstrates that we're recruiting to a functional outcome. In terms of our fellow eye analysis, the fellow eye studies are difficult because the baseline characteristics are not balanced between treatment groups. We're essentially an all-comers analysis in the fellow eye group.

So it's not surprising that we see some differences both in the sham event rate as well as the treatment event rate. But it's important to emphasize that we saw a directional benefit with vonaprument in the fellow eye analysis as well as a dose-dependent benefit, every other month doing well, the monthly group doing better. So consistent with what we saw in a much more controlled group in the study eye.

Yes. I guess the way we put out -- the reason we put out the fellow eye data to Lloyd's point, is a sensitivity analysis. So as you've seen in our data, we put out all of the data related to vision preservation, 10-letter, 15-letter, 20-letter, fellow eye is another sensitivity analysis that Lloyd dose dependent and certainly a pronounced effect, 57% versus the fellow eye. The eyes are not matched at baseline because you can't do that in these studies. And that's why these studies have not been recognized for approval.

Maybe looking forward to the Phase III here, frame for us your expectations for that data set in the fourth quarter, including the sham arm and what your view would be on a favorable outcome here?

Yes. Maybe I'll start, Lloyd, and then get you in on the sham arm. So a favorable outcome is statistical significance on BCVA 15-letter loss. Again, it's the gold standard, represents about 50% of your vision loss over whatever period of time in which you are studying it. And there's just been no false positives.

It's an exceedingly high bar. And so we're really encouraged by that. So any statistical significant demonstration on BCVA 15-letter in talking to the regulators as well as the physician community is deemed clinically relevant and sufficient for an approval with regard to sham event...

Yes. And in terms of the performance of the groups, I think, is sort of to your question, again, we've informed our expectations with the trial with a number of data points, but we lean very, very heavily on the data that we have collected in the Phase II study because we have a number of parameters that we've evaluated to have a good understanding and an expectation for what a sham event rate should be in this specific population, which is different than other clinical trials. And so we feel very good about those estimates as we move forward towards the data...

It's really an important point because I think what we're seeing is folks are trying to compare sham rates from study to study without really understanding, one, the objective of the studies, are they the same? And two, at a patient level, are you really clear on what are the key factors with regards to each patient characteristic whether it's lesion size, location, baseline visual acuity, what do each of those factors contribute to a patient actually losing vision at a prescribed period of time.

We have the only data set in geographic atrophy where we can look at that deeply on a per patient basis, and that's what we use to the power of the Phase III study. So this comparison from one study to the other in sham rates in absolute terms, really difficult to do, even more so in neurodegenerative rarely die.

And given geographic atrophy is initially foveal sparing, how, I guess, how confident are you that this BCVA endpoint is achievable in this -- in the context of this disease, just given what we've seen with the other 2 drugs?

Yes. I mean our enrichment strategy and making sure we're identifying patients who are losing vision, but not so far gone that you can't protect vision is very, very important, which gives us a great deal of confidence. We're able to do it in the Phase II. We expect to do in the Phase III, but it's elaborate on.

It boils down to patient selection. There's really 3 phases of disease in geographic atrophy, early disease, there are several years of progression where patients lose no vision. And then towards the end of disease, once patients develop large subfoveal lesions, they've lost all the vision that they're going to have.

So our inclusion criteria are designed specifically to pick those patients in this middle phase of the disease where they have rapid vision loss. And so that -- we know that our drug is beneficial to all patients with geographic atrophy and dry AMD because it protects photoreceptors. But from a regulatory perspective and from the perspective of designing a trial for approval, it's critical to pick that specific group of patients to evaluate.

And how likely is it a statistical significant benefit on GA lesion growth rate reduction at the 18 to 24-month time point? And if you don't achieve that, how do we reconcile the vision benefit with the long-term risk of a lesion growing into fovea?

Good question. I'll start and you can please dive in. So first, I think it's quit likely. Well, maybe even before, let me just back up on RPE and lesion growth. It's just really a debunked hypothesis. And I just need to say it that play. There is 0 data preclinically or clinically that protecting RPE lesion growth translates to vision.

As a result, Europe has not required us to study that as an endpoint nor has the FDA. We're looking at it as an exploratory endpoint in our study. So scientifically, there's just not a wealth of information that supports that as a viable endpoint. Be that as it may, we are studying it as an exploratory endpoint because we continue to get the question, we just want to take it off the table.

As Lloyd alluded to, if you look in the second 6 months of our study in the ARCHER study, what we showed is that we protect it against lesion growth at a rate more than 3x greater than in the first half of the study. The reason we're doing that is C1q localizes on photoreceptors, we're protecting and strengthening the retina neuron, which then over time strengthens the RPE cells that provide trophic support for the neuron. So we're quite confident we'll do that. And I don't know...

Mechanistically, I guess, how much data is there or just literature to kind of support this neuroprotective dynamic that's playing out with C1q?

Great question.

Yes. So well, it's clear. There's loads and loads of basic science evidence to support the idea that C1q localizes on neuronal synapses for removal. That occurs in the brain. It occurs in the retina, it occurs in the peripheral nervous system. That is well established across multiple different neurodegenerative disease -- so this idea is universal if you consider this drug as a neurodegenerative disease state.

So the mechanism of action is well worked out. The other thing we know is that in the aging retina, C1q is upregulated almost 200x above normal levels. And it localizes on damaged photoreceptors in a light animal model. And so we know that it's there. And we also know that when it is inhibited with a C1q knockout model, then the retinal function improves as well as retinal anatomy does. So we have both preclinical as well as animal evidence to suggest that this is absolutely a violent mechanism and central for protecting neurons as well as photoreceptors.

I'm glad you referenced the preclinical data, Lloyd. We invite folks to go in and look at the package different again from the RPE story, we actually demonstrated preclinically what we demonstrated clinically, that is C1q localizing on the photoreceptors and stopping the damage or loss of these photoreceptors and protected their function. So we measured all of that before going into the Phase II study, which is why we prespecified BCVA 15 as a key secondary endpoint.

What are your thoughts just long term on immunosuppression or just overall safety in the context of targeting upstream complement cascade?

Well, specifically with our drug, I'd say in terms of safety, this drug is very similar to all of the other small fragment biologics that have been used in retina. I'm still a part-time practicing retina specialist. I have 20 years of experience in development of these drugs as well as using them. And this -- our drug has all the same characteristics of the important drugs in the exudative space. So from a safety profile standpoint, we feel really good about that. In terms of the systemic risk associated with our drug, it's important to understand because it is a small fragment antibody, and it's delivered in the eye, you're giving minute concentrations of the drug in the eye in terms of a systemic concentration. Now once that drug leaves the eye, it's metabolized almost immediately. So the take-home is you cannot -- you can't identify any vonaprument systemically in our patients in the Phase II.

And on a regulatory standpoint, the Phase III trial that has been designed to be evaluated as 2 independent substudies speak to your confidence in the powering of these individual substudies?

Yes. First, maybe just to clarify kind of regulatory status. single pivotal study is all that's required for approval in Europe with EMA. With the U.S., we have a single protocol, 2 substudies, as you alluded to, both are powered in high Phase III greater than 90% at the substudy level. I don't know...

No. I mean it's -- we're well aligned with FDA in terms of our 2-substudy approach. In fact, it was really their idea when we were in the trial design period prior to the initiation of the ARCHER-2. So we have a prespecified plan where we'll split at the site level to identify 2 very, very similar patient populations, which should increase our [ PF ].

Perhaps jumping over to the commercial opportunity here. Maybe frame how you view the opportunity today. We have 2 players that have pretty much divided the market here. How do you plan to, a, integrate into that market; b, lead the medical education effort to kind of shift the narrative towards vision preservation for lesion growth, which be honest, I think the doctors understand vision preservation more. But I'm just curious how you're thinking about this.

Well, exactly how you said it. So vision is what matters. It's very clear to us. We've done extensive research with the physician community, the patient community as well as the payers who are questioning now at some level, continuing to pay for these RPE preservation type drugs that after a year, you're losing 50% of your patients. The dropout rate is really quite enormous.

So we expect to displace them all together with a vision preserving therapy. We're excited by that. So we anticipate we will get the switchers. We will bring new patients into the fold. We know only about 20%, 25% of GA patients are currently getting therapy. So the vast majority of the sidelines with the opportunity to preserve their vision, they're going to come in. And then when you look at our data, which is what you want to see with a neuroprotective approach, patients who are earlier in the disease process, 0 out of 56 lost their vision in our study.

And so we have an opportunity to capture patients earlier in their disease. And with the new imaging techniques like EZ, OCT, where you can assess damage to your photoreceptors earlier even before you lost significant vision, we really think we're going to open this market up, and it's a real opportunity.

Yes. One other comment. Physician activation is key in this space. This is still, in many ways, considered maybe not an optional therapy, but one that clearly patients and their physicians have to consider. Only 20% of the retina specialists in the United States are currently participating in the GA market.

And there's a number of reasons for that. But I think the efficacy, safety balance is a very, very important piece there. So I think with a drug that demonstrates functional benefit, I think the vision activation will be increased, and that will be key to utilization. So the market is significantly underdeveloped.

One other just quick thing is sometimes we get questions on durability of our treatment effect and whether or not that will be lasting. What we saw in our study is that the protection against vision loss was increasing over the 12-month period of time. If you look again at the second 6 months, not only in the RPE and on the photoreceptors, but also on vision preservation, really a pronounced growth.

And then when we stopped the drug, we saw that vision began to return. So our drug is having a disease-modifying effect. And that's why we built our study with this off-treatment period where we could follow the patients. So we expect that we're going to convert patients early, both new patients and switchers and grow the market, and we expect we will keep them over the course of their lives.

Just to go back to a statement you made about 20%, 20%, 25% of the market is penetrated and only 20% of the doctors actually prescribing. Do you feel that over time with the existing drugs, they've gotten more comfortable with the safety profile in the context of efficacy? Or what are the -- is it -- I guess I'm just trying to understand...

The headwinds. The headwinds. Yes. So I think the headwinds have differed depending on the time, right? So I think that the initial launch of the first-generation therapies was quite risk, actually, very successful. I think the safety headwinds were significant post launch, and that really blunted market development and growth.

From there, I think that there's -- to me, I think there's a fair amount of fatigue on -- both on the physician side as well as on the patient side because they're not seeing, they're not experiencing a functional benefit. So I think the market is fairly stagnant. And it's kind of the way it feels and the way it's going to be until there's a breakthrough therapy that demonstrates more of a benefit than an anatomic benefit alone.

How do you think about the competitive landscape here in terms of drugs in development, there's a systemic external drug from Regeneron among others?

Yes. For me and Lloyd can weigh in, I'm confused by the follow-on approaches in development because you're still targeting this RPE lesion growth story. And one, you just said to yourself, you're throwing away the EU market, like you're not going to get an approval.

And how are you going to penetrate the U.S. market because physicians and patients are going to continue to use those drugs if you don't demonstrate vision. So at a macro level, it's just a little confusing that development strategy -- but I don't know.

No, I agree. And the other issue with systemic complement inhibitors is to your question earlier, the issue of risk in an otherwise healthy but elderly population, it introduces a significant amount of systemic risk. Is it really -- is there really going to be any benefit over the currently available complement inhibitors that you can deliver in high concentration to the eye. So I think that, that's a difficult program in particular, to have a lot of confidence.

And speak to the commercial strategy here in terms of whether you'll go at it alone or look to a partner?

Yes, we like it. We're going to go at it alone. It's a super efficient commercial footprint, about 3,000 retina doctors in the U.S. and a couple of large practices control roughly 50% of the prescriptions there. And so there's a well-worn template for smaller biotechs to come into these spaces and commercialize, and we are appreciative of the first generation.

It's done a lot to make the market already. And we just feel like this is a highly differentiated asset on safety, on efficacy and on route of administration. So we're looking forward to getting after it.

Perfect. Switching over to your drug, tanruprubart for the development of Guillain-Barré syndrome. Describe the development path here and where you stand with regard to regulatory approvals. And remind us of the key features of the Phase III data set that drive your confidence here.

Yes. We're really excited about this asset. Really the first clinical demonstration of blocking upstream classical complement in a neuroprotective way in Guillain-Barré syndrome. In our Phase III study, what we saw is roughly 90% of patients benefited by week 1, which translated to a 2.5x greater likelihood of improvement by week 8, which was the primary endpoint and a 2.5x greater likelihood of being normal by month 6, which are blocking effects in this disease that has not been studied in more than 40 years by anyway, it's the first randomized study program.

We're really encouraged by that. We ran this program ex-U.S. because it was deemed unethical to run placebo-controlled studies here in the U.S., and we run controlled studies. We don't rely on kind of natural history, whether it's a rare disease or not. We're really kind of fundamental in that regard. So we ran these in Southeast Asia with alignment of the regulators, both in Europe and the U.S. on 2 fronts. One, we needed to demonstrate substantial evidence of effectiveness as well as secondly, generalizability of the patients in our study with patients in the West.

Clearly, have satisfied the first box, and so we're really pleased by that. We also feel like we satisfied the second box. We did a lot of work to establish that the patients in our study are comparable to the patients in the U.S. The propensity score matching of the patients with patients in the West and measure their outcomes versus placebo as well as against IVIg, which is the standard of care.

And so we are now on file in Europe for approval. We're on pace for an approval early part of 2027. So we're really encouraged by that. And we anticipate filing shortly in the U.S. The U.S. asked for additional information on patients here in the U.S. and Europe, just to really satisfy themselves, I guess, cross every T, if you will, dot every eye to ensure themselves that the patients were comparable.

So we initiated an open-label study here called the FORWARD study. FORWARD study is really designed to provide experience with our drug in the U.S. and Europe as well as provide additional information to the regulators should it be a topic. Really encouraged by that. We will release data probably later this summer on the FORWARD study. It really shows the impact of tanruprubart in the West, which is quite similar to what we've seen in the Phase III study.

Just going back to the Phase III studies, they were conducted in Bangladesh and the Philippines. Just speak to the translatability of this data to the U.S. and European.

Yes. The most important part is GBS is GBS. So GBS is an antibody-mediated disease, preceding infection drives it. It's the same all over the world. And that's been widely studied. We have every KOL in the globe working with us on this program, which we're really encouraged about. So really important that the disease presents and plays out similarly across the board.

Secondly, with regard to the patient populations, it really is the same. It doesn't matter. You have an antibody-mediated attack and the question is whether you can stop that attack soon enough to show protection to your peripheral nerves and recovery from there from. And so we've seen that now, as I said, not only in our Phase III study in the FORWARD study as well as the propensity score real-world evidence work that we've done. So we're really confident in that.

In the context of the FORWARD study that's required here, what is the regulatory risk that's left around that trial itself?

Until we go back to the regulators, we don't know. What I can say is we're really, really pleased with the consistency of the data that we're seeing in the FORWARD study with what we're seeing in the Phase III study. And that's in 3 regards. One, the PK/PD profile. So if there were different profiles, that would be an area for concern. We don't see that.

If there were differences in safety outcomes, we would be concerned. It's important to know this is a single infusion. Our safety profile is really akin to placebo. So really, really important. And I alluded to some of the efficacy outcomes that we're seeing really rapid benefit that's durable over time. So we're not really seeing anything that's different between the patient population. And we didn't expect to because GBS is GBS, wherever you are in the world.

Speak to the commercialization dynamic here because this would be one where you would partner ex-U.S. but take it forward yourself in the U.S.?

Yes, absolutely. Yes. So it's a rare disease, and it's just really not our bandwidth to partner it or to commercialize it in Europe. And so we will either do that in ex-U.S. partnership or some type of distribution type of an agreement. In the U.S., however, a very efficient footprint. GBS is a population-based disease. So there are about 50 or so health care centers that see more than 50% of the patients year-over-year for 7 years. That's a very targeted footprint.

What's key is this is a hospital-based disease. So you need to be on formulary and you need to be reimbursed in a large field force. You need [ MS sales ] and you need field managed care. We're well underway in that process here in the U.S. So we're encouraged and we're really excited. The other thing I'll just say is it's a really significant market opportunity.

I mean, there are 8,000 patients a year that get GBS and about 95% of those patients are being treated currently with standard of care IVIg, even though it's unapproved and its treatment effects the midland. What that means is you have a ready-made market. We have an approved therapy, particularly when you look at the outcomes in our study. So we're excited to really make hay with this in the commercial.

We do also have a pipeline behind these 2 programs? And how do we think about 1502 and when we could get proof of concept from that oral small molecule?

Yes, we like it. It's coming. So this is the first small molecule in the classical complement space, really designed to target activated form of C1S, which is a target that's been clinically validated by multiple antibody approaches in disease like myasthenia gravis, et cetera.

Our thought is that if we can provide an oral therapy, we really have an opportunity to capture a market where about 70% of the patients are currently on oral. So we really like this from that perspective. We're in a small proof-of-concept study, really a translational stage study to show that we can effectively engage this activated complement and normalize it as well as looking at disease markers like bilirubin, et cetera, in a very objective fashion to see if we can normalize that as well. We anticipate data this year, second half of this year for the GA data.

And how would it be differentiated versus the other complement targeting drugs in myasthenia gravis, for instance?

Well, importantly, C1s, as I said, has been validated. So it will be similar in that regard. It could be perhaps a little better, but we rolled that back until we see the actual data. The big differentiation is ease of administration though. These patients are really, really in significant conditions. And so the ability to take an oral at home is a game changer.

And then speak to your cash position. Given the current set of programs that are advancing, do you foresee the need for additional funding as you look to commercialization?

Yes. So I think we reported $225 million on the books at our last earnings, which gives us runway into -- well into the second half of 2027. So through all of the key catalysts. So that includes the GBS filings and approval, that includes 1502 proof of concept and importantly, the Phase III readout in geographic atrophy.

So we are really comfortable from that perspective. That being said, we're engaged in a lot of nondilutive efforts. We do have -- all of these assets are wholly owned. We're not commercializing GBS, for example, outside of the U.S. So we'll look to do some things here to kind of beef up our balance sheet in the not-too-distant future.

Great. Maybe a last question here. Anything else that you want to highlight about the company's strategy? And as you look to these big data reads that are all.

Yes. Listen, we're excited. We call this a wind season for us, like we've been at it now for 11.5 years after we brought this technology by Stanford University. And we're encouraged -- more encouraged than ever that by stopping inflammation right where it starts on disease tissue, we're seeing differentiated outcomes in downstream approaches in all the diseases that we've been in.

Folks talk about GA and upstream versus downstream. But look at GBS, I mean, Alexion ran a Phase II and a Phase III in GBS. Our outcomes are dramatically different. We're seeing it in GA. So for us, this is a period of execution, like we're really sharply focused on executing, coupled with that, doing a bit more -- actually a bunch more on the education front, making sure that people understand this is a novel approach. All complement is not the same. And we're looking to return people's lives by really providing function depending upon the disease in which we're pursuing. So it's an exciting time for the company. We appreciate being able to talk about it here.

Great. Thank you so much.

Thank you, all. Appreciate it.

Good afternoon or still good morning, I think. Welcome back to the Bank of America Healthcare Conference. I'm Tazeen Ahmad. I'm one of the senior biotech analysts at the bank. It's my pleasure to have our next presenting company with us, Annexon Biosciences. Presenting for Annexon this morning will be Doug Love, who is President and CEO. Doug, welcome back to Las Vegas.

Thanks so much, Tazeen. We're always happy to be here. We appreciate Bank of America.

So maybe we can just do a quick overview of Annexon, your platform and your programs, and then we can go into a little bit more detail on some of the upcoming data catalysts.

Yes, happy to do that. I'll be brief. Annexon is a leading neuroimmunology company -- it has been already. Anyway, we're targeting complement, which many of you are familiar with, a very differentiated approach. So we're targeting the classical complement pathway. And importantly, C1q, the initiator of the pathway, it's completely different from any other complement approach people may be familiar with in that C1q localizes and binds to disease tissue and a host of neuroinflammatory diseases in the body, brain and eye. We're 11 years into the journey, and we're more excited than ever at where we are. So after 11 years, we are led by 2 leading programs, one is in Guillain-Barre syndrome, an acute neuromuscular disease.

In fact, the leading cause of acute neuromuscular paralysis in the world. There, we were successful in a pivotal Phase III study, really showing dramatic improvement in patients within a week and durable out to 6 months and beyond. And so we're really looking forward to getting -- making this drug available worldwide to patients we have filed in Europe for approval, and we will be filing in the U.S. for this program as well. The second lead program is geographic atrophy, a separate drug candidate intravitreal administration of Vonaprument. There, this is the only program to demonstrate significant vision preservation on all measures of visual acuity, including the gold standard measurement of best corrected visual acuity, 15-letter loss.

We also showed importantly significant preservation of retinal neurons in the eye responsible for visual acuity. These are photoreceptor cells and even more pronounced protection in the central retina. So really excited about this program. We are in a large Phase III program, 659 patients that will read out in Q4. Last program is a really novel first-in-kind small molecule program -- first small molecule program targeting the classical pathway. All 3 of our programs are designed to be market winners. And so as it relates to the small molecule, we're advancing it in a proof-of-concept study with the aim of ultimately taking it into a host of neuromuscular diseases that have currently been clinically validated, but are being treated by antibodies, either by IV and more recently by subcutaneous approaches.

So a holistic approach with the aim to treat millions of patients worldwide suffering from neuroinflammatory diseases, and we're energized by that.

Okay. Thank you for that overview. So maybe let's start off on geographic atrophy. You've got the pivotal study that's going to be reading out this year. Just mechanistically, on C1q, it's differentiated from the other 2 approved drugs in the market. We've talked about this in the past, but just remind us why, mechanistically, you think that there is a higher chance of showing a benefit on visual acuity, which is what your primary endpoint is for Phase III?

Really good question. So as I said before, not all complement is the same and targeting C1q in the classical pathway is very different than the first-generation approaches targeting C3 and C5. What C1q does is it binds to the locus of geographic -- the disease, geographic atrophy as it relates to visual acuity. These are photoreceptors, synapses and neurons that are responsible for receiving light so that we can go forth and conquer. C1Q binds that and drives their removal, this process happens prior to what the downstream complement target -- components we're targeting, which are RPE or lesion growth. It's really important to understand that. So the way geographic atrophy works, the photoreceptor neurons, as I said before, receive light, and that's how we see. Underneath the photoreceptors are called RPE cells that provide trophic support for your photoreceptors to be healthy. These are durable cells.

Unfortunately, for the programs that have already been approved, you lose your photoreceptor cells before you lose your RPE cells. The downstream approaches are targeting RPE cells after you've already lost your vision. And so as a result, you're not able to protect vision by protecting RPE cells, whereas by blocking C1q, you are protecting your photoreceptor synapses in cells, which we've demonstrated preclinically and now clinically, and that's led to the vision preservation that we see in our studies.

Okay. So just remind us about powering of the study and -- how many patients do you have in each of the arms? And when should we -- what should we expect to see at the top line when the press release comes out?

Yes. So as I said before, the data will read out in Q4. The study is a 659 patient double-masked study. It's randomized 2:1 treatment arm to the sham arm, it's the 5-mg monthly dose. And what we will read out in the top line is both outcomes on multiple visual acuity measures as well as the key structural measure in our study, which is protection of photoreceptors as measured by EZ or OCT analysis. So we're really encouraged by that.

So FDA is the primary endpoint, there was kind of one way to win on this, which is you show a statistically significant impact on that endpoint. With your discussions with FDA, I'm just curious if there -- if the results come, and it looks like it's a trend, but for whatever reason isn't stat-sig, is that -- does that provide an avenue to continue to pursue an approval?

Yes, it's a good question. So we do think there are multiple ways to win. Our base case is that we will win on the primary endpoint, best corrected visual acuity, 15-letter loss. We are looking at key secondary measures, like I said before OCT, low luminous visual acuity, et cetera. The way the study is designed is it's a single protocol study of 659 patients. For approval in Europe, we need to win on that single analysis. In the U.S., in agreement with the FDA, we have 2 sub-studies that roll in under the single protocol, each sub-study has been powered at a high Phase III powering so greater than 90%. And so our base position for winning is in Europe, we win on the overall study. In the U.S., we win on the 2 sub studies. If we find ourselves in a circumstance where we went on the overall study and one of the sub studies, I think that's a discussion we would have with the FDA for moving it forward as well.

Okay. Now if you think about the uptake that you've seen with the other 2 approved drugs, what do you think has been rate-limiting for those?

Yes, it's twofold, actually. The first is, of course, you are not providing visual benefit for a patient population where vision is the key endpoint for these folks. This is what they're looking for. A point about best corrected visual acuity in 15-letter loss, what that represents is 50% of your vision over whatever period of time in which you're assessing that. So that is quite significant. By law, you're having to turn in your driver's license, in effect lose your independence. And so you can imagine as a person who is elderly, the average age of the patients entering our study is 80 years old. So if you're coming in to get a shot in the eye every month or every other month, you're looking for preservation of your vision. The drugs that have been approved, unfortunately, have not done that after 4, 4.5 years' worth of data. And because they are targeting a lagging indicator of the disease, RPE lesion growth, it's unlikely that they are going to demonstrate vision preservation, certainly not in a reasonable period of time.

We've already seen that. And so that's impacted the market uptake, if you will, we know 80% of patients are not being treated in the GA market currently with the current therapies of those 20 or so percent of patients who are being treated somewhere between one-third and half of them are discontinuing treatment within a year of therapy. So the current first-generation therapies, they're an advancement, but they're not really solving the need for this patient population. On the other hand, with our approach with Vonaprument by blocking C1q and protecting retina neurons or photoreceptors in the eye which result in functional preservation of vision.

Again, we've measured that on every assessment, BCVA, low luminous visual acuity, et cetera, we are giving patients their independence and their life back. We expect the uptake to be quite, quite significant early on because it's a complete paradigm shift. One other thing to note about our data in the Phase II and what we're encouraged about with the Phase III is that when you look at patients who are earlier in the disease -- excuse me, earlier in the disease process, as described or defined by low luminous visual deficit of 30, 0 out of 56 of those patients in our study lost vision. So this is early neurodegeneration. You want to stop the disease process so you can go forth and conquer the remainder of your life. 0 out of 56% lost vision, whereas in the sham group, about 17% of those patients lost vision.

So why that matters for us is we anticipate rapid uptake just because we have vision preservation alone, but we think it's going to be even bigger because we're going to be able to punch into earlier-stage disease and being able to attack neurodegeneration before it gets too far advanced. And that's what you see in all neurodegenerative diseases, whether it's Alzheimer's, Parkinson's and whatever. You want to treat patients earlier in the disease before you've had too much neuronal damage, and that expands your market opportunity as well. So we're really encouraged by the opportunity of this commercially.

Okay. What type of commercial footprint do you think you'll need to have, assuming that you're able to launch?

Yes, good question. It's a really efficient opportunity here. So there are about 3,000 retina specialists here in the U.S. Most are in large practices, although not all. And we know that we can get to these patients or these physician practices in a multitude of ways, but in a very concentrated way. The thing I love about the retina community is it's very well integrated. There are a lot of conferences. There are a lot of communications. They read the publications, et cetera. We anticipate a really very efficient footprint overall, but it will be reasonably sized to attack these 3,000 retina physicians. Two of the larger practices in the retina space see about 50% of the patients so it's really quite nice being able to contract with some of these larger practice groups and then making sure we're doing the effective education with these sites around the country are really important. We're doing that now from a disease perspective as well as educating on the mechanism of action with Vonaprument.

So we have a full med affairs team out, a full disease campaign behind that. So we're bringing them along now as we work through the Phase III study and then ultimately, we will launch with some vigor thereafter.

Okay. So maybe let's -- one more question about GA, and then we can move on to GBS. For the other 2 drugs that were launched, over time, it became a little bit more apparent that safety became a little bit of a concern. Now this might just be a numbers game. You haven't had any similar type of events as it relates to infections with patients after injection. But how should we be thinking about that in a real-world setting? So this does get approved. This does get adopted. What should we think if over time, you start to see similar side effects as to what the other injectables have.

Yes. Well, so a really good question, a really important question for this community. Again, safety is very, very important. And you're right, a number of just pokes in the eye will help inform your safety profile over time. But you're also right, as we sit here today, we just have not seen the types of safety events that have been seen with some of the downstream approaches. And we've got a few views on why that's likely the case. First relates to the drug candidate itself Vonaprument. So this is a fab fragment. It is a small fab fragment. It is 50 kD. So really small, with low viscosity, no viscosity at all. The volume is about 25 microliters, about 1/4 of what it is for SYFOVRE, for example. So that allows for really simple and efficient ease of administration.

And importantly, it's non-PEGylated. So you're not getting kind of the viscosity and other issues that are associated with PEGylation with our drug. So that's really, really important. The second aspect from a safety perspective is our mechanism itself. We are solely blocking the classical pathway. We're allowing the lectin and alternative pathways to continue to function to perform their immune support for the eye. That's really important from an immunologic perspective. As a result, what we saw in our Phase II study is we saw very little of no conversions to wet AMD. If you'll recall, the approved drugs have conversions to wet AMD, somewhere in the neighborhood of 10% to 15% of their patients come in to get treated for GA, they come out with GA and wet AMD. When you look at our Phase II data, our conversion to wet AMD very much resembled sham and natural history over time in many other studies.

So we're not seeing the conversion to wet AMD, which we think is really important. And then that, coupled with allowing the other 2 pathways to perform their immune function. We think over time, this drug is going to have a really positive safety profile. And I don't want to underestimate or underemphasize the route of -- the way we are administering this drug and 50 kD and 25 microliters is really, really important. It just allows physicians to do a quick administration and move on. And so you don't have, at least thus far, the infection risk that we've seen with other approaches.

Okay. So let's move on to GBS. Can you just give us an overview of that program? And then we can talk a little bit more about the market opportunity and where you stand on.

Yes, we love this program. This is a labor of love. As I said before, the #1 cause of acute neuromuscular paralysis, you're completely healthy. That's an indiscriminate disease. It can strike anyone at anytime and anywhere. You're completely healthy. You get some preceding infection like food poisoning, or something or another, your immune system classical pathway kicks on to rid the body of these sick cells, which is the appropriate role. For whatever reason, a month or so later, your immune system kicks on aberrantly targeting peripheral nerves, which leads to ascending paralysis of your body -- up through your body, 1 in 4 patients are on a ventilator within a matter of 10 days. So a really significant debilitating disease and many, many patients never fully recover.

In fact, 20% of patients with GBS even with current treatments are unable to walk without assistance a year after the disease. We know the mortality rate for GBS within a year after GBS if you are 60 years or older, is around 25%. So this is a devastating disease. And we're really proud from a company perspective to be the only company to study this disease in a controlled study in over 40 years. And the reason we did it is because we know C1q is the key effector driver of the autoantibody attacks to drive the disease. And so that's led to robust outcomes in our Phase III study as I alluded to before. And so we really, really want to emphasize that this is an important medicine for patients to give them their lives back and their families around the world. Where we are today, having won our Phase III studies as I said before, we have filed for approval in Europe, we will file for approval in the U.S. And I just want to make sure I'm answering your questions.

Yes. So let's talk in a little bit more detail. So you filed for approval in Europe, what type of feedback have they given you so far.

Yes, we've had really good engagement with Europe, some initial responses from them in terms of questions exactly what you would anticipate. And so really nice ongoing dialogue. They've also begun the inspection process of our facility or our sites in Southeast Asia, which we like. So it's a really active process. The thing I will say about Europe, which is a bit different than what we see in states is there's a lot of expertise in Guillain-Barre syndrome in the European setting. There are multiple institutions in Europe that are studying GBS and there have been a round of studies that have been conducted over the last 15 years. They are not controlled studies, but studies nonetheless. None of that has happened in the U.S. Why that's important is the regulators in Europe understand GBS at a depth that we've not necessarily seen here in the U.S. yet.

We will get there with that. So we got a round of discussions with them at the country level. We've had rapporteur meetings, and we filed the document, and now we're engaged in discussions with them on our submission for EMA approval. So we really like where things are with Europe. I'm sure you're going to ask me about U.S., but I'll wait for you to do that.

Yes. A couple more questions on Europe before we move on. So what type of treatment regimens that they have there that might be different from how they're treated -- patients are treated here.

Yes. In Europe, it's pretty much the same types of therapies are being used. So IVIg is used in Europe like it is here. IVIg is not approved in the U.S. It is approved in Europe, but it's approved on a [ named patient basis ] for use is not based on a study that's been run. About 80% of patients get IVIg. The other 20% get plasma exchange or plasmapheresis. So that's a really involved approach. IVIg is 5 courses of therapy over 5 days and unfortunately, about 1/3 of the patients get a second course of treatment. So they go 5 days. Look and see how the drug is affected. And if the drug is not working well, which happens in many, many instances, they'll do an additional 5 days not ideal for patients, not necessarily a safe approach for patients, but it's what's done given the debilitating nature of the disease. And then for plasma exchange, you're -- that's 10 days of plasma exchange it is not at all comfortable versus our approach, which is a single infusion in a matter of hours, hospitalized and you're really arresting the disease right away day 1, if you will.

And how would you think about what reimbursement would look like in Europe.

Yes. Reimbursement in Europe is obviously an important topic, a more relevant topic today than any other time I can think of. So very much like most drugs in Europe and it's certainly rare drugs. It's done at country level. And so we've begun having those discussions at the country level, really educating on the disease and the burden of illness of the disease and the cost associated with the disease. So we've done significant, I would say, the most extensive health economics work ever done in Guillain-Barre syndrome. There's one paper out there 20-some-odd years ago from an academic institution. We've done robust assessments. We had multiple publications at AAN, and you'll see additional ones out at PNS and other conferences upcoming. That's predominantly centered on the U.S., and we've now pushed into Europe with some of that work as well.

So we are educating the payers in Europe, if you will, on the advantage of using our drug and the cost savings associated with it. Europe is very much a value-based system in terms of reimbursement for your drugs there. So we like where that is today. More work to be done from an education perspective.

Okay. But you expect to keep rights to Europe, you're not going to partner it?

That's a TBD. So it would be much more efficient to put it in the hands of the partnership. We've had multiple partnering discussions. In fact, we've had multiple partnering term sheets. I don't mind saying that. We want to make sure we do this in a way where we take a global perspective on the overall availability of the drug and the pricing of the drug. So MFN is relevant to us as it relates to an ex-U.S. deal. And so as we navigate through that, that may or may not lead to a partnership. They're certainly at the table. I feel like there's a path forward for that, but until we get a bit further we kind of hold that back a bit.

Okay. All right. So now let's talk about the status in the U.S. Just remind us about everything that's happened up until this point.

Yes. So to get approval for Guillain-Barre syndrome, both in the U.S. and Europe, there are 2 requirements. One is to demonstrate substantial evidence of effectiveness. The standard there. Because we ran the studies outside of the U.S. and Europe, we have the additional requirement of demonstrating generalizability, that is the patients in our study are consistent with the patients that would be treated in the west and the outcomes would be consistent. So we did a real-world evidence analysis of the patients in our Phase III study, we matched them with a 2,000-patient natural history data set run worldwide countries across the globe, including the U.S. and Europe and Bangladesh. And we were able to match our patients one for one in a propensity score matching. So we feel very good about the patients in our study are consistent with what you would see in the West.

We also compared outcomes with the patients who were matched in our study with patients who were treated with IVIg or plasma exchange from the natural history data set. And we showed that we were superior on every measure as it relates to GBS. So that's really, really important. So those are the 2 requirements for approval. Both in the U.S. and Europe, we've submitted a full package on both of those requirements in Europe. In the U.S., we are going to submit both of those, the U.S. appears to want some additional data in the U.S. as it relates to treating patients in the U.S. and Europe with our drug. That's an important concept for us. We've, of course, treated patients in the U.S., in Europe with our drug in other diseases like HD and ALS, but had not done so in GBS.

So we took it on. We've got an open-label study that's ongoing called the FORGE study really pleased with how that study is going. We're able to kind of track that on a per patient basis. And the purpose of that study is really a bridging-type study to show that the patients in the U.S. and Europe progress similarly as they do in Southeast Asia where we ran our Phase III studies.

And the outcomes with our drug are similar. We're looking at things like PK and PD predominantly. We're also going to show efficacy data because we're encouraged by what we're seeing so.

How long do you think it will take to collect that data and submit it to FDA?

We're well on the way on that. We still anticipate filing this year. Obviously, there's been some adjustments in the FDA more recently.

Sorry, you do and you don't?

We do.

You do.

Yes, we do anticipate filing on that this year. We're watching kind of the landscape within the administration at the FDA to make that final determination. But we're -- from a data perspective, we'll be in a position to file this year.

Okay. And then you mentioned the change that was announced yesterday at the head of FDA. Does that have any impact, do you think?

I wouldn't think so. I mean, I think one of the things we're in the neuro division, the thing I would say about the neuro division of the FDA is that they're really well familiarized with our program. We've had more than 10 interactions with them over the course of the conduct of this program and they're experts, and they're showing up every day and doing their jobs. I expect they'll continue to do that.

Okay. So how do you think about the market opportunity in the U.S.?

Yes, I love it. I mean the thing about GBS because of its devastating nature, everyone gets treated. 90% to 95% of patients currently are getting treated with IVIg or plasma exchange. Now these patients are getting treated way too late. Way too late to have a meaningful effect. In fact, we know 1 in 4 patients are diagnosed upon first presentation in the U.S. And that's because there's been no education for the physician community out here on the diagnosis of GBS, which is really straightforward, really just have to capture a history of the patient. And then the protocols are very diverse across institutions around America. And again, because no one has centralized this. So a new therapy is going to allow for better outcomes for patients across the board. From a market perspective, it's about 8,000 patients in the U.S. every year, incidence based disease, get GBS, another 15,000 in Europe or so.

And given that 90% to 95% of these patients get treated every year, that's a meaningful market. That is a large rare disease opportunity, one of the largest I've seen before, which we're really encouraged by. From a commercialization perspective, it's an incidence-based disease, which means these patients tend to show up in larger population areas. There are 50% of the practices in the U.S. see about 50% of GBS patients in larger centers. Because we're running this FORGE study, we're in many of these practices. So we're working with them already getting them familiarized with our drug how to diagnose GBS a bit more efficiently and making sure the protocols of moving the patients through the system are really, really efficient.

So I really love the experience that's happening with this study as it relates to this opportunity. From a commercial footprint, however, really, really small. And that is we're not going to have a bunch of sales reps walking the halls and hospitals, they're not going to allow you to do it. So our focus is really twofold. One on the medical education side, which, again, we're already out there with our MSLs and others with disease education, education on our Phase II or Phase III program, et cetera, on that.

And so really making sure people understand that we have just started to educate on our health economics outcomes, they are really demonstrating the cost to the health care system at a system or hospital level basis for treating GBS on an annualized basis and the potential savings of a drug like ours where we showed patients get out of the hospital or they walk 30 days sooner. They get off the ventilator 30 days sooner. They get out of the ICU 10 days sooner. These are hard dollar savings to the health care system. And so we're going through that burden of illness, burden of cost to these systems with them now. So we really like this from a commercial setting in the U.S.

And then maybe on the point of pricing, obviously, you're not going to announce that right now, but what's the range or what's the comp to look at.

Yes, I appreciate you saying that. Yes. So we are doing the work now on that. I think the thing I think about when I think about pricing is, I think this drug is quasi analogous to a CAR-T type of therapy. The reason I say that is hospital-based single treatment, but it doesn't have all the downside kind of circumstances that go, right? Like it's just an infusion. You're not having to go through difficulty in terms of administering and have some of the issues with it. we don't anticipate pricing anywhere close to where the CAR-Ts are. When I look at the analyst reports covering it, they have somewhere between $150,000 for course of therapy for the drug. That's probably not unreasonable, but we're continuing to do a lot of work. So I will say, the value of the drug in getting patients back to their life sooner is where the opportunity is from a pricing perspective.

So this would be a little bit of a paradigm shift in terms of how patients are treated. Not a little bit, it would be. And so how do you anticipate what the initial responsiveness if this does become available would be by physicians?

Yes. Just based on what we're seeing in the FORGE study, I think it's going to be quite robust and exciting. What we're seeing is, is that patients are having a really rapid benefit. If you looked at our data in Phase III, just by way of example, 86% of our patients showed benefit by week 1, day 8. And we're seeing consistency in the FORGE study. You've never seen that with the current therapies that are out there. Well, firstly, it takes 5 days to infuse these therapies, 5 to 10 days, right? So we are immediately arresting the disease and getting patients back on their feet and the response to that has been really dramatic. We're really, really encouraged by that. More to do, but thus far -- so far, so good.

Okay. In the minute that we have left, I wanted to quickly touch on 1502. So you've got a program, a proof-of-concept study that you're running in CAD, can you just talk to us quickly about that and why you've chosen that indication.

Yes. We chose an indication really as a tool indication, if you will, it's an objective measures of impact on hemolysis by measuring bilirubin as well as complement levels which are elevated in this disease. So really objective measures, and that's why we chose it. We will not advance commercially in the coagulation disease, but it really will allow us to understand our drug's profile.

So what would be good data?

Good data would show that you're normalizing bilirubin and importantly, you bring your complement levels down to normal in a reasonable period of time. And with safety as well.

Right. Is there anything mechanistically to look out for on safety?

Not that we're aware of or I have seen.

So what would be the next step if you see what you want to see.

Yes. One of the things we have seen in this study is that we have seen a food effect with this formulation. So what I will need to see, we'll need to see when we get all of the data pulled together. Should we stop and do a reformulation or do we advance and move forward. So that's a TBD. Otherwise, the next step is to moving into late-stage study in one of the neuromuscular diseases like MG or CIDP.

Okay. All right. We're about at the end of time so we'll have to leave it there, but I'd love to continue that conversation next time.

Absolutely.

All right, Doug, thank you for spending time. Thanks everyone for listening.

Really appreciate it. Thank you.

All right, folks. Well, listen, good afternoon, everyone, and thank you for joining us today. I'm Doug Love, President and CEO of Annexon Biosciences.

And we're excited, delighted that you've joined us this afternoon for our Investor Day focused on vonaprument for the treatment of geographic atrophy or GA. Here we'll discuss its robust scientific and clinical underpinnings that support the vision sparing data that we've seen in our Phase II study and really gives us a great deal of encouragement for our Phase III program.

We'll be making forward-looking statements, of course, and we direct you to our legal disclosures here and on file.

So over the course of today's program, you'll hear from members of the Annexon management team as well as leading experts in geographic atrophy. We think our experts are coming out today, Dr. Nora Lad, Vice Chair of Ophthalmology Clinical Research at Duke; and Dr. Charles Wykoff, Retina Specialist and Chair of Clinical Trials for the Retina Consultants of America.

Following a brief company overview, I'll turn the baton over to Dr. Lloyd Clark, our retina specialist who also serves as SVP of Ophthalmology and Strategy and Innovation for Annexon. Lloyd will then pass it over to a very important talk by Dr. Lad, who will provide a deep dive into GA's mechanism of action, and importantly, the role of C1q in the classical pathway that drives vision loss in this disease. Dr. Wykoff will then come up to review the outcomes of blocking C1q inflammation from the Phase II ARCHER trial, including the important structural and functional benefits that are demonstrated in that study. Finally, Jamie Dananberg, our Chief Medical Officer, will provide a review of the ARCHER II Phase III pivotal program and provide a brief update on that status of that program as well. We'll then close with a roundtable discussion with our experts and then ask you to join us for a reception. So an action packed agenda, and we're just going to dive right into this.

Before diving into the heart of the program, I'd like to quickly provide a little bit of background on Annexon and how we got to here today. Annexon was founded with the bold mission to create an entirely new class of targeted immunotherapies to treat neuroinflammation by stopping harmful C1q driven inflammation where it starts on diseases in the compartments of the body, the brain and the eye. Our mission was and is to deliver meaningful functional benefit for patients living with a host of devastating neuroinflammatory diseases. And importantly, all of the diseases in which we are pursuing have significant unmet need and afford us the opportunity to help millions of patients globally.

Given that we're first in class, we've intentionally pulled or assembled a team of industry veterans with a track record in drug development, market-making and winning, who are playing with their hearts and minds to deliver on what is a meaningful mission for us. So it's a purpose-driven company.

Now the journey began over 20 years ago with the scientific work of Annexon co-founder, the late Dr. Ben Barres, former Chair of Neurobiology at Stanford University. Ben and his lab discovered the beneficial role of C1q in the classical pathway in early development, driving the removal of excess synapses to ensure appropriate neuronal [ surrogatry ] and function so that we can all go forth and conquer the world. It was a groundbreaking discovery that our immune system played a key role in scoping our brains and vision.

Ben and his lab went on to discover next that C1q accumulates on synapses as part of the aging process in all neurodegenerative diseases or in all of us, and is aberrantly triggered, which results in the removal of functioning synapses that are necessary for sculpting the brain and for sculpting vision. This is a very important discovery and really led to the formation of Annexon, where our goal was very clear: to stop C1q right where it starts on disease tissue to preserve function. Full stop.

Annexon was later founded in December 2014 to develop this platform approach and since has studied this mechanism of action in a host of diseases with diverse drug candidates. We've created more than 40 de novo assays studying C1q and the entire classical pathway in the specific diseases in which we are pursuing to really help understand the best way to target these really high unmet neurodegenerative diseases.

That has led to a robust and highly consistent preclinical package, which is the underpinnings for all of the clinical programs in which we have pursued. So we have not gone directly to the clinic. We have studied these diseases first in the preclinical setting to really inform what we did in the clinic. And we're happy to report that we've seen real significant consistency between what we've done preclinically and the ability to replicate that clinically in both acute and chronic diseases in a wide range of patient populations.

So with these learnings, we're more energized and we're closer than ever to really demonstrating or delivering on our promise of ushering in a new class of immunotherapies to treat these neurodegenerative diseases across the globe.

Today, our scientific foundation has translated into 2 late-stage registrational programs with blockbuster potential in large, underserved markets. GBS is our most advanced program, having demonstrated the first placebo-controlled data set in this devastating acute neuromuscular disease in over 40 years. There, we're blocking C1q inflammation both in the body and in the brain to provide complete protection against this inflammatory cascade. And that's resulted in a landmark Phase III pivotal win where approximately 90% of our patients improved by week 1, which translated to a 2.5x greater likelihood to returning to a full state of normal by month 6. Really unprecedented findings in this disease. We've now gone on to file for regulatory approval in Europe and we'll be filing thereafter in the U.S.

GA, of course, is next in line, where we're targeting C1q, this time specifically in the retina to preserve synapses and neurons to protect against vision loss. We demonstrated this in our Phase II study, Dr. Wykoff will review, and we're looking forward to our Phase III data readout in Q4 of this year.

And there's more to come out of this platform. Behind our 2 lead programs, our programs are focused on small molecules targeting this inflammatory cascade in the body. And we're also targeting a host of neurodegenerative diseases in the brain like Huntington's disease, ALS and TBI, where we have robust preclinical packages and, in some instances, early Phase II clinical data as well. So we're quite serious about our mission of helping millions of patients suffering from this devastating disease.

You'll hear more about the cascade later, but I just wanted to quickly punctuate that by targeting C1q in the classical pathway, it's a significant competitive advantage over downstream complement approaches that you are likely familiar with, like C3 and C5. That's because C1q is a recognizing molecule that localizes on disease tissue. It anchors and activates this entire inflammatory cascade, which amplifies over time. In other words, it gets far more aggressive and deadly as it moves on. Only by stopping C1q, again, where it localizes on a disease tissue, can you stop all of the downstream inflammation associated with the classical complement pathway. And as a result, this approach is the earliest and most complete protection one can provide against neuronal inflammatory damage.

Given the broad applicability of our platform, we've developed a diverse late-stage pipeline of neuroinflammatory diseases that we're pursuing with a diverse set of drug candidates. Each of these drug candidates -- we've taken learnings from each of these drug candidates to inform the overall platform and to give ourselves a greater likelihood of success in each of the respective indications. We've seen that now by, again, targeting GBS and stopping this cascade right out the gate, as well as in Huntington's disease and other programs. So we're really excited by that.

Today, however, we're focused on vonaprument for the treatment of GA, and for good reason. GA is a leading cause of blindness, as you well know, that unfortunately afflicts 8 million people globally, making it a major blockbuster market where scores of patients need an effective therapy to protect against vision loss. vonaprument is designed to do just that and drive immense value for patients and shareholders by, again, protecting the structure that is associated with visual acuity in this disease, which translates to robust vision protection on a host of measures and patient populations.

We also like this differentiated profile from a safety perspective being a nonpegylated fragment with really nice penetration. And you'll hear more about that in time. So we look forward to coming back to you later in the year to do a robust update on the market opportunity for geographic atrophy. It's immense. This is a patient population that's motivated for treatment. Concerns around vision is -- ranks high in this population. And we look forward to providing them a treatment.

So with that wind up, I'm going to pass the baton over to Dr. Lloyd Clark, who will give an overview of the GA clinical market. Lloyd?

Well, good afternoon. I'd like to thank you all for coming. I'm Lloyd Clark. I'm still a practicing -- part-time practicing retina specialist who's been involved in drug development for over 20 years. I've joined the Annexon team to work on ophthalmology strategy and innovation really excited about our program as we have the opportunity to bring a transformative therapy to the market.

An important takeaway for today is to make sure you understand that geographic atrophy is a neurodegenerative disease with central vision loss, and we currently have no approved vision preserving therapies. This really is foundational to our company and foundational to our program.

These patients continue to lose vision in our practices. And this is the highest, the largest unmet need in retina today. These patients have significant symptomatic problems. They develop gradual loss of vision. And then later in the course of their disease, that vision loss can be quite dramatic. They have difficulty in low light settings, which is an important clinical finding. And these symptoms start out mild but progress to more severe symptoms later on in the disease state.

Although these patients are somewhat older than our patients with exudative diseases, with the increased life expectancy, the number of these patients continues to increase in our clinical practices. This is a major issue for us as practicing retina specialists and a tremendous opportunity in drug development to provide meaningful therapies for these patients.

So again, GA is a chronic, progressive neurodegenerative disease. The figures on the right-hand side of your slide are 2. Color fundus images or color retina images that look at the back of the eye. In the middle of the slide, you see an eye with a normal retina that normal. That sort of regular orange brown color is normal for the retina. And then on your far right, you see a patient with a large geographic atrophy lesion where you have almost total loss of the underlying retinal pigment epithelium.

We know that GA is a neurodegenerative disease and that photoreceptors are lost first. That's what leads to vision loss. And then later, these patients lose underlying retinal pigment epithelium, a lagging indicator of disease activity.

We've asked patients about what's important to them as they think about geographic atrophy. When they're asked about the 3 activities that they're most worried about doing or struggle with, those include activities of daily living: recognizing faces, driving a car, watching TV or reading. These are real-life activities that these patients struggle with and ultimately affects their ability to live independently.

What are they most worried about? Well, by far, the leading answer is loss of independence for these older individuals. But again, the loss of the ability to perform their activities of daily living is key to these patients. So this is an important problem for our patients that we see every day in clinical practice.

As Doug outlined earlier, this is a large disease state, about 8 million patients worldwide, about 1.5 million patients just in the U.S. that are affected with geographic atrophy and would be immediately benefited from a vision preserving treatment. But keep in mind that 1 in 100 patients over the age of 50 have advanced AMD. This is a significant problem, the largest unmet need in retina, one that needs effective therapies for our patients.

A minute about endpoints. Clearly, visual acuity is the most important endpoint in retina clinical trials. In short, ophthalmologists, retina specialists, we're in the vision business. We're here to protect vision and improve vision. You see a number of transformative products here on this slide for different disease states that have been approved over the last 2 decades. All of these transformative therapies were approved based on 15-letter improvements or 15-letter protection of visual acuity. So this is a clinically meaningful and relevant endpoint for patients as well as clinically relevant for regulators when we talk about transformative therapies. We'll talk more about the endpoint a little bit later. But this really is key to understanding our program as a transformational program. We have to use the gold standard endpoints to demonstrate clinical benefit for these patients.

So with that, we're going to start our formal program. I'd like to introduce Dr. Eleonora Lad. She's Vice Chair of Clinical Research and a Professor of Ophthalmology at the Duke Center and the Duke University Medical Center in Durham, North Carolina. She is a practicing retina specialist, full, busy clinical practice. He also holds a PhD in neurosciences and really is a world expert in the science that she's going to present to you today, the role of C1q and the mechanism dry AMD with GA.

Nora, thanks for joining us.

Thank you, Lloyd, very much for the too generous introduction. It's really a pleasure to be with all of you today. I know it's a really cold day, so thank you for joining us. It is a treat to talk about dry AMD and geographic atrophy and dive a little deep into mechanisms of disease and the important role of C1q. I have a personal story behind I hope you'll enjoy and some really cool images.

So we all know geographic atrophy is important. You've heard from Lloyd, it's the biggest clinical unmet need in retina right now. And the treatment landscape is rapidly evolving. So we have the recently approved C3/C5 inhibitors that are designed to stop RP atrophy and lesion growth. And these studies are based on human genetics that show the complement inhibition is a viable therapeutic strategy for GA. And the C3/C5 inhibitors were designed to target the alternative pathway to preserve RP cells and reduce the lesion growth, so a structural issue. But the protection of RP has not resulted in preservation of vision in a predefined matter in the clinical trials, and we all know those data.

So now, fortunately, in retina, we now have recent advances. And these are advances in technology with Annexon therapeutics and also imaging. So photoreceptor neurons now are increasingly understood to be as the locus of disease based on OCT imaging and what's called ellipsoid zone image segmentation. Ellipsoid zone is a layer of mitochondria, and Dr. Wykoff will go into that in detail. And the recent data shows conclusively that GA is a neurodegenerative disease amongst the list of all the neurodegenerative diseases out there that are very important to patients. And this results in photoreceptor and vision loss.

And loss of photoreceptors through the classical pathway C1q, importantly, precedes RP loss. So it's an early phenomenon. C1q is very important. You've heard, all of us have it, in development is very important. We have -- we otherwise would have had all these aberrant synapses, some of us might still have them, but the C1q is very important developmentally. The problem is it becomes recapitulated in disease, in neurodegenerative disease.

So today's opportunity that you'll hear a lot about is this vision preserving therapy that will meaningfully improve patient lives. And I like the word meaningful because what our patients care the most is vision, and you'll hear a bit about that.

Because this is what the patients look like. So the normal ones are on the left. This is what a picture looks, hopefully, to all of us with normal vision. We have a normal retina with intact structure and function. The photoreceptors are the life sensing cells in the back of the eye that convert electrical signal and transmit them to the brain, to the optic nerve. And the RP are the supportive cells underneath the photoreceptors, but they're pretty sturdy and they degenerate later.

However, in a retina with GA, we have loss of signals because the photoreceptors are missing or dysfunctional. And then the RP over time also degenerates in this area of atrophy. They look like the cookie-cutter area that you saw on the back of the eye that Lloyd showed you. And what that translates visually for our patients over time is what you see here, a blind spot. That's a central blind spot. So they cannot see the faces of the dear family members, cannot drive, cannot read materials or look at their phone. So it really impacts their daily life.

And some of these patients are very healthy until they're 90s, but they're really impacted by GA. And we didn't talk about the burden of depression and anxiety related to this, but also hugely important. Because vision, again, is so important to our patients.

So now this is where the fun begins, I hope you're ready for a couple of colorful images here. So to orient you on the anatomy of a healthy retina in histopathology, this is human, and you can see this uniform layer of photoreceptors and synapses. This is a functioning, structural, well-integrated unit. So we have here, we have the photoreceptor cell synapses, the outer [indiscernible] layer. You can follow this across. It's nice and intact.

The cell bodies of the photoreceptors are stained in blue. That's the outer nuclear layer. And then the retinal pigment epithelium are those 30 supportive cells underneath. That's a normal retina.

But then what happens in GA? And this is complex, so we'll take this slowly from left to right. So in an intact case, similar to the prior image, intact photoreceptors, intact synapses and cells, and you can see this nice layer of synapses and the cell-bodies and RPE. However, this is an eye that has GA, which is way on the right. But in between the normal area -- and this is actually technically intermediate AMD stage in this eye, the zone of intermediate AMD, if you will, it's still functional. But over time, you see decline in photoreceptors. They become thinned out. Their synapses are missing increasingly. And their cell bodies become rarified as well. The RP also becomes more irregular, sometimes hypertrophy, then becomes thinner at the edge.

This is an eye of geographic atrophy with complete loss of photoreceptor, synapses and RPE. Synapses are gone, the cell bodies are less and then the RP is completely missing. And the loss function corresponds with that blind spot that you saw on that image.

Now going back to the pathway, the therapeutic pathway that we're addressing here today. So this is my personal story. I did residency at Stanford. And right after I moved to Duke to do fellowship and stay on as faculty there, I was reading the papers on the right because they started coming around right before Annexon was starting out as a company. But I was really impressed with this MOA. My background is in neuroscience, so I read the papers with great interest. Because I thought this molecule is fascinating. It plays a key role in neurodegeneration broadly. Again, it's important in synapses elimination development for all of us. But later on, it goes, haywire. It's pathogenic in neurodegenerative disease with aging and the pathways get recapitulated abnormally.

So C1q inhibition protects against synapse loss and neurodegeneration. And that's the basis of the research presented to you today. This functions very well in a list of diseases. We're talking about dry AMD today and the photoreceptor damage in the patients, glaucoma, retinal ischemia, Huntington's disease. These are really terrible debilitating diseases that can be addressed with this MOA, ALS, Alzheimer's and traumatic brain injury.

So you can see all the high-impact publications on the right, and they speak for themselves. These are really good animal models of disease and really important data over the year.

Dr. Ben Barres was the Chair of Neurology Stanford and also members of National Academy of Sciences. And this is just a really, really exciting MOA.

So you've seen this slide before. Now C1q inhibition works at the top of this, complementing the inflammatory cascade. Because what it does, again, C1q attacks functional synapses that are perfectly good otherwise for removal and disease. So it's aberrant. It activates the classical pathway. It attracts microglial cells, and I'll show you some examples of these beautiful cells, but they're not helpful in this disease state, driving neural death and resulting in loss of vision in patients.

In contrast, and that's really important and exciting to understand C3/C5 are downstream and the alternative complement cascades, they're removing dysfunctional cells at the edge of GA, driving cell clearance of RPE via alternative pathway. And this happens after the photoreceptor damage and loss happens.

These dysfunction RP cells, also important to understand, secrete VEGF. So you have an increased CNV risk with inhibition of C3/C5.

And going back to some histopathology here, you can see on the left an image of a retina where C1q is closely associated with synapses. So C1q is in green, synapses are in red. That could be good color-coding for the next image. Same thing happens in the brain, in CNS and Huntington's, you can see the exact confirmation of the synapses, C1q binding this closely. So it aberrantly binds to synapses in neurodegenerative disease and triggers damage and elimination of these synopsis where this should not happen.

On the right, there's some really promising Phase I clinical trial data in Huntington's disease. And you all know that's a debilitating neurodegenerative disease. The patients, they compensate function [indiscernible] over time. However, C1q inhibition stabilize these patients over 9 months in on-and-off period. And from what I remember from your science, that's a really difficult thing to do and it hasn't been accomplished in this terrible disease. So again, the MOA works very well in HD, and looking forward to seeing more promising data there soon.

But back to retina, C1q again recognizes and eliminates good photoreceptor synapses. They will be really good otherwise. And this is data from a light-induced neuron model of receptor degeneration. On the left, you can see healthy retina with nice synapses and photoreceptors. And then in the light damage model here, the synapses are really thinned out. You can see there's less red here. A ton of C1q in green that binds the synapses, attracting all these microglia, these pink cells [indiscernible] processes. And they're causing damage functionally to the synapses, and that's why they're missing. So quantitatively on the right, you can see a decrease in synaptic density in this animal model of light damage.

Does this happen in humans? Yes. But before we get there, so one more slide on how C1q inhibition helps. So vonaprument reduced inflammation and preserved photoreceptor synapses and cell bodies. And so you can see the control on the left with tons of inflammation from these pink microglial cells, a ton of C1q, synapses are really ragged, and C1q inhibition has C1q abolishing effect here and much less inflammation.

And the quantification of the microglia shows they're reduced the numbers, the photoreceptor synapses are protected and you have protection of the cell bodies as well. Functionally, not just structurally, you see protection of retinal function on electroretinogram in these animals.

Does this happen in human? Yes. So this is an image from a GA patient, again, back to histopathology. And you have here the C1q deposition on the synopsis. So the green with red gives you colocalization in yellow. But then you can see what happens. So this is a microglia cell body. It sends us processes actively in this area of synapses, and right there, they're missing because they are being trued up by microglia. And similarly, this area, you can see topographic localized loss related to a neuroinflammation.

So going back to progression of disease, I showed you the complicated histopathology slide. This is a nice diagram, we'll take it easy from left to right because I think it makes a lot of sense. So think of this as happening in the same eye, that illustrates zones of disease, from intermediate -- the normal to intermediate to GA, and also shows disease pression in the same eye.

So again, from left to right, we have an area of functional photoreceptors with intact synapses, intact RPE. The next stage, as you move towards GA, you have the RPEs intact because, again, this cell is quite sturdy and it generates late. But the ellipsoid zone starts to be coated as C1q and the photoreceptors as well. And over time -- so C1q binds the photoreceptor synapses leading to vision loss. So this is why the patients are starting having all the symptoms we talk to you about over a period of time.

Later in the disease process, you can see the photoreceptors become highly dysfunctional structurally as well, and then C3 and C5 come in because they start to clear these dysfunctional photoreceptors, and also the RP cells that now become affected at the lesion edge. So right at the edge of GA, you have a lot of C3 and C5 deposition. But again, remember, C3/C5 targets dysfunctional cells, so the inhibition addresses that at the lesion edge after the photoreceptor damage already occurred.

And then in the GA, you can see this is bare bones, basically you only have [ Brooks membrane ] and RPE photoreceptors are completely gone. This is irreversible. This is why GA is neurodegenerative disease, you do not get restoration of photoreceptors. They're terminally differentiated neurons, like in the brain, you cannot restore function. That's why I think the impetus is addressing the disease early in the zones before 4. By 4, it's too late.

So in summary, GA and vonaprument role in protecting vision loss in GA patients. So blockage of C1q is meant to stop photoreceptor damage at the genesis before the disease is irreversible and late. Vision loss in GA is driven by photoreceptor, synaptic and cellular loss. And this is neurodegeneration, you have photoreceptor damage and vision loss. And again, this is before RP atrophy. It precedes RP atrophy that's been targeting -- targeted by the recent complement inhibitors FDA approved currently.

C1q is an aberrant upstream trigger. It's quite different of this neurodegenerative process in GA. So it's a differentiated MOA from the current approved drugs. It tags as functional, perfectly good for receptor synapses and cells and disease for removal. And then you have the whole activation of the cascade. You have a cellular microglia recruitment and your inflammation galore with synaptic loss an irreversible vision loss. So we want to be ahead of it by inhibiting.

So again, this is -- there's a clear mechanistic differentiation between C1q inhibition and the inhibition of the downstream complement inhibitors. So upstream, we have protection of photoreceptors necessary for visual acuity, a very different mechanism. This allows for normal clearance functions of the alternate pathway, so it keeps those intact downstream or more intact downstream and they're helpful. And a downstream C3/C5 slow RP lesion growth, but do not slow vision loss prespecified in the Phase III clinical trials, as you've seen.

So with that, we will talk about the clinical data. It is my true pleasure to introduce Dr. Charles Wykoff, busy retina clinician and Chair of Clinical Trials for Retina Consultants of America, the biggest retinal practice in the United States. Charlie?

All right. Hello, everybody. Good afternoon. Great to be here with the whole team. Nora, that was an amazing overview of the science. I think it fits really nicely with the clinical data that we'll see.

Before I dive into what I have to share, I'll just give you my perspectives on the field. It's a fascinating and a really important pivotal time in retina, specifically for GA. And if you look at the pipeline of drugs across retina, there's more in retina than ever before. But by far, from what I can see, the majority of that is in GA.

And there are good reasons behind that. Lloyd and Nora just beautifully laid out what those are. Patients want to maintain more vision tomorrow and the day after that. They really want vision. And we have a huge unmet need to give them that opportunity.

And when you look across the trials, this one holds a key position because it is the next most important one to come out. There's actually a lot of data sets, probably 12 really important data sets across retina over the next year to 18 months to fascinating next year. But this is the most important one from a GA perspective because this truly a differentiated MOA has the opportunity to provide visual benefit to patients and it's the one that people are thinking about because it's the next Phase III trial that's going to really inform what could be for patients.

Okay. So let's take a deep dive into what the drug is, then we'll talk about the Phase II clinical trial, both the anatomic and the functional outcomes. So vonaprument, ANX007 as I would rather call it because I can't quite pronounce that yet, so forgive me, but this is a small biologic.

So I can tell you from a physician perspective, we like biologics. We've been using biologics in the space for 20 years. And they have an incredible safety profile in our hands, and that is attractive to me. 50 kilodaltons. Importantly also, it's nonpegylated, low viscosity and it's a small volume. So in the Phase III clinical trial, all patients are receiving 25 microliters per dose. That's a very reasonable volume lower actually than any of the anti-VEGFs, which is great, because the lower the volume, the less fluctuation in IOP for patients, which can be an issue.

And then as we'll show on the Phase I data in a second, most importantly, we're seeing good pharmacokinetic and pharmacodynamic signaling here. And it's fascinating, the complement cascade is complicated, and Nora describes it in a beautiful way. And it's fascinating because in some discussions, you think about, well, let's target the alternative cascade, and that's the whole goal. The whole goal here is actually the opposite. It's to preserve the alternative cascade. And I think we as a field are still trying to figure out where do all these things play.

I think the mechanism that we're talking about today, importantly, for you to understand, is actually preserving some of the important physiologic roles of the complement cascade in the back of the eye, which may very well be important for long-term health and optimal functioning of the retina even in the context of GA.

So this is the early human clinical trial data that gives us an indication of pharmacokinetics mostly. So the blue bars here are the sham-treated patients. These were actually glaucoma patients that got a single injection, in red. And the red arm was 2.5 milligrams and 5 milligrams given once a day 1. And you can see complete target engagement there with this small-format biologic after 29 days. So a month after an injection, you're still getting full target engagement. That's impressive. You're not bouncing back, suggesting you get at least 2 monthly dosing and, commercially, maybe there's an opportunity for significantly less.

So let's dive into the Phase II clinical trial data, ARCHER. Here's the design. You've been seeing this for years. Gold standard clinical trial design. 270 patients, so a large trial. Sham-controlled patients are in gray through all of these graphs that I'll show you. And then the 2 active arms in red and blue. The red is every-month dosing with 5 milligrams and the blue arm is every-other-month dosing.

Importantly, really important geographic atrophy trial is to understand who is the patient population that's been enrolled. So in this patient population includes patients with both foveal-involved GA lesions and non-subfoveal lesions, and we'll talk about why that's important, randomized, double-mask and gold standard design.

Primary endpoint was looking at GA growth based on fundus autofluorescence. We'll talk about that, and then a lot of prespecified endpoints related to function.

Really nice trial design also because there's this 6-month ticker at the end. You get 12 months of active treatment, but then a really nice scientific design there at the end where you have 6 months off treatment that really gives us an indication of the disease-modifying potential of this drug, and we'll come back to that as the last slide of this data set.

Okay. So here's the baseline characteristics overall. Well balanced between the arms. No outliers here. Average vision was about 20/70 in each arm. Visual acuity was -- or foveal involvement was at about 50% of patients. Half of the patients had GA lesions that involve the center point of their vision. Average size was 7.3 millimeter squared. And the majority of these lesions were multifocal. And about 1/4 of them had wet AMD in their fellow eye.

Another important thing to notice, because some trials exclude those patients with wet AMD in the fellow eye, specialty programs that are worried that their drug may cause wet AMD conversion. This one did not exclude that in the fellow eye.

Okay. Let's go through the anatomic outcome squarely and then we'll dive into the functional outcomes. So this is the primary outcome data here. As you know, this primary endpoint was not met. This was the rate of change of GA lesion growth as measured by fundus autofluorescence, right? So we'll talk about 2 major imaging modalities: FAF, or fundus autofluorescence, is what was used to gain FDA approval of the 2 commercially available drugs for GA currently. And essentially, it's measuring RPE cells. It's measuring the [ lipofusion ] collected in RPE cells over time.

And if you look on the graph and you double-click on it and you look closely, you see, well, is there a separation there, right? Is that red line separating a little bit? The answer is maybe. Numerically, it's 6% slower growth than the control arm with monthly dosing.

But then if you look at the right graph, this is where this may be a reflection of the pathophysiology that Nora beautifully described. And that is there appears to be no benefit on slowing GA lesion growth from an RPE perspective in the first 6 months. But if you look at the second 6 months, there is a signal there. And what that might be suggesting is that if you preserve photoreceptors by inhibiting C1q and you stabilize that visual transduction signal through photoreceptor protection, maybe then you get secondary protection of the RPE cells, right? They're in complex. These photoreceptors and RPE cells have a very close relationship. And so if you stabilize one, photoreceptors, which we know are dying, before the RPE cells in this disease process, you very well may subsequently protect the RPE cells.

I like that signal here, and it tells me if I did a longer trial, 18, 24 months, that's where I would expect to see further separation of this curve, focusing on RPE cells.

Really important subpopulation of patients for a lot of reasons. This is looking at patients with subfoveal lesions, right? So these are patients where the GA has actually affected their central vision, right? When you look at me and you look at the slide, you look at your computer, right, you're using, yes, your fovea, but you're using your center point of your fovea. Because the fovea is actually still an area, but center point is just a single dot in the back of the eye where you actually are reading from. And all the patients included on this graph have involvement of that center point.

It's particularly important because these patients are probably much more likely to experience a 15-letter loss or a 10-letter loss or a 20-letter loss because their fixation point where they're seeing from their high acuity area is actually much less stable. And in this patient population, you're actually seeing a potentially larger signal of efficacy here of slowing GA lesion growth with fundus autofluorescence here. Again you see that same greater benefit in the second 6 months and the first 6 months, up to 14% to 16% growth reduction in that second 6 months among this subfoveal patient population.

So that's all fundus autofluorescence based imaging outcome. It's really important to look at that, largely, I think, from a historical perspective because that's where the field was headed for 20 years. I think we've become much more sophisticated as a field and thinking about geographic atrophy and intermediate dry AMD that a lot more information can be gleaned from the OCT. And that's what I'm going to unpack here.

So Nora showed some beautiful images here. This is the OCT correlate of what Nora was showing, right? This is a cross-section through hopefully your and my fovea. This is a normal cross-section. This is about as thick as a human hair. So if you pull a hair off your head and you hold the sideways, it's about how thick the human retina is.

And the photoreceptors make up about half of that thickness, right? The dark band there, the photoreceptors and then there's multiple different layers of photoreceptors. But the one that we're focusing on is the ellipsoid zone. And that one is important because it houses all of the mitochondria, right? Photoreceptors are powerhouses. They are incredibly active at generating ATP. Vision takes a lot of energy. And those photoreceptors are packed into that small zone called the ellipsoid zone.

And loss of that ellipsoid zone is a critical biomarker strongly associated with visual function in GA, in AMD, but other diseases also [ Mactel ] type 2, for example. That's how revakinageneor the Neurotech Encelto implant got FDA approved, based on this biomarker analysis.

So within the ARCHER Phase II clinical trial, we took all patients that at Heidelberg imaging was 192 out of 270, and specifically quantified this photoreceptor health over time by looking at this ellipsoid zone.

And here's what that data shows. So this was across the entire volume scan. So as we talk about these 2 imaging modalities, important also to think about the field of view. So with OCT, we're taking a 6x6 area. So it's 6 millimeters on each side. It's a cube essentially. And then across that zone, you can see that, with active treatment here, you've reduced lesion growth, GA lesion growth that's focused on ellipsoid zone by 27%.

But then really interestingly and something that took me a while the process when I first saw this data, is that this appears to change. The potential benefit of the drug seems to change depending on where you're looking geographically in the back of the eye, right? So the whole OCT volume scan is 6x6 millimeters. But if you tighten that in the middle and you come into a 2-millimeter diameter and you tighten them more on the right and you come close to the central subfield, here slightly larger, 1.5 millimeters, you can see that those percentages of slowing GA lesion growth by focusing on photoreceptor EZ zone actually increases from 27% to 48% to 59%, slowing of progression of the disease.

And why is that? I don't think you would see this with other drugs. I think you're seeing that specifically with this drug because the photoreceptors have a particular proclivity there in the center of the macula where this drug can be most beneficial.

So let's show this on a specific patient example to kind of put this into perspective. This is a single patient in the sham population. Many patients would fit this, but this is just one illustration. So on the top left here is OCT cross-sectional imaging. And below that is the corresponding fundus autofluorescence, right? So top left, looking at photoreceptors, in particular, the ellipsoid zone.

So green is good here, right? The green is intact photoreceptors. On Nora's imaging, was sort of Zone 1 and 2 essentially, photoreceptors that are still working. And then in the black, you have total loss of the photoreceptors. So you want more green.

And if you look in that central red circle, that's where patients' high visual acuity comes from. So when they're checking their vision, that's what they're seeing with. And when you look at that, you think, okay, there's about 50% of that red circle is green. And then if you go forward to 12 months in this sham-treated patient, you can see you've lost most of that green in that central red circle. You can see now a much larger area of black in that zone, indicating photoreceptor loss. And that corresponds nicely in this patient with a loss of vision, from 66 letters down to 51 letters. That's an irreversible progressive decline. A 15-letter loss is a very meaningful loss for patients. This is a life-changing event where they lost half of their visual function.

In parallel, there at the bottom, on the fundus autofluorescence, that change in that central circle, much less evident to the naked eye, right? So what we're doing with OCT is we're able to at a granular level what we think is actually happening from a visual function perspective. It's a nice link between the anatomy and visual function that I think is much more difficult to glean from fundus autofluorescence.

So in summary, from an anatomic perspective, and then we'll dive into function, OCT-based ellipsoid zone measurements have quickly become a key component of any AMD trial. And I think over time, are going to really replace what we think of with fundus autofluorescence. And they're probably the best way to link structure with function in AMD and many other neurodegenerative diseases, including [ Mactel ] and retinal diseases.

Okay. Let's look at function. That's what patients really care about. We can show patients they're imaging, but what they really will care about is what can I see today and tomorrow. So this is the key endpoint that you've heard about before and is the primary endpoint there in the Phase III ongoing clinical trial that we'll talk more about in a second.

So this is showing dose-dependent protection with active treatment at preventing visual acuity loss. That visual acuity loss here is defined as 15 letters loss. And left side and right side of this graph are showing the same thing, but measuring it in a slightly different way. Both of these are confirmed visual acuity loss. So patients have to experience that either twice on the left or at the last visit at 12 months. And then on the right, same thing. You have to confirm the visual acuity loss with 2 visits at any time point, including at month 12, when it would have to be repeated at month 15.

And the point is that you're seeing the same outcome regardless of how you assess this. When you look at confirmed 15-letter loss, you see a dose-dependent protection with active treatment.

If we look at this on a Kaplan-Meier curve over time, you can see a 73% reduction in the risk of 15-letter loss with every month dosing, there in red. And importantly, you see an increasing impact over time.

This is now a sensitivity analysis where you broadened the view. So before we were looking just at that 15-letter loss in the middle graph here, now we're adding on the 10-letter loss on the left and 20-letter loss on the right. Each of these has their own sort of important clinical and potentially regulatory discussion, which happy to get into more later. But all of these, I think, are quite relevant.

And then if you look at average visual acuity, right? Average vision on clinical trials, especially in geographic atrophy, I think, can be challenging. But on average, you would expect, in an untreated patient population, 4 to 5 letters of loss. We've seen that repeatedly in all the control arms from all the GA trials over the last few years.

And here you're seeing again a consistent signal of dose-dependent protection and visual function, mean visual acuity there on the left, which is high contrast, meaning the lights are on for patients. And then on the right is the same protective benefit with treatment there in a dose-dependent fashion under a low-luminance visual acuity setting. Worth talking about what we mean by low luminance. It simply means that you've turned the lights down. So you put a filter over their glasses that they're using the check vision that prevents a certain percentage of light from going in, so it's a darker setting.

You'd think, well, why is that? Why are we turning down the light especially on these patients? You're doing it to stress the visual system. As Nora pointed out, in that Zone 2, Zone 3, there are still some functioning photoreceptors, but they're on edge. They're not doing as well as they would in Zone 1. And so if you stress them, if you give them less light, you actually can see a greater deficit in these patients over time.

So then diving into that low-luminance setting on this slide on the left, you're seeing the same dose-dependent protection here with active treatment every other month and then every month in blue and red, decreasing the proportion of patients that are losing 15 letters of low luminance.

And then on the right, low luminance deficit. Again, showing the same dose-dependent protection.

So what is low luminance deficit? It is important because the next line will bring this out a little bit further. It's the concept of, well, what's your visual acuity? And then what's your visual acuity under the high luminance normal light setting versus low luminance darker setting? And a greater difference there suggests more advanced disease. I'll go to that first.

So if you look at low luminance deficit now on a specific threshold, so these are patients that have theoretically less advanced disease. In other words, their low luminance deficit is smaller. This has been defined in other trial program before, probably first in the lampalizumab program. You can see that in this population of patients, which maybe we could call earlier in the disease process, even though they all have GA, these are slightly less advanced GA patients, we see really a potentially profound effect of drug treatment here with none of the patients in the every-month arm experiencing a 15-letter loss.

If we then look at hazard ratios for all the baseline characteristics, you can see consistent potential evidence there of drug benefit, with monthly dosing there in red and every-other-month dosing on the right. Again, these are all the baseline characteristics related to function and phenotype, for example, specific phenotypes that may bring out more aggressive disease such as diffuse trickling and the presence of [indiscernible].

Okay. So now some subgroup populations here of particular interest. The foveal and non-subfoveal patients, worth going into this a little bit detail. So why is this relevant? Well, first, it's relevant because a lot of trials have excluded the patients on the left. They've completely excluded them.

And they did that in the field for an interesting reason. They did that largely because they were trying to show a functional benefit with their drug, and that has not been shown by any of the drug yet in a pivotal trial. But that logic may have been flawed.

Because in this case, where we think we're actually preserving visual function, we actually see more events in those patients. In other words, if your fovea is involved and you already have an involvement with the disease, where you are seeing detail with, those eyes become much less stable from a visual function perspective. Where they're seeing from is much less stable. It migrates around within the fovea and perifoveal area. And so you see that on the left. The gray bar, for example, many more events of 15-letter loss. Really important enrichment strategy of the Phase III clinical trial where you want to have more of these events rather than less to be able to show a benefit with your drug.

Importantly, you're seeing the drug benefit in both populations, foveal and non-subfoveal patients, but you're getting more of these events with foveal involvement.

And this is the last graph related to efficacy before we get into safety, and this is often a favorite. And I think there's a couple of interesting points here. The most important is the scientific rigor of this to me. So it's one thing to develop a head-to-head trial with sham where you have an active treatment arm, but it's unusual in retina to actually haven't an off-treatment arm. And we've seen this before in retina in a few select cases where it's been really useful. And here, I think it's similarly useful.

Why is that? Well, if you look at the active treatment in the first 12 months, you can see in the first 6 months, there's not much separation of the curves. But then by the end of 12 months, you're seeing that separation that we've already talked about where the proportion of patients that have lost 15 letters is meaningfully lower in the blue and the red trajectories there at the bottom of the graph, compared to the sham patients in gray at the top.

But what do you notice when you transition into the gray shaded area of the graph? You see now all of these slopes appear the same. In other words, events are happening now equally in all of the arms when you're off treatment, which is supporting this concept of drug efficacy. It's supporting the concept of a disease-modifying effect on treatment that goes away when you stop the therapy in the last 6 months. I think it's a really elegant component of this trial design.

Really important to take a close look at safety across many retina program. We've seen a lot of safety challenges in many different areas of drug development in retina over the last 5 years. Importantly here, we're not seeing an increase in choroidal neovascularization. Remember that patients with wet AMD and their fellow eye were absolutely enrolled in this trial, and that is an increased risk factor to begin with. And you're seeing what you'd expect for natural history, probably a 3% to 5% rate of wet AMD development over the course of the year in all of these arms.

From a retinal vascular occlusion perspective, we had 1 patient on every other month dosing arm, which was not associated with any vasculitis. It was a [indiscernible] occlusion believed to be related to other comorbid diseases with the patient. There were no cases of vasculitis, 3 cases of [indiscernible] inflammation, all mild or moderate and resolved with a short course of topical steroids. And no cases of ischemic optic neuropathy.

So in summary, I think the way I would put this is that patients care about their vision. Of course, they care about their anatomy. But they really only care about their anatomy if it translates to visual benefit to them over time in this disease process. We've learned a lot about how to measure anatomy, about how to measure function over time. I think what you're seeing here is a correlation between anatomic preservation with an easy targeted approach here and then multiple lens of evidence suggesting a potential disease-modifying benefit of preserving visual function, both high contrast and low luminance across patients in a on-treatment off-treatment trial.

With that, I will turn this over to Jamie and look forward to discussion.

Thanks, Charlie. I'm going to take a few minutes and talk about the Phase III program with you. So we can go to the next slide.

The Phase III study is directly based on the Phase II program, the ARCHER study, which Charlie just shared the data with. And we did this in order to ensure consistency across the entire program throughout time. The pivotal program is based on the global ARCHER II protocol, which is a schematic of which is depicted here. It is a double-masked, sham-controlled, randomized 2:1 active-to-control study. 659 patients have been randomized to this study around the world, including the U.S. and Canada, Europe and the U.K. as well as Australia and New Zealand.

The primary time point of this study is reached when we have efficacy data available from all patients through 15 months. We completed enrollment last summer. And so -- which brings us to top line pivotal results expected at the end of this year, in Q4.

The study will continue through 24 months in a masked fashion at the patient level, and those data will be subsequently available.

The single protocol, importantly, serves as a registration package globally. In Europe, we have been -- the EMA has -- supports the use of a single analysis from this study and the single study for registration. We have been granted prime designation, which stands for priority medicine from EMA, which actually underscores both the unmet medical need as well as the potential opportunity that a product like vonaprument represents to them, which is well recognized.

In the -- from the U.S. In the U.S. perspective, we have been -- the FDA has also agreed that we can conduct this study as a -- under the single protocol, so one study under a single protocol. But they've also recommended that we divide this study, that we assign sites to 2 independent studies once the study is completed. And that allows us to run 2 analyses on substudies to meet their historical precedent for requiring 2 studies for registration packages. So that allows this one program to be able to serve both the Europe and U.S. registration.

As I said, we conducted this study highly parallel to what we did with ARCHER. But we did take the learning from the data that Charlie just shared. And 3 things stood out in particular when we designed the Phase III program in this.

The first is that patients who had low baseline vision were far less likely to lose 15 letters. In other words, they already lost a substantial amount of vision and they were just unlikely to lose additional visual acuity over the course of the study. Given that, we've excluded patients who have BCVA of 45 letters or less at baseline, and that corresponds to about 20/120 vision.

Additionally, we noticed that patients with foveal lesions were much more likely to have 15-letter loss events, and Charlie showed those data. And so we have enriched the data set from both the current -- in the current ARCHER II program to include a higher proportion of patients with subfoveal lesions, which allows us to have a higher rate of events in the study and better likely to show a treatment effect.

And then finally, also on the last graph that Charlie showed you, patients continue to lose vision beyond 12 months, especially in that sham group. So by extending the primary time point to the 15-month time point, we ensure a steady stream of patients will continue to lose vision over the course of the study to be able to better demonstrate a treatment effect for vonaprument.

Now this means, taking all these things together, what it means is that the Phase III is a highly powered study. So the single study is highly powered as well as the 2 sub-analyses that I shared with you, are both highly powered in terms of Phase III standards.

Finally, I also wanted to highlight some ongoing work with this program that's being done in a masked way. First, we're tracking the number of events that are occurring within the study. And those events are accumulating right on track to what we both expected from ARCHER from the Phase II study, but also what we predicted for the ARCHER II study for the Phase III program. And so we're right on track with events, which is a very good sign.

In addition, we've also noted that we are retaining patients very well. This study is keeping patients in the study better than other studies in the field. And that just speaks to the quality of the ongoing execution of the program.

And then finally, we have ongoing safety surveillance, also in a masked way, but we have had a data safety monitoring committee watching this study in an unmasked way. And they've given us -- and they have met recently and basically have said "There's no signals for which we require any changes to the protocol" and we just continue as is. And so we're on track to deliver the results, as I've shared.

And with that, I will turn this back over to Doug.

I want to thank our speakers for the prepared marks. We're going to now move into a roundtable discussion with our experts. They'll tee up a couple of topics to talk about, and then we'll open it up to the audience for any questions that you may have.

Doug, thank you very much. Let's have Dr. Lad, Dr. Wykoff, Dr. Dananberg. And then I'd like to introduce Ted Yednock on the end. He is the Executive Vice President and Chief Innovation Officer to Annexon, has done incredible work on the -- a lot of the basic science that you've seen and his team. He's got a very, very talented team. And they've done some outstanding work in terms of understanding the disease state, understanding, really establishing this as a neurodegenerative disease. So great work. And so we'll hear from our panel on a few questions that we've prepared and then we'll give you guys an opportunity to ask some questions as well.

I'm going to start with the endpoint. Our endpoint is confirmed 15-letter loss visual acuity. Nora, what does it mean to a patient when they lose 15 letters of vision? I mean what do you see in the clinic? What do they experience?

So 15 letters of vision loss is really debilitating. When they come in, they're very distressed, Charlie and I had this conversation. They're really anxious, they don't know what's happening. And so as retina specialists, we do a full workup. I mean we do fluorescent angiogram, ICG. We want to make sure there are no other causes. But if it's GA progression, which is likely this is, involving the fovea, and that's the worst-case scenario, their central fixation is gone. So suddenly, they cannot see faces, they cannot read, they cannot drive. It's a huge loss to them. I mean and it is highly reproducible also in our clinic measurements. And it's meaningful. I mean it is -- it takes a great toll in their life.

Yes. And so one of the observations that I've had as well is that these folks, once they lose a certain amount of function, they're not independent anymore. So when they come to see Nora in the clinic, they've got a family member or they've had to hire a driver. These are serious impacts on their quality of life. Can you speak to other sort of quality -- direct quality of life issues you hear from folks?

Well, they're just afraid. They don't know their life will suddenly change, if they can continue to be independent. They do come with a family member and they're very distressed. So I think it has a broad impact on their life.

And oftentimes, at least in North Carolina, people live a long time now and they're quite healthy. But GA is so debilitating to them. I mean it's one of the greatest fears, I'd say. Vision loss is one of the patient's greatest fears in life.

Yes. So I think we clearly established that geographic atrophy is a major problem, biggest unmet need in retina. We also understand that the loss of 15 letters of vision has a profound clinically relevant impact to patients. We know that from dry AMD, but we've known this over the last 20 years as we've been involved in drug development for the more commonly treated diseases such as age-related wet AMD and DME. So it's very clear that this endpoint is highly clinically relevant to patients.

What about regulators, Charlie? What does this 15-letter loss mean in terms of designing -- you've designed dozens and dozens of clinical trials. You've run over 300 as a principal investigator. What does this endpoint mean in terms of designing clinical trials and what does it mean to regulators?

Yes. I think 2 things. One is it's highly reproducible, as Nora pointed out. And the FDA has stood behind 15 letters as a clinically relevant threshold for a long time. And they have not budged. I mean we've all -- all 3 of us have been in rooms directly with regulators trying to actually convince them, look, we can go to 10 letters. 10 letters is also quite meaningful, because it is clinically. But they have always stood fast on the "No, we want 15 letters."

And there's a rationale there, right? What that means is that it's a doubling of the visual angle. So what does that mean for you guys? Well, if you're sitting feet away from us and you're looking at us, what does that mean if you lose 15 letters to you? It basically means you have to walk half the distance towards us to see the same thing, means you're losing half of your vision.

And they like that quantification. They like that doubling of the visual angle because you've lost half of your visual function. And they like that absolute threshold of like, this is definitely a meaningful quantitative measure.

Yes. So one of the wrinkles, there's a lot of different ways to look at visual acuity, there's several different ways to look at 15-letter change. In this case, a 15-letter loss. One of the key observations that we had in the Phase II study was that when patients have 15 letters of loss in this disease state at 2 consecutive visits, they don't typically come back. This really eliminates the noise.

So is it important, when we talk about, again, designing clinical trials, when we talk about talking to regulatory bodies, is it important to have a reliable endpoint. So I think there is quite a bit of variability in these patients, but the goal here, can you comment on the goal of eliminating noise in and endpoint like this?

If you're a regulator, you want to make sure that what you're approving truly has the benefit that is reporting. And so you want to pick a threshold that's going to be consistent, and to make it reproducible, say, you don't have to lose 15 once, you actually have to lose it twice, is quite a meaningful threshold. And there's a reason why we don't talk much about 5 letters lost or gained because that can be all within noise. But once you're sort of in that 15, above range, it's pretty reproducible and that's why regulators like to use it because you do minimize that risk of noise.

Yes. So Nora, let's presume we have -- we'll run the clock forward into the year and we have a drug that protects 15-letter loss in a statistically significant manner. What does that -- how do you apply that in clinical practice? You have a busy practice, see lots of patients with dry AMD. How would this impact your decision-making when you see these folks?

I think it'd be game changing, to be very honest. That's what the patients are asking for now. What can we do to slow down my loss? How can we prevent me from losing vision? I want to be independent. I want to be able to do things I enjoy.

So I think it'll be game changing. I think the risk-benefit profile is critical. So if we can prevent vision loss reproducibly earlier in the disease process would be key. And then having less risk of complications like choroidal neovascularization, wet AMD formation without injections, because it also takes a toll on their life in terms of coming in frequently for appointments related to injections and the rest because the clinics are busy, but so our patients. They're active in their communities and their family members who bring them are also busy. So I think it'll be -- they can maintain their lifestyle and ability to do things they enjoy and not have to come see us as much, as much as we enjoy it.

So we practice in an area where we had replacement drugs, for lack of a better term. We had [ Macugen], for example, was approved by the FDA for AMD. And then once we had more effective anti-VEGF agents, those drugs really became standard of care. Is this an addition to the armamentarium that you see today? Is this a replacement drug? What do you do with patients that are treated currently with downstream complement inhibitors? How would you integrate this?

Right. It's a great question that's going to get more complicated over time. Hopefully, more and more options come available. And the way I would answer that is I am a big believer that the current medicines that are FDA approved and commercially available are useful. I think it's important to slow this disease process. And so I offer them, I talk with my patients about them and I use them clinically.

That said, every patient with GA, if you talk to them and you listen to them, and those that are in the audience that haven't, I encourage you to, they are very eloquent in describing what we're talking about, much more so than we are. They describe vision loss on a daily basis, not like once every few months when you lose 15 letters. They notice it every day that their vision is slowly creeping away. So even though I'm treating them with the current FDA-approved therapeutics, they still bring up "I'm losing vision."

And I kind of say, look, I think we're doing the best we can. You're getting the best drugs available. But if there was a drug that had on label vision protection, it's a very different discussion with patients and circumstantial, "Well, we're slowing the progression of the anatomy so that we can hopefully preserve your vision." To be able to talk directly and bluntly about on-label vision protection would be a very different scenario.

Do you think it would impact the number of patients that you actually treat?

I think it would broadly change how physicians think about treating GA. I think a lot of physicians are unfortunately currently turned off with the current options because of the risk-benefit ratio in some cases and because of the lack of prospective visual benefit in the core Phase III clinical trials. And if you change both of those factors meaningfully, yes, you're going to change the market opportunity, which is good for patients.

When Charlie talks about the benefit-risk profile, Nora, I think we understand the benefit component to that in terms of really a different type of benefit in terms of functional benefit. But let's talk about the risk side.

I think one issue that's important here is the rate of choroidal neovascularization, right? I mean so we -- in the Phase II studies, there was no increased [ CNV ] risk in these patients. Give us a sense of what that would mean to you as you make treatment decisions.

I think that will be very important to patients. They like to be safe, so I have a thorough discussion about risk-benefits and alternatives every treatment that I do. So I go over the clinical trial data in as much detail as I can within the allotted chair time, which is limited these days in the retinal practices. But I think it'll be so reassuring to have this great risk profile and side effect profile, so we don't have increased risk of CNV in these patients.

And then they know they're not going to have to come in as much and get additional injections on top of the ones that have a protective effect to the retina to maintain that good vision. So everything Charlie said resonated with me because I actually hear my patients seeing pretty much the exact same things.

Yes. So a real opportunity for improvement. Charlie, you gave a great sort of perspective on where we are today. Any other final comments about sort of the current landscape, not just clinically but also in terms of the importance of sort of moving the field forward to try to find better functional outcomes for these folks?

Man, I would tell you, it takes a team. And those of you who sit in the audience are a key part of the team. I mean someone's got to fund these projects. And I think that to be able to benefit patients, there's a lot of shots on goal out there right now. And hopefully, more than one will work. But I really hope as you guys do your diligence out there, you look for programs that are going to improve visual function for patients because that's truly what they care about.

I'm a big believer in using ellipsoid zone as actually an approval endpoint. It's not what this project is doing, that it's an important sort of part of the package here. They're focusing on vision, which is even more important. Very interested in sort of understanding ellipsoid zone better over time. But really when you look at programs, ask, okay, functionally, what are we going to demonstrate here? Because that's what patients really care about.

Great. Let's talk about the product. Let's actually talk about the product formulation just a little bit. Charlie went over some key differentiators in terms of vonaprument relative to current therapies, right? So there are some -- obviously, some factors that are important from a biologic perspective, and those are certainly important, and we've talked a lot about the complement cascade and how this drug works upstream in terms of protecting photoreceptors first. But let's talk about some of the practical issues, because some of these are important to us as clinicians as well as to patients. And they may not be readily understandable.

So what's the value here of small volume, right? So we've got drugs that are available anywhere from 0.5 ccs all the way up to 100 microliters. This drug is delivered in a small volume. What does that do for you in the clinic? Does that give you flexibility? Does that help you in certain clinical circumstances?

Yes, I think as Nora pointed out, most of our specialists are busy. There's a lot of patients, a lot of injections being done. And so anything to minimize risk and improve that efficiency is good for patients.

So with drugs that are over 50 microliters, there is a change in that risk profile. We've seen that with 70 microliters with recent anti-VEGF. We've seen that with 100 microliters with some of the GA drugs, both the GA drugs? And what that does, that just adds in their level of complexity. You can certainly deliver all those drugs safely, but you just have to think about things a little bit differently. Because every patient is different. Some have high-risk glaucoma, some go dark with the injection. You've got to think about the physiology of the eye. And when the pressure goes up with the volume, you put any volume into the eye, the pressure is going to go up by definition, simple laws of physics, and the more volume that you put in, the more we worry about that pressure fluctuation.

So it just adds another level of complexity. It doesn't mean you can't do it safely. But to have lower volumes overall is going to be preferred by physicians.

Yes. So one clinical scenario that is certainly identified by us as retina specialists and fairly common, are patients that have GA as well as exudative disease. And there are opportunities where you can actually treat both conditions concurrently. Nora, do you have patients like that?

Yes, I do. And the 25 microliters will be so easy. So otherwise, you have to wait. So just give you the practical view here. It just takes a while for the IOP to come down the high-volume injection, 100 microliters. So there's a few -- there's patient issues. So they don't like the vision dimming and then it's uncomfortable when the IOP rises in the eye because of pressure sensation. They might need Tylenol or IOP-lowering drops in clinic, but it also takes time. And this is -- it takes up an injection room and technician time. So the whole staff is involved too, and it really slows down the clinic processes and the volume has gone up.

So I think it would be hugely important to have this small volume to be able -- and then the IOP would barely go up and then you can also treat with an additional anti-VEGF if you have to.

Yes. And the other issue is oftentimes, we bring these patients back for multiple visits. So they get a dry AMD injection, a wet AMD injection on the other. Small volume GA therapy would likely eliminate a lot of these complexities. Any other comments sort of about the -- other thoughts about the drug product itself? Certainly got some key differentiators.

And I think it makes sense. We've had biologics in the space for a long time. I think physicians are [ comfortable with ] biologics, pegylation of both the GA drugs out there are currently pegylated, so unclear exactly what role that plays, certainly is there for a very specific reason to increase the half-life in the eye. But I think overall, if I'm a physician and I can have less things on the drug that's better.

Great. That's wonderful. Let's go into -- we're going to spend a little bit of time on the mechanism. Nora did an absolutely fantastic job walking us through the science of dry AMD as well as the mechanism of action of vonaprument and how it impacts this neurodegenerative disease.

I want to ask Ted to sort of walk us through, so much of this work has been pioneered through his lab and through his group here at the company. I want to give him an opportunity to work through the mechanism of disease here to help us better understand this disease process. Ted, give us your sense.

Sure. So this slide shows a mechanistic understanding of how C1q is involved in neurodegeneration. It's really a foundational science of the whole company. So on the left side of the slide, as Nora has already showed, you have the photoreceptors in blue, and these are the cells that collect light. They send that signal up through the synaptic network up there. And then underneath those cells are the RPE cells, they're epithelial cells that support the photoreceptors.

But as you move closer to the geographic lesion, you can see that the photoreceptor cells are becoming stressed. And this is where C1q is playing a very different role than C3 or C5. It's actually binding to the functional synapses on photoreceptor cells. This is a carryover from development where C1q is designed to eliminate excess synapses, which we want to make the strong circuits functional. But in disease, it really -- this is an aberrant elimination.

So then when you move to Zone 3, synapses are gone, these cells are not functional because they can't communicate with the rest of the retina. And here, the alternative cascade comes into play a role. It recognizes dysfunctional cells, it really facilitates the removal. So that's what you're seeing on the lesion edge, is dysfunctional cells being removed, as they're gone, the RPE cells are gone, the lesion grows.

So a big distinction between C1q, which is early in the disease process, recognizing functional cells, versus C3 and C5, which are expanding the lesion [ area].

That's great. Thank you very much. So the construct here, even though this is sort of based on the histology that we saw in a patient with GA, this construct sort of lays out the 4 zones of the progression of dry AMD, on really Zone 1 and to a large degree Zone 2, sort of intermediate AMD.

Currently, we have very, very limited clinical options for patients that have earlier disease states prior to the development of either choroidal neovascularization or, frankly, geographic atrophy. Nora, what do we do for patients currently with intermediate AMD?

Not much. We put them on our [ REDS 2 ] vitamins, and that's based on a post-hoc analysis of the age-related eye disease study too that show that the vitamins are basically a mix of antioxidants, protect against conversion to CNV by 20% to the wet disease.

And also, I advise a Mediterranean die because now there's quite a good data from [ NEI ] on a 10-year study that that's protective across disease progression. And that's just a good diet, I think, to have, and it protects the neurons as well, interestingly, in preventing against dementia.

And then the only FDA approved by now is photobiomodulation [indiscernible] used as a device. So not a lot. But we would -- the other thing I would have added to Charlie's advice on what the company is doing that's so revolutionary and promising to me is intervening early I think is key, before these synapses become dysfunctional and lost, and again, it's an irreversible loss.

Yes. So generally, what we're doing at the time of treating intermediate AMD with vitamins is trying to protect photoreceptors from oxidative stress, essentially is the concept of what we're doing here. So these are still functional photoreceptors, but they're stressed. This is sort of Zone 1. And that really is sort of where we're falling into in terms of this construct of Zone 2, where once these stressed but functional photoreceptors are tagged for elimination, that's really sort of where the process starts, right, Ted? I mean that's really when we really start to see significant functional decline. That's a time that -- where we can intervene, as we understand it, right? Because when you think about the histology that we saw earlier on, we still see active but reduced photoreceptors over this area of intact RPE. This is a critical time to intervene.

Charlie, why -- I mean, this is sort of a basic question, but photoreceptors are the key division, right? So we've got to protect -- do they regenerate? That's a great question in terms of these folks. I mean once we lose the photoreceptors, what happens?

Yes, certainly an overly simplistic view, very specific regulators have said the photoreceptor is vision. I mean the most important cell in the back of the eye. That's definitely debatable because if you don't have [indiscernible] cells, you don't see either. I mean the other cells that are important. But it's where vision happens. I mean it's where light turns into the chemical and electrical signals that we think of as vision. So it is the tip of the spear.

And what's fascinating about AMD, and I love this cartoon because I think it resonates with what we see clinically is that there is a huge amount of dysfunction in these patients even when they don't have foveal-involved lesions, right? They complain bitterly about walking into dark rooms and not being able to see. You get this feeling that they are clearly impaired functionally even if their high-contrast visual acuity appears normal.

So you're getting broad dysfunction of the retina because a lot of the retina probably in Zone 2, in these eyes with geographic atrophy. And we didn't get time to go into detail. But if you look at that EZ slide I showed, right, it's 15 millimeters squared of EZ loss, whereas it's like 7-millimeter squared of RPE loss. You have a much larger zone of photoreceptor damage outside of the areas of GA.

And so I like the concept of let's broaden and not just target expansion of GA, but let's actually protect the photoreceptors that are actually doing what patients want, which is see.

Right. Yes. So it's critical to intervene early. The idea here -- this term upstream, I think, is important for this program, because it's upstream not only in terms of the cascade, in terms of affecting the cascade early on, but it's also important in terms of upstream protection of the neurosensory retina.

And the other linchpin on that is the bidirectional feedback. So you're targeting photoreceptors with this target. But the real hope is that by stabilizing those photoreceptors, you also then will prevent the RPE loss. Because, right, if we only protect photoreceptors and RPE, still die at the same rate. That's going to be a problem. And that's why I like that sort of second 6-month data in the core data set. When that gets borne out over 18, 24 months, that will be really important because you can preserve photoreceptors, which will stabilize the RPE and then slow the growth of the underlying fundus autofluorescent pattern.

Great. Well, I'd like to thank the panel, in particular Dr. Wykoff and Dr. Lad, for spending the day with us. We're going to -- I guess we're going to...

Open it up. Yes.

We're going to transition on to some questions from the audience.

Really good discussion. So we've got a microphone that's being passed around, please, any and all questions. I see we've got some hands here. Awesome.

Hi, everyone. I'm Samantha Schaeffer with Pete Stavropoulos with Cantor Fitzgerald. For Dr. Lad and Dr. Wykoff, we're curious to hear your thoughts on GA lesion size growth and whether it's a clinically meaningful indicator of disease control. And more broadly, what is your sense on how community docs view this metric and how up to speed are they? And just a follow-up question for the team afterwards.

Okay. I'll start. Geographic atrophy, I think -- so far, historically, that's how we design our studies. And that's why the Phase II study was designed with the prevention of GA loss, measurement of autofluorescence as the gold standard because there was FDA guidance at that time. And those -- it's well tailored perhaps to mechanism of action to target RP as a direct correlate. And I don't know that the retina community, I think they're increasingly understanding this, and we're helping them now understanding this more and more.

It is a neurodegenerative disease. And again, the RP are supporter cells, are very important. I think they're tightly linked. And we understand a lot, and I think increasingly so, but if the photoreceptors are dysfunctional, there's a lot that RPE has to clear also. So I think they are synergistic, and that's why the RPE data lags behind. But the RPE is a very sturdy cell.

So I do think it's an important biomarker of GA progression if it reflects the MOA or RPE MOA. So this mechanism of action is a photoreceptor mechanism of action. It's a neuronal one. It's seen in other neurodegenerative diseases, as you saw. It helps patients with their preventing neuronal impairment in bad diseases. So I think we need different measures. We need a functional measure and others.

Yes. I totally agree with Nora. And the thing that -- the one point I would layer on is that in clinical practice, we don't really use fundus autofluorescence in the way it's used in the clinical trials. We're not measuring lesions on fundus autofluorescence.

OCT, you do have the opportunity to do that. We don't have the software yet in the U.S. There are some software programs that are that are approved in the EU that are being used, and I think those will be used over time in the U.S. and then we will get better actually quantifying not only EZ but RPE and all these different layers over time. And it will become much more relevant because you'll be able to project this for a given patient. But right now, it's very qualitative.

And for Doug and team, building off of that, what level of effort would be needed to change physician understanding? And have you started that education process? Or when do you expect to start?

Yes, we have started. So obviously, as you've heard here today, vision is what's most important from a patient perspective, but also from a physician perspective. And so doing events like this, one on one and in group settings, to assure them that we are protecting vision. And that's what matters to the patients. So that's well underway.

We're also doing disease education work on GA itself, which is actually really quite important. You've heard today the field for 20 years really have focused on the RPE story. More recently with the advent of EZ and other technology, starting to look at photoreceptor neurons and their role in driving this neurodegenerative disease process. So just baseline disease education on this disease is actually really important to understand our mechanism of action and the data that we've produced.

Tazeen Ahmad from Bank of America. Doug, I just wanted to ask you, have you stated what the effect size is going to be for the ARCHER II trial, what's it powered to show?

We have not. No. As Jamie said, the study is powered very highly as a Phase III study because BCVA 15-letter loss is a meaningful -- clinically meaningful endpoint. Any significant protection on the BCVA 15-letter loss is deemed an acceptable or approvable endpoint. So we have not stated the specific effect size.

Okay. How should we be thinking about what the sham arm is going to look like at 15 months on that primary endpoint?

Yes. It's a good question. I'll flip over to that slide. And maybe, Jamie, you want to take that while I pull that slide out.

So we use the ARCHER data set closely and we also use the lampalizumab data set. it was a very large study, 2,000 patients for which lampalizumab did not have a significant effect. So you essentially have an entire placebo arm of 2,000 patients to look at what happens over time. Importantly, both ARCHER and the lampalizumab study both included the foveal and non-subfoveal patients in [ mold ]. So we get a good sense of the rate that we would expect. And typically, it's in the mid to upper teens per annum. So you can just extend that out to approximately 15 months, add another 25% on to the rate, and that's approximately the rate we're using.

Well, and Jamie, maybe talk about kind of the approach we took to powering the study as it relates to the treatment and the sham group.

Yes. So we basically use a conservative set of estimates. So I shared with you kind of a general way of getting that. We took a bit of haircut on what we believe the rate to be. So we basically overestimated -- or underestimated the rate of increase that you'd see in the sham group.

But we also took a haircut in terms of the amount of effect size that we anticipate seeing from a treatment effect way. So we powered the study conservatively to make sure that we stayed within the likelihood of a positive result coming out of this.

Okay. And can I squeeze in one last one? On looking at that 15-letter loss, the company and the doctors on stage have done a really good job of talking about the rationale for why it shouldn't be a noisy endpoint. My question is on a relative scale though, it's still a small number of patients that you're going to be looking at. And how do you get comfortable that you'll be able to show the level of difference that you're looking for over this time period?

And then related to that, once you look past 15 months, and maybe this is a question for the physicians as well on stage, what's your level of confidence in durability of response?

Let me speak to the program first. The key component here is to have a high enough sham event rate to see a treatment effect, right? That's really key. And that's -- we've designed the trial and we monitor the trial with that really as our primary sort of in-trial metric, is to do a very specific model for event rates and then see where we are as we move along.

The way we have tried to maximize event rates -- so we've seen the numbers here, but we did employ 2 important strategies to support that rate, if not exceed that rate. The first is we had a goal of greater than 50% foveal lesions involved because we know from the Phase II study that these patients have significantly higher event rates when they have foveal disease compared to nonfoveal RPE atrophy. That difference was -- that was between 25% and 17%, so a substantial difference.

The second group that's really important to understand was, in the Phase II study, we included patients with very poor vision down to 25 letters. Patients between 25 letters and 45 letters in the Phase II study had no events. And so the event rate that you see in the presentation today is based on the total cohort. We eliminated the bottom 20% that did not have events in the Phase II study. Those 2 strategies, we believe, will have a significant impact on supporting event rates.

So really, to answer your question, the key to seeing a substantial benefit is having enough event rates in a Phase III study.

And as I mentioned, Tazeen, we are tracking events and we're right on the money in terms of where we should be at this point in time in terms of patient months in the study. So that's very reassuring, in terms of the treatment effect associated with vonaprument.

And then a question for them about durability, right?

Well, first, I'd like to address the first one just briefly because independently, we look at the natural history data in lampalizumab, which basically was a large history study, unfortunately. And we published some work on that independent of anything we did here today with Annexon. And so we did find that those subfoveal lesions lost vision precipitously, that 15 letters and more, and that's clinically meaningful.

So we wrote an editorial in Ophthalmology and said, if we were to design a study, they use BCVA as a primary end point, we would use subfoveal patients. So I'm very pleased to see that's actually in real works here.

And also I love the stratification by BCVA because some patients, you either have a ceiling or a floor, and you want to eliminate those. And we see those in other clinical trials. So smart clinical trial design, kudos to the team. And so independently, we found the same thing.

And clinically, durability, I think, is always nice to have. We do feel like once patients lost 15 letters over 2 visits, that's a point of no return just because it's irreversible loss. But we'd love to see long-term data. So I know the company is committed to generating some long-term data and overall pleased with the approach.

Yes, durability in these GA drugs, I think, is a challenge. And the 2 points of data we have, and I'll give you my comments on them, are the Phase I data, which show that you have full target engagement in a month. That's good. That's great. That's very supportive. It tells you, you can go at least a month. It doesn't tell you can go 2 or 3 or 4 months, but it doesn't tell you can go 1.

And then we know by 3 months, based on that off-treatment graph, it probably is one-off, because they have a 3-month visit and a 6-month visit on that off-treatment component of their 6 months through 18 months. And so by 3 months after, it probably went off. You'd expect that for a small-format biologic. It's gone by then. And so there's your range, somewhere between 1 and 2, maybe 2-plus months, who knows.

But it's challenging for GA drugs because there's no easy biomarker. I mean easy, E-A-S-Y, no EZ. Unlike for anti-VEGFs, you got a great biomarker. Or the OCT, you just look at the fluid. You can tell when the drug wears off because the fluid is coming back.

The problem with GA drugs, for any GA drug, unless we come up with new biomarkers, is that you can't tell. I give you a patient -- I get a shot of vonaprument to a patient, their OCT day 2 and day 7 is going to look exactly the same. Whereas an anti-VEGF, it totally changes. So that is a key challenge for all companies developing drugs for GA. What does that mean? It means maybe we've got to come up with an [ AC tap ] or something else to judge how long a drug is going to work for a given patient.

I think we have more questions?

So it's Darryl Wise, Vestech Securities. You kind of answered my question. I was curious about how rapidly decline in visual acuity was happening with patients. So you kind of answered that question, thank you so much. Then I got a pivot. These are biologics which are historically difficult manufacturing. And stability. Can you talk to those 2 points?

Yes. We're manufacturing with Lonza, have been doing so for 10 years, the drug is quite stable. It's on their Light Chain path, so there's no special manufacturing tricks with regard to manufacturing. And what's important about our drug is it's a fab fragment of an tanruprubart, a full lift monoclonal antibody, which we've also been manufacturing for 10 years with Lonza on their Light Chain path. So it's been really quite stable. No concerns or topics in and around that.

Just on that point. As we look at patients' visual decline, I was curious about height and weight. Does that parlay into an understanding the demographics of the patients, whether they're tall or short or heavy or lightweight? I'm just curious about that.

We've not broken the study down in that regard. There's not data to suggest that that would be a concern. The eye is actually pretty standard size no matter how tall or weight that you are.

And I think what you want to think about with regard to our approach is we are selectively inhibiting C1q specifically in the eye, in the retina. So it's a contained compartment. Your overall body weight, I would think they have very little effect.

Yes. Is this a question about like you got to give more drug to big people? I mean essentially?

That's what I was trying to ask.

Yes. So the answer to that is no. So the good news is -- so we got full product engagement. And that's not an issue with these small biologics inside the eye. Even if the patient is 6'7", their eyes are the same size, roughly, as a 5-foot person. So the amount of drug that you deliver is really basically the same.

And the way -- these drugs are not metabolized in the eye. They're actually cleared from the eye as a molecule, and then they're metabolized in the systemic circulation.

So one of the benefits of these types of small biologics that are specifically designed for use in the eye is that they're stable inside the eye. But then once they're cleared, they're rapidly metabolized. So for example, we don't have to worry about vaccinations or any concern about systemic complement inhibition because the drug is gone when it gets to the bloodstream. So one size fits all here.

More questions? I think they're coming to you with the microphone. We need 2 microphones.

Brian Balchin here from Jefferies on behalf of Andrew Tsai. Maybe a couple for management. In the event that only one substudy is positive and the second shows trends, do you think you could still file given FDA's new default stance?

And then secondly, from the blinded safety data set, can you confirm that you're still seeing 0 cases of retinal vasculitis?

I'll take the first, Jamie, and turn safety over to you. So yes, with regard to the first, in Europe, there's only a single study requirement. So we certainly can file there. In the U.S., obviously, if you hit on 1 sub-analysis and you're close on the second, you're going to have a discussion. I think all of this is supported by what you see with the structural endpoints as well. So showing significant protection of photoreceptors via an EZ analysis would certainly be quite meaningful. So we think there are multiple ways to win, and we've prepared multiple scenarios for that.

And then just with regard to safety.

And we've seen no cases of occlusive vasculitis at all.

This is Ananda Ghosh from Wainwright. I have a couple of questions on the trial design and then one general question. So one of the questions we keep getting is regarding the confidence in interval that you have seen in terms of the risk reduction of vision loss in the Phase II. And how does it -- like how it got implemented in the Phase III trial design. And then I have like 2 more.

Yes. That's the Kaplan-Meier curve he's talking about, Doug. So we powered the study based on the proportional analysis, so not the Kaplan-Meier. We'll do this analysis. But the study was powered based on the proportion of patients who experienced a 15-letter event. So it's just a proportional analysis versus the 2 groups.

But in this, you'll notice -- is the Kaplan-Meier up? Yes. So we don't -- you could see the confidence intervals were quite high. You can see the 0.09 to 0.8. So we have a very strong confidence. Remember the study -- the Phase III study is almost 3x the size of this, plus 2:1 active. So we -- the study is very well-powered for this analysis as well.

And probably one question you might always get is like, how is the trial kind of differentiated from lampalizumab trial, Roche's?

First, mechanistically.

Yes. It's very different mechanistically. This is a completely different program. The second piece is that in -- similar in terms of taking both subfoveal and non-subfoveal patients, but in the lampa study, they actually included patients with vision down to 25 letters. So they had a lot of very poorly visioned patients. But again, mechanistically, it's apples and oranges here.

Got it. Can I have the last question on -- there's this issue of like how do you control the acentric fixation when you are measuring like the BCVA [indiscernible]?

Yes. So it's actually not specifically controlled because the patients are able to sort of tilt their head or look askew slightly to try and find the best point. They're actually encouraged to be able to find a focal point that they're able to resolve as best as they can. And they're put in the machine that we all know about, to be able to correct their vision. That's why it's called BCVA so that you fully correct vision as best as you can. So you give patients every benefit of the doubt to try and get the best vision that they can.

I don't know, probably, Charlie and...

Well, I was going to bring up the case here, which kind of speaks to your question about acentric fixation. You see green is good, black is bad. So the answer to your question here is at month 12, this patient is desperately seeking to acentrically fix it. And that's, in fact, why they've lost vision. But they don't have really intact ellipsoid zone until well outside the -- you've got these tiny little islands in the fovea [indiscernible].

So this is in essence why these patients are likely acentrically fixating to some degree even at presentation. They are searching. That's the whole point of these patients with foveal disease, is that they're right on the cusp of consistent clinically meaningful vision loss.

So at baseline, you could imagine this patient is doing some degree of searching with acentric fixation. By month 12, it's a much more dramatic effect. But we don't -- clinically, you're not really able to evaluate that with protocol vision. Is that fair, Charlie?

Yes, I agree with that. You actually see this constantly in GA patients. They don't look right at you. They look at your ear, they look at the side of our shoulder to see your face. They're constantly changing geographically what the retina they're using.

And once the fovea is involved, even if it's a tiny involvement, even less than the left picture here, they'll start doing that. And you can see it on microperimetry. So microperimetry is checking vision across 60 or 100 spots to the back of the eye depending on your pattern. And you can see where they fixate and it will migrate around.

So patients can stay 20/20, for example, and yet use different photoreceptors, depending where they are. That's unusual, but that's why high-contrast visual acuity is such a challenge for many of the programs.

Bill Maughan, Clear Street. So 2 for me. So first of all, for the practicing physicians, how -- what would you expect for patient compliance for a monthly injection? And then for the company, with the new default stance being one study for approval, is there the possibility of changing the analysis plan and simply looking at this as one large study and helping your statistical powering?

I'll start with the first one. So patients are desperate for something that slows down this disease, I can tell you that. They don't mind coming monthly. This is absolutely no problem. So as long as they get visual protection, they'll have no issues coming, I could tell you that.

The currently approved drugs have a flexible dosing interval, and I have the real -- even if they know that it's less protective than what's proposed here, they'll still come in every month, because they're so motivated to not lose vision. So I don't think that's much of an issue. Charlie, what do you think?

Agree, completely. Yes.

And then just with regard to the single study, we will have the discussion with the regulators. Again, we're well overpowered for single protocol analysis. And we saw [ Dr. McCary ] communication through the New England Journal of Medicine, which is an interesting way to communicate a regulatory guidance. But be that as it may, we will have a discussion with them. So for us, that's upside on the program, and that's how we view it.

This is Joyce Zhou on behalf Anupam Rama, JPMorgan. First, for the physicians, assuming the Phase II hits us a win scenario, what profile of patient would make a great initial candidate for this drug given the vision preservation benefit? Would it be patients at highest risk of vision loss?

And then one for the team. Could you remind us, if ARCHER II succeeds, what your plans are for developing a prefilled syringe?

I'm happy to take that first. I think it depends on the drug. I'll explain what I mean by that. So when anti-VEGF, if you have a patient with new wet AMD, they're going to 99.9% just want to get treated because the drugs work. They work really well at protecting vision over time.

In GA, it's a much more complicated scenario right now commercially. There's a lot of doctors and patients sitting on the sidelines not getting treated because of this thought of a risk-benefit ratio and also a question mark of efficacy. And you've heard that debate played out 1,000 times on podium over the last 3 years. So that's why a lot of GA patients are not getting treated.

But yet if we had a drug that, just say, a perfect scenario, improve vision in GA, reverse the lesion growth, everybody would use it, every patient. So it depends on the drug, right? So in this case, if this drug bears out and shows exactly in Phase III what it did in Phase II, I think you're going to see a lot more patients getting treated a lot more consistently, because patients don't like to lose vision. And they tell us that every single day, whether they're on treatment with current drugs or not.

I agree. And again, these patients are motivated. And even if they have good vision, if they lost one eye already, it's a no-brainer, those are patients to treat, and they'll be the most motivated by. I think, everybody, the whole idea here is to intervene as early as possible, before those synapses are dysfunctionally lost. And so I think patients will understand that. The clinical data is so good and if the vision will be protected and the risk profile, the side effect profile is so great, no increased CNV effect, no vasculitis, I think it's a very easy conversation to have. And honestly I would treat everybody or offer the treatment to everybody. And the data will speak for themselves at that point.

Great. In terms of the prefilled syringe specifically, sort of life cycle management generally, work's already underway in terms of the prefilled syringe. We all recognize the value of a prefilled syringe. There's tremendous efficiencies that are offered to clinical practice. There's also safety issues that are very important as well. So that work is already underway.

The other comment I'd make about life cycle management generally is that, as a small-volume drug, we have a bit of flexibility in terms of how we manage longer duration of action. There's certainly more volume as an option, alternative pathways that extend the lifespan of the drug in the eye with different types of extended-release platforms.

So one of the nice things about our formulation as it stands today as it gives us a good bit of flexibility in terms of life cycle management going forward.

Joseph Stringer with Needham & Company. Just wanted to follow up on some commentary that you had earlier on the impact of the patients with BCVA less than 45 letter. Maybe just expand a little bit more on the expected impact of excluding those patients in the Phase III. And then in the Phase II, if you excluded those patients that had less than 45, what does the treatment effect look like?

And then a second question on EZ loss. What does EMA need to see on the relationship between the EZ loss and BCVA? Is it as simple as hitting stats on both of those? Or would you need to show more or additional correlation in those.

Jamie, you want to take the first?

Yes. So in the first case, what we did -- again, we haven't shared these data publicly previously. But if you take the same criteria which we applied to Phase III and apply that to the Phase II study, we see an improvement in terms of the effect size. Because if you eliminated, as already pointed out, as Lloyd pointed out, almost 20-ish -- a little more than 20% of the patients had a baseline BCVA below 45. So if you take those out of the denominator, your effect size goes way up in the sham and the treatment effect just gets greater. So it's quite a positive.

But we took the ARCHER II data as it is, and that's how we powered the Phase III study. So the Phase III power goes up.

Yes, that's correct. Look, we're a conservative company so we just haven't shown that analysis. We could do it, but we've got to demonstrate it in the Phase III.

Just as it relates to the EMA, the requirement is just to win on the BCVA 15-letter loss. We, of course, want to support with structural data. I think it's important for the treating physicians and the community alike. But for the approvable endpoint is BCVA 15-letter loss.

Any additional questions? I think we've got another one in the back. I think we got to use the microphone on that. Yes, there you go.

Okay. It's Darryl Wise again, Vestech Securities. Great panel. Thank you, guys, for your candor. Curiosity on the GA platform. You mentioned that maybe as patients lose vision, they will be eager to be able to take on this new therapeutic. I was just curious at what price? Has anyone talked about pricing at this current level?

Yes, we're certainly doing the work now. The pricing that's in place for the currently approved therapies would probably be the floor. We think this is a potential superior premium opportunity. What that is needs to make sense. I mean at the end of the day, our core mission is to serve the patient population. So we will not price this in an outsized way, but we want to make sure we get value for the product that we're bringing forward.

Right. Any other questions for anyone else?

All right. Well, listen, that brings us to a close today. I hope this has been helpful for you all. As you can tell from the company as well as from the expert panel, we're really excited about this opportunity. Vonaprument is a differentiated asset, both from a mechanistic perspective, which translates unique outcomes from a structural and functional perspective. But also we think the drug candidate itself has the potential to be differentiated on the safety side. So a really unique benefit-risk profile to change the lives of millions of patients worldwide with regard to that. It's a large market.

And we again, we'll come back on the market. We've heard various discussions about, is this truly a market based on sales today? Not a good barometer. I think if anything, what I would do is look at what sales were in the first 9 months or so when Syfovre was launched, it was a hockey stick. We think we can do that and more. And so we're excited by that. And I can't see the slide anymore.

The Phase III study is really thoughtful, as you all can see. We took a lot of time in really mining what is the first vision sparing significant data set with ARCHER. But we didn't stop there. We looked at all of the other GA programs, importantly, lampalizumab, probably the best learning study that's been conducted in the space. And so we're really encouraged in the way that we thought through the patient population and the design of the study to give us the greatest opportunity to succeed.

And I'm happy to report that the regulators are in agreement with us. This is the only Phase III program that has full regulatory alignment on both continents, in the U.S. and Europe, and we've got all the designations to go with it. It's a very warm relationship with them. They're pulling for us and they're working with us. And when we want to meet with them, we meet with them in person. And so we really like that. That's really unique in today's regulatory environment.

And we're beginning to prepare for the opportunity from a commercial perspective. If you think about what's occurred predominantly in the wet AMD space as well as in the GA space, these have been smaller biotechs at the time they've launched. And that's because there's, what, 3,000 or so retina specialists with a few large practices predominantly driving the opportunity here? We can do this ourselves. We're preparing to do this ourselves.

And so we're excited by the opportunity to bring this drug forward to patients worldwide. We appreciate your all support. And I want to thank our panel, once again, certainly, Dr. Lad and Dr. Wykoff from coming out. It's a cold day in New York, but we're happy to be here.

So thank all of you all once again. We will have refreshments in the room next door for a small reception. Come join us there. We'd be happy to talk to you one on one. Thanks a lot.

All right. Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I am one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, Joyce Zhou, Priyanka Grover and Rathi Pinhe. Our next presenting company is Annexon. And presenting on behalf of the company, we have CEO, Doug Love. Doug?

Great. Thank you, Anupam and JPMorgan. We're delighted to be here for our 10th JPMorgan presentation. A decade into the journey, we're more excited than ever to achieve our mission of delivering game-changing immunotherapies for patients suffering from devastating neuroinflammatory diseases. And so we're going to dive right in. Hopefully, I'll get my voice back. Great. There we go.

I'll be making forward-looking statements and invite you to review our materials on file. All right. For those less familiar with Annexon, we're a [ Bayera-based ] biotech company, leveraging our unique immunotherapy platform to unlock the next era of neuroinflammatory diseases to treat millions of patients suffering from these diseases. We're led by 2 blockbuster registrational stage programs with the opportunity to treat more than -- or to address more than $10 billion of market opportunities with these diseases and treat more than 10 million patients on an annualized basis.

Our lead program is in dry AMD with geographic atrophy, a devastating disease, a leading cause of blindness. And our lead program or our drug candidate, vonaprument, ANX007 has demonstrated outsized vision protection in this population. Our second drug candidate is tanruprubart targeting Guillain-Barre syndrome and acute neuromuscular disease, a really very significant disease. We've run the first programs in this therapy in this disease area in the last 40 years and demonstrated a robust win in our Phase III program and now are pursuing global regulatory approvals.

Each of these programs are transformational and have the potential to completely reshape the treatment paradigm in their respective markets as well as being market leaders in those areas as well. And so we're really excited to be advancing those as we move through 2026.

2026 is indeed a pivotal year for significant value creation for Annexon, leveraging our clinically validated platform and our diverse portfolio of drug candidates. We have several key milestones over 2026 that we are seeking to achieve. First, with vonaprument in geographic atrophy, we will be releasing Phase III data in the second half of this year, which we really are looking forward to.

For tanruprubart and GBS, we have filed for European approval last week, and we anticipate filing for approval of this drug with the FDA later this year. And last and certainly not least is ANX1502, the first oral small molecule candidate targeting a host of autoimmune conditions targeting C1 inhibitor. There, we will have the first proof-of-concept data set in cold agglutinin disease population also later in 2026.

Coupled with that, we're really well positioned to make the markets in each of these 3 therapeutic areas with funding into late 2027 or more than a year after our GA readout and the know-how to make these markets with effective targeted medical education, pre-commercial activities and the like. So overall, we're really quite excited about the look ahead for 2026.

Now everything we do and our competitive advantage comes down to our scientific approach and our overall platform. Based on the discoveries of the late Dr. Ben Barres, former Chair of Neurobiology at Stanford, Ben discovered the role of targeting C1q, the initiator of the classical pathway, which drives harmful inflammation in a host of neuroinflammatory diseases. Importantly, this approach is quite different from downstream first-generation approaches targeting C3 and C5, which provides some protection against harmful inflammation, but it's incomplete.

As a result, we have seen differentiated efficacy and safety in all of the diseases that we have pursued in which they have also studied diseases like GBS, geographic atrophy, ALS and more, and I'll show you some of that data. Based on this pipeline or this platform approach, we've built a robust pipeline that's diversified by drug candidates and types of diseases that we're pursuing. The common denominator for all of these diseases is C1 and the classical pathway, and we're targeted differently in different compartments of the body, brain and eye.

With tanruprubart, we're targeting Guillain-Barre syndrome, which blocks C1q throughout the body as well as in the brain. Vonaprument is a fab fragment of that, which selectively blocks C1q solely in the eye compartment. And of course, ANX1502, the first small molecule that I alluded to, blocks C1q in the body only in a host of autoimmune conditions. So we're really excited about where these are and where they're going. And importantly, the learnings from these lead programs have really informed what we are doing with our next wave programs.

We've got multiple next wave programs, all of which we've already studied in the clinic. And we look forward to updating next steps on them as we progress further into the year. One of the key interesting aspects of Annexon as we think about 2026 is this opportunity to cash in on our asymmetric value opportunity. With 2 lead blockbuster late-stage programs, we have the opportunity to create really unique value not only for patients but for shareholders, particularly in comparison to the first-generation drug candidates who have set a strong foundation or precedent for value creation at the Phase III and registrational stage. That's exactly the stage we're at.

You see where our value is in relation to these opportunities. And so this is not a bad time to think about joining us on this journey. Last but not least, in our wind up, we're led by a very seasoned crew of biotech leaders. Collectively, we have more than 100 years of biotech experience ranging from corporate through research, development, of course, commercial, a lot of experience bringing first-in-kind drug therapies, blockbuster therapies in a range of diseases. We always talk about internally. The game actually doesn't start until you run into adversity and figure out how to navigate through that.

We've been able to do that over the last 10 years, and we're now at an inflection point for which we're really quite excited. So with that lined up, let me take you through some of the programs for which is generating this excitement. The first being vonaprument for the treatment of geographic atrophy and with the potential to be the first vision-sparing therapy in this space. You all may be familiar with geographic atrophy, but suffice to say, the unmet need remains, and it's really quite significant. And that's because there are multiple approved therapies, but none of which that have been approved to preserve vision in this very large patient population, 8 million patients worldwide, 1.5 million to 2 million patients in the U.S. alone.

And one of the really unique characteristics of geographic atrophy is it is indeed a disease of aging. So it strikes patients at a really vulnerable time. The average age of the patients entering into our study is 79 years old. And as you can see in the picture here on the right, they're losing their central vision. So at that point in their life, they're, in effect, losing their independence. They lose the ability -- inability to make out faces, to read, to make their breakfast in the morning. And so it's a really significant disease for which we are sharply focused on and ensuring that we can at least preserve their vision and allow them to operate independently.

One of the questions we get regularly is, how are we able to demonstrate vision preservation when the early generational programs targeting C3 and C5 were unable to do so. The short answer is by blocking and complement right where it starts on disease tissue, we're able to preserve against the loss of photoreceptor neurons that are responsible for visual acuity.

Geographic atrophy is a disease of neurodegeneration. You very rarely hear that said, but indeed, that is what it is. When you lose your photoreceptor neurons, you lose your ability to see. C1q localizes on photoreceptor cells and synapses shown here in the blue and red on the far left. This is a picture, a histopath of a geographic atrophy patient's eye. You could see here on the left in blue and red, the photoreceptor neurons are in red -- in blue, the photoreceptor synapses are in red. That connects the neurons and allows you to see really, really critical.

On the far left, those are fully intact, and so that's a healthy aspect of the retina. As you move closer to the right, however, you can see that the photoreceptors in blue and in red become dysregulated and actually become sparse and begin to go away. It's only at the far right when you actually begin to see loss of RPE cells or lesion growth. The 2 programs that have been approved prior to us are studying against the loss of RPE cells, which are in green at the bottom there on the far right. The challenge with that is, by the time you are targeting RPE cells, you have already lost your photoreceptors and your photoreceptor synapses.

So you have already lost your vision.

Protecting against the loss of RPE cells is a good thing to do, but it will not preserve your vision. And we see that not only in our data, but we see that in the approved drugs data where you're looking at 3, 4 years' worth of data where they're protecting RPEs in the neighborhood of 20%, 30%, but they have no vision preservation. And so it's a completely different mechanism, targeting complement upstream versus downstream, and that's the key takeaway for what we're doing.

And I can show you that with actual data. So looking in the central retina of the patients in our Phase II, we're able to measure protection against loss of photoreceptor cells in the eye. Here, we're showing a whopping protection of between roughly 50% and 60% of your photoreceptors in the central retina of the eye that is responsible for visual acuity. This data has never been shown before by any other therapy or approach in the geographic atrophy space, and it's just simple math. If you protect the neurons that are responsible for vision, you will protect vision. And that's exactly what we did.

Looking at the functional endpoints in our study, first, on the left, looking at best corrected visual acuity, 15-letter loss. This represents 50% of your vision loss over a 1-year period of time. By law, you are required to turn in your driver's license. So indeed, you have lost your vision. And what we demonstrated with vonaprument treatment every other month in the blue and every month in the red was a dose-dependent significant protection against vision loss. Patients who were not treated with vonaprument in the sham arm, 21% of them lost 50% of their vision in 1 year versus roughly 10% in every other month and roughly 6% in the every month arm.

We are moving for -- we have moved forward the every month arm into our Phase III study. Looking at a companion assessment of vision loss with LLVA or low luminance visual acuity, this is an assessment of vision loss in low light conditions. Rarely do we have perfect light. So it's important to show that your drug can protect against the loss of vision in all conditions. And that's what this shows here on the right, where 20% of the patients who weren't treated lost vision versus 7.5% in those patients in the every other month arm and 10%.

So a really profound effect. This is just a snapshot of our data. We actually protected vision on every measurement of visual acuity in the study. So we're really, really encouraged by the outlook for that. Importantly, by protecting vision with vonaprument on every month basis, we reduced the risk of losing vision by 73% at month 12. That's a really significant number. So when a patient comes in to see a physician, the physician's talking point is very simple. If you take this drug, you reduce the risk of losing your vision over 12 months by roughly 75%. And that's really important.

It's also important to note that, that protection against vision starts right around month 6. And as you can see on this slide, it increases over time such that by month 12, the impact is greater. The longer you treat, the greater your impact will be in preserving against the loss of vision. And perhaps the most important slide and certainly the most important slide from a regulatory perspective is what vonaprument did in preserving vision on treatment versus off treatment, which really evidences this disease-modifying mechanism of action.

The on-treatment portion is in the left, the unshaded area. And you can see similar to the other slide -- the prior slide that starting right around 6 months, you begin to see protection with the treatment in the blue and the red through month 12 when we stopped the drug. We then followed these patients for 6 months after stopping treatment. And what you see is the patients begin to lose their vision again after we stop treating them. What's really important, however, is that we reset the baseline for the disease in these patients. Although they began to lose vision at a rate similar to sham in the off-treatment arm, they never caught up to sham.

So we reset their baseline, which is important from a disease-modifying perspective. That's not chance. That's biology. And so we're really encouraged by that. We've taken these learnings to develop a really well-informed and well-powered Phase III study. It's virtually identical to the Phase II study with some important kind of enhancements, one of which is we enrich for patients who are most likely to lose vision over a 12- to 15-month period of time, but they are not so far gone that you can't protect them against the loss of that vision.

So we have a lot of information on how to do that, and we enriched the study for that, which increases our overall PTS. This is a large study, 659 patients, exceedingly well run. One of the things to note is that as we went out and explained our data and our mechanism of action to physicians across the globe, studies run in the U.S. and Europe. This study was enrolled roughly 2 months ahead of schedule and over enrolled by 30 patients. That's a really good sign. Well-run studies tend to produce better outcomes.

The primary analysis is at 15 months. Recall that the Phase II primary analysis was at 12 months and the protection was getting bigger over time. At 15 months, it will get even bigger. And so we increased the likelihood of showing a great outcome with that as well. And as I said before, primary endpoint is best corrected visual acuity, 15 letter loss, what I showed you previously in the Phase II study for which we had statistical significance. We have global regulatory alignment on this single protocol approval. So this is the study for approval.

We've got PRIME designation in the EU, Fast Track in the U.S. And so we're really encouraged at bringing forward the potentially first vision-sparing therapy for the treatment of GA. This drug -- this study will read out, as I said, in the second half of 2026.

Last slide, as it relates to geographic atrophy relates to the market opportunity. This is a mega blockbuster opportunity. The opportunity in this space is somewhere between $7 billion to $10 billion on an annualized basis. What you're currently seeing in the space is the 2 approved drugs that protect against lesion growth or surrogate biomarker for vision, currently doing about a combined $1.5 billion a year in sales. Our view is by offering a drug that preserves vision, which is keenly most important to patients and the physicians, we have an opportunity to capture this entire market.

And we're actively preparing for it. One of the things I didn't touch on is I showed you where we do on efficacy from a vision preservation perspective. I'll just quickly say -- state that we also have a very differentiated advantage from a safety perspective. Our drug is a very small fab fragment 50 kD, low viscosity and importantly, non-PEGylated.

So we have not seen many of the safety events that have been observed in other clinical studies with GA with other downstream complement approaches. And last but not least, because our mechanism is only blocking the classical pathway and allowing the lectin and alternative pathways to remain intact to perform their immune function, we have not seen conversion to wet AMD.

You will recall that the approved drugs have conversion to wet AMD in the neighborhood of 10% to 15%. Our conversion to wet AMD was virtually no different between sham and the treatment arm. So we like the overall benefit risk from the profile of this drug, very differentiated from the drugs that are currently approved on mechanism, on efficacy and also as it relates to safety.

Turning quickly to tanruprubart and Guillain-Barre syndrome, a program that we are really, really proud of. This program represents our mission-based approach to make our drugs available to patients suffering from neuroinflammatory diseases around the world. Guillain-Barre syndrome is a [ nary ] disease. For those of you who are not familiar, as I said before, it is the #1 cause of acute neuromuscular paralysis and it is a sudden indiscriminate life-altering disease.

The way it works is you get some type of preceding infection. It could be food poisoning, it could be the flu. It could be a vaccination. For whatever your immune system turns on, drives inflammation to clear that infection out of your body, which is an appropriate role. Sometime later, 2 to 4 weeks thereafter, your immune system drives inflammation, this time attacking your peripheral nerves. 2 or 3 days after that, you are oftentimes bed bound with the inability to walk without assistance. 2 or 3 days after that, many, many patients, 1 in 4 are on a ventilator in the ICU.

You are otherwise completely normal when you're struck with this disease. Fortunately, it's a rare disease, but it's not a small rare disease. It impacts 150,000 people worldwide, 8,000 in the U.S., 15,000 in Europe, and there are no approved therapies. IVIg is used off-label. It has not been studied in randomized studies, has a midland effect on this disease. But even notwithstanding ICU, 30% of patients are still going to the ICU, 75% are requiring ventilation in the ICU and 20% can't walk after 1 year.

And so there is a real need to tackle this disease. It's a very expensive disease. Patients are hospitalized, patients are in ICU, patients are ventilated. They ultimately will go to skilled nursing facility, physical therapy, et cetera. It costs the health care system in America more than $7 billion a year to treat 8,000 patients. These are million-dollar patients.

And so we're encouraged at getting after this and providing a real solution with a targeted immunotherapy that's fast acting and it's complete, and I'll show you some information on that. Importantly, from a market opportunity, although it's a rare disease, it's a unique disease and that it's actually a blockbuster opportunity. And the reason for that is 23,000 patients a year get this disease, 90-plus percent, actually, it's 95% of patients get treated currently with IVIg or plasmapheresis. So you have a ready-made market.

Everyone gets treated because of the devastating nature of the disease. You're trying to stop it as quickly as possible. And it's a very concentrated commercial market here in the U.S. Our top 50 health care systems see more than 50% of the patients on an annual basis. And so that allows you to target your resources, your sales force, your MSLs, your medical education, et cetera, towards that.

And then I'll just say tanruprubart is very uniquely situated to capture this market. It's a single infusion that shuts down this entire inflammatory pathway. 90% of the patients that we treated improved by week 1. The safety data looks like placebo, which is really, really important. And we offer a potential savings to the U.S. health care system based on other measures, which I'll show you momentarily.

Looking at our study, one of the key measurements in the study are these inflammatory biomarkers that are responsible for driving the disease. There's 25 of them. In our study, tanruprubart reduced all of the biomarkers within the first week of treatment, really, really important, whereas when you look at IVIg and placebo on the right side in this panel here, they had no effect on these biomarkers.

What that tells you is that the current treatments actually are not immediately arresting the disease, which is leading to the large disability that occurs with this disease. By knocking down these biomarkers rapidly, what we showed is that by week 1, we were able to have a significant impact in returning your muscle strength. This is a 10-point improvement on MRC sum score, which is a whopping score versus placebo. And by doing so, by week -- month -- or week 26 or month 6, we had -- we gave patients a 2.5x greater likelihood to returning to a normal state, completely unheard of in the history of this disease, and we're really excited about that.

Most important to patients and health care providers, it's this slide here and some of the data. With our treatment in our Phase III study, we were able to return patients to walking 31 days sooner than placebo. We got them off a ventilator 28 days earlier. We got them out of the ICU 7 days earlier. So we were able to return patients back to their activities of daily living much sooner than had they not been treated with tanruprubart, which is really, really important from a patient's independence perspective and also from a value perspective. There are hard dollars associated with being in the hospital and with being on a ventilator in the ICU, and we're saving all of those dollars. So we're really, really encouraged.

One of the things I didn't mention is that our Phase II program is the only -- or our Phase III program is the only placebo-controlled program that's been run in this space in 40 years. And so we're encouraged that we were able to go ahead and do this.

We are now running an open-label FORWARD study. We're calling the FORWARD study in the U.S. and EU. All patients are getting treated, and we're encouraged by the early results and what we're seeing in that study. This is just an example patient that I have here. This patient came into the study with moderate to severe disease, meaning that he was bed bound and hospitalized.

We were able to treat this patient within 4 days of signs and symptoms. By day 8, the patient walked out of the hospital with the cane, really a stunning outcome but very consistent with what we saw in our Phase III study. And by day 29, the patient was walking independently. And so we're continuing to run this study. It's really important that physicians get experience with our drug in the U.S. and Europe. And we'll also be providing this data as part of our BLA submission package to the FDA in 2026.

So with that, I'm going to come to a close. This is a really important year, as I said, 2026 for Annexon. It's a transformational year to create outsized value for patients and our shareholders. We're sharply focused in really changing the treatment paradigm in geographic atrophy with our Phase III data later this year and getting tanruprubart approved in GBS worldwide for the 150,000 patients afflicted by that.

And then last but not least, our mid-stage program, ANX1502, we will have proof-of-concept data in that as the first oral inhibitor for a host of neuroinflammatory autoimmune conditions that are currently being treated with IVs and subcus. So an opportunity to really shape the market in that space as well.

With that, thank you for your attention, and we're open to any questions you have.

Thanks, Doug. I'll ask the first couple of questions, but we'll also open it up to the audience to get their questions in, just raise your hand, and I call on you. On just ARCHER II, can you remind us what the powering of the study is and kind of what would be a win scenario? You're obviously moving with the monthly, which had a 73%, I think...

Yes, 73% reduction in risk. Yes, really good question. So the Phase III is powered as a standard Phase III would be powered into -- high powered. So greater than 90% power with regard to that. And a win is any statistical win on best corrected visual acuity. No drug has ever demonstrated that before other than our drug in the Phase II study. That's protecting 50% of your vision. And so any significant win on that measurement is considered clinically meaningful.

So -- but if I could push, what are you assuming in the sham arm of what kind of decline you would see there? And then what kind of benefit on top of that would be clinically meaningful?

Yes. In the sham arm, what we saw in our study is that when you confirmed at 15 months, patients lost about 15 -- high teens, 17%, 18% in the sham arm. And you saw our treatment effect in the [ phase ]. And I'll just kind of go back to that while I'm kind of talking you through that.

In our treatment arm, we saw a protection in every month group of roughly 6%. We did a conservative powering estimate, meaning we reduced what we anticipated the sham arm would be in our Phase III study, and we also reduced the treatment effect on what we would see on the treatment arm from vonaprument. So we were conservative on both ends of the barbell to ensure that we are exceedingly well powered for this Phase III win.

Your competitor actually talked yesterday -- or maybe a couple of days ago about having a prefilled syringe really opening up the market. Do you guys have plans for a prefilled syringe?

Absolutely. Yes. And really uniquely situated to do so. As I said before, vonaprument is a drug that is a very small fat fragment, 50 kD and perhaps more important, it's really low volume, 25 microliters, which is about 1/4 of the microliter levels of our competitors. They're about 100. What that makes it is uniquely situated for a prefilled syringe. So we're doing that as well as extended release formulations for the commercial presentation. We'll launch with every month, but ultimately be looking to dose this drug once a quarter or so.

And how are you thinking about the OUS opportunity for the drug? It's been difficult for competitors...

Yes, really important for us. Again, because we are studying vision, visual preservation, best corrected visual acuity, we have full alignment with the regulators in the EU for approval of this drug with a win on this study here. And so there's 3-plus million patients in the EU who get GA every year, and it's a meaningful commercial opportunity. We've got prime designation with the FDA -- with the Europeans, which is in effect, breakthrough designation in Europe, which we're encouraged by.

They've also assigned a specific product development coordinator to our program. This is a pilot program that's being run out of Europe for 17 select programs of high interest for the European regulators. So we really have an opportunity to have up close and personal interactions with the regulators in Europe on this program. We've had multiple interactions. So we're really encouraged with the outlook for the approval of this drug in Europe as well as in the U.S.

Questions from the audience? Yes, over there.

Will there be any time line for the GBS because we decid to talk with U.S. government? I don't know what kind of data we still need to have a conversation with FDA.

A really good question. So as I said before, we filed for regulatory approval with the EU last week. That package consisted of substantial evidence as well as a generalizability assessment. That will be the same package that will go into the FDA, but we will supplement that package with additional U.S. and European data from this open-label FORWARD study. This is why the study is so important. We have real-time data that we're able to provide the regulators here in the U.S. in conjunction with that submission. And so once we get an appreciable number of patients in this study, and it's enrolling pretty well as we sit here today, we will then go see the FDA and submit our package. Thank you.

Go ahead.

Just following on from that, would you then plan to launch in Europe before an FDA approval?

It's a really good question. That's a TBD. The hope is the European review process is a bit longer than the FDA's process. Typically, it's 12 to 15 months. The thought is depending upon when we submit for approval here in the U.S., approval will be close in time with the Europeans, in which case, we would certainly prioritize launching in the U.S. first, to establish pricing and other things before going to Europe.

What's going to be the size and scope of the FORWARD study? And has FDA talked about how much data and follow-up you need from FORWARD study to file again?

Yes. So the FORWARD study is currently up to 30 patients. We don't believe you need 30 patients to actually add as a supplement to our overall submission package. We have not had a specific discussion with the FDA on the number of patients. And so we intend to just go in and let the data speak for itself. One of the things that's very unique about tanruprubart in GBS is the data is highly consistent. As I showed you before, 90% of the patients roughly got better at week 1. We anticipate that's what we will see in the FORWARD study.

We also know the PK/PD profile of our drug, having dosed our drug not only in GBS now here in the West, but also in diseases like Huntington's disease and ALS. So the PK/PD profile from a bridging study is already well elucidated. So we anticipate it's just a handful of patients that we would need to support our overall package. But we'll have that discussion with the FDA once we have the data in hand, the full data set.

Questions from the audience? Go ahead.

Yes. I just worked very closely about your data about GA. And for the inflammation rate, I think it's much higher than Regeneron's EYLEA in wet AMD. So is there any improvement maybe about the injection procedure or maybe we have a longer half-life?

I'm not sure -- could you maybe repeat that? You said what was that?

Yes. According to your data, and I noticed that the inflation rate -- inflammation rate, yes, it's higher than something like wet AMD.

Well, these are very different diseases. So the thing with wet AMD is a very fast-acting disease. And you actually -- your endpoint there is actually vision enhancement, whereas in geographic atrophy, the way the inflammatory disease process plays out is very different. And so what you're looking to do is just preserve the loss of vision. It would take years, if ever, for you to return vision.

And in fact, I think it's unlikely because with inflammation playing out over the course of a slow-acting disease, you're losing your photoreceptor neurons, they're dying, and they don't regenerate. When you lose neurons, they don't come back. So it's really not a good corollary to compare wet AMD to dry AMD. They're completely different diseases.

Maybe we could touch a little bit on ANX1502. I noticed that you're going to have some POC data this year. Just walk us through where you are in terms of what you're trying to accomplish in the proof-of-concept study relative to what you learned last year about the compound.

Yes, yes, really good question. So this is an audacious program. Let me just start there. No one has tried to bring forward a small molecule program for autoimmune conditions, particularly neuromuscular autoimmune conditions. But given our research and our learnings with our antibodies and our understanding of the pathway where we have more than 40 de novo assays, we've made drug candidates against every node of the classical pathway. We've ventured into the small molecule space, and we've taken learnings every step of the way.

As you alluded to, Anupam, last year, what we learned is that our drug initially in its film-coated presentation caused a bit of emesis in patients. So we switched over into an enteric-coated formulation, which solved that topic, but it created a new topic in and around a food effect. And so what we've learned is that patients really need to be fasted at around 2 hours or so before or after taking the medicine and then it appears that the drug has -- exceeds our target drug levels.

So we are now running the proof-of-concept study where the patients are fully fasted. This is BID dosing. They're fasted in the morning and in the afternoon. And we then want to see what their drug levels are. The key measurements for this are super objective. So this is done included cold agglutinin disease, and we're looking at hemolysis, namely looking at bilirubin and looking to bring down patient's bilirubin levels to levels of normal as well as complement activation, which goes up exceedingly high in a disease like cold agglutinin disease.

So with really a well-controlled drug that does not have the food effect that we've seen heretofore and the impact on bilirubin and complement levels, we'll be excited about moving this program forward. It may require some additional formulation work because I think we can probably solve this food effect with doing that. But first, we want to make sure we understand this drug's target drug levels. If it achieves the target drug levels, we consider that a home run. We'll then go solve the formulation topic and keep going forward with this.

Any final questions from the audience? Okay. Thank you, Doug.

All right. Thank you all.

So welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, biotech analyst with Cantor. With us, we have Annexon, a company I cover, and I'm pleased to introduce Doug Love, CEO.

So let's start off with the introduction of yourself, a brief description of the company and your therapeutic strategy.

Yes. Hi, Pete, and thanks, Cantor, for welcoming Annexon to this year's conference. Happy to be here. I think this is our fifth or sixth in a row. So we're excited by that.

So I'm Doug Love, as Pete said President and CEO of Annexon, Founding CEO of the company. We started the company roughly 10 years ago, focused on the classical complement pathway. And importantly, what's unique about our approach is we're targeting the most upstream aspect of classical complement which localizes on disease tissue and drives a damaging inflammatory disease process in a host of diseases across the body, brain and eye.

What's unique about what we are doing is all of our programs are first in kind or pioneering, and we're really pleased with the consistency in the outcomes we've seen across all of our programs. We're led by 3 flagship programs. Guillain-Barré syndrome is our most advanced program, having completed a robust Phase III program, and we're now in dialogue with regulators across the globe for approval worldwide.

Tanruprubart in geographic atrophy -- or vonaprument, I'm sorry, in geographic atrophy is our second flagship program. It's the world's largest GA Phase III program, the only program to have demonstrated significant preservation against vision loss as well as robust protection against photoreceptor cells. I'm sure we'll talk about all of that in the Phase II proof-of-concept study. We fully enrolled the Phase III study ahead of schedule, and we're looking forward to reading out on that in the second half of next year.

And last but certainly not least is ANX1502, first-in-kind small molecule program in the classical complement PET space. This is a translational stage, earlier-stage program, but one we're quite excited by, and we'll talk more about how we're walking that down to hopefully bring that to patients.

So why complement pathway inhibitors? So with a number of complement pathway inhibitors approved or in development, why do you see the need for an additional complement pathway inhibitor?

Really good question. Yes. So all complement is not the same. Most of the programs that have been approved in complement target downstream components of the pathway, C3 and C5. The challenge with that approach is that the inflammatory process starts at C1q right at the start, such that by the time you get to C3, C5, you've had this buildup of this inflammatory cascade, which has caused significant inflammation and tissue damage in a host of diseases. So as a result, by targeting C1q upstream, what we're seeing is differentiated outcomes in many, many diseases, including ALS, Huntington's disease, GA, Guillain-Barré syndrome, et cetera. So we really think it matters which node in the complement pathway you target and starting right at the initiator of the pathway, you can do no better than that.

So you are developing it in GBS. You did run a Phase III study. Just walk us through some of the basic outcomes.

Absolutely. So just a little bit on GBS. This is a really acute neuromuscular disease, #1 cause of acute neuromuscular paralysis in the world, a really debilitating disease overnight that just robs people of their lives. Our program is a bit nontraditional in that we've run a really extensive program where we've conducted 4 studies now predominantly outside of the U.S. with the aim of running placebo-controlled studies. The standard of care here in the U.S. is an unapproved agent with no well-controlled data. So we're unable to run comparison studies here in the U.S. So we went ex U.S. to run this study.

Suffice to say, we had a robust proof-of-concept data set, which then led to a robust Phase III data set. And in the Phase III data set, in particular, we saw a really diverse set of outcomes. First and foremost, 90% of patients treated with tanruprubart in the Phase III program got better by week 1. That is a staggering outcome. We know the unapproved drug that is standard of care, patients are still declining at week 1. And week 1 really matters because that's when physicians are making treatment decisions about who goes to the ICU or how long they'll be in the ICU, ventilation, et cetera. And so being able to show improvement, getting patients up and on their feet immediately is really, really important.

We also showed really good outcomes on related measurements such as days on ventilation versus placebo. Our patients spent 30 less days on ventilation -- ventilator versus placebo, 30 less days. They walked 30 days sooner. They're in the ICU, 20 days less than treated with placebo. So a really profound effect on multiple measures.

All right. So you did mention that you ran out of the states in the EU, but you didn't say why? Like you did mention that you can't do a head-to-head comparison, but why can't you do a placebo-controlled study?

Yes. Well, it's just unethical to run a placebo-controlled study here in the United States because of the debilitating nature of the disease. The way GBS works is typically patients are completely healthy. They get some type of food poisoning. Their immune system kicks on, triggers complement to rid the body of these cells that are associated with food poisoning. The immune system is then supposed to shut off and perform its normal function.

Unfortunately, in GBS, it aberrantly reactivates, attacks peripheral nerves. And overnight, you can't work through remote. By day 2, you may not be able to get out of bed. By day 3, you could be on a ventilator. So it's a really debilitating disease that robs people of their lives, not giving them any treatment was deemed unethical by all of the IRBs and treating physicians around the globe candidly when you had the standard of care available to give them. So that's why we're unable to run a placebo-controlled study here in the U.S.

Okay. So I guess another question is that you've -- that we've spoken about a number of times is the neuro type observed in the, let's say, Bangladesh population, is it similar to the Western population, namely AMAN versus AIDP?

Yes. So there are 2 neuro types for Guillain-Barré syndrome. It really relates to which aspect of the peripheral nerve is being attacked by complement, but the diseases are the same. They're all antibody-mediated diseases, which complement is the key effect or you stop complement, you have the same outcomes. I will say that AMAN appears to be more of a severe disease and typically -- it's all gradient, typically more severe than what you see in AIDP. In the United States, the preponderance of patients have AIDP, where we ran the study, the preponderance of the patients had AMAN. So we, in effect, had a higher bar to go against because these were more severe patients that we saw here in the U.S.

That being said, when we looked at the patients in our study who had AIDP, the less aggressive form of the disease, our outcomes are even more pronounced than what we saw in the full Phase III data set and so -- on every measure. So we're really encouraged that not only can we treat patients who have a very severe aspect of the disease, we can treat those patients with a milder form of the disease and see even more rapid and durable outcomes as a result.

Okay. And so I guess some of the outcomes was -- you did have 2 doses, 30 and 75. And 30 outperformed 75. Rationale for that? And you have shown some graphs.

Absolutely. Yes, really good question on that. So with regard to 2 doses, 30 and 75, it relates to duration of inhibition of the complement pathway. Both doses fully inhibit complement. 30 inhibits complement for about a week, 75 inhibits complement for about 2 to 3 weeks. And what's important about that disease -- GBS is an acute monophasic disease. The disease process lasts for somewhere between 1 to 3 weeks.

And what we learned, and we see this now in multiple studies from others as well as with IVIg use is that you really want to inhibit complement for a limited period of time, just so long enough to stop the disease process. And then you want complement to come back and be part of the repair process, which is its normal function. And what we learned in our proof-of-concept study, which was replicated in the Phase III study is that shorter inhibition is better. IVIg has seen that in the studies they've run where they've done 2 doses of IVIg treatment, 1 dose of IVIg treatment outperforms 2 doses as well. So it's a very consistent outcome, limited inhibition of complement, then allow complement back to help with your recovery.

Okay. So for an approval, you need to conduct a real-world evidence study, I guess, comparability. Just describe the real-world evidence study and how it was conducted.

Yes, absolutely. So as I said before, we ran this program ex U.S., outside of the U.S. because we cannot run placebo-controlled studies here. The study was run in Southeast Asia, in Bangladesh and the Philippines, where standard of care IVIg is not readily available, so it was deemed ethical to do so. We knew at that time per agreement with the FDA as well as EMA that to get an approval, we needed to demonstrate 2 things. one, substantial evidence on the Phase III study; and then two, that the data that we generated in the Phase III study was generalizable or comparable to what we would expect to see in a U.S. patient population.

To do that, we ran a real-world evidence study in -- well, globally, where we looked at patients from our study and we matched them in patients from a 2,000-patient natural history data set called IGOS, International Guillain-Barré Outcome Study, that's out of Erasmus in Europe. There, we did a propensity score matching to match patients based on their baseline disease severity, which is the key prognostic factor for how patients are going to do, how severe is the disease at baseline.

We were able to match every patient in our 30 mg per kg dose, the dose we're moving forward, with patients in IGOS to really satisfy that we had a comparable patient group to what we would see in the West. We went the additional step of also comparing outcomes with these matched patients versus those patients in IGOS who got IVIg. And there, we showed benefit against IVIg on every measurement that we looked at, including the primary endpoint.

What are some of the key clinical and efficacy outcomes when you compare it to IVIg and plasma exchange? And which seems to be the more effective from the data you generated? I mean you just did mention that you beat IVIg?

Yes, I want to say a bit more, happy to. So starting always with week 1, which is where we start because you want to arrest this disease right out the gate. We showed a 10-point improvement on IVIg, highly statistically significant. As I said before, 90% of the patients got better at week 1. At week 1 with IVIg, patients are still declining. So really important finding. There's not a lot of data on IVIg. And one thing I should note, this real-world evidence study was actually not done by Annexon. We sponsored it, but it was done independently by Erasmus, the University there, who has presented this at medical conferences and are in the process of publishing it. So they're fully standing behind their work here, and we quite like it as well.

Anyway, so at week 1, we showed 90% of patients getting better, IVIg still getting worse. At week 4, week 8, we're showing on the disability scale that we significantly improved people's function and disability at those time points, whereas IVIg has a midland or mild effect there. And then we showed a durable outcome out to week 26, where nearly 2.5x more patients got back to a state of normal by month 6 versus IVIg, also statistically significant.

So every measurement from a functional strength perspective, we outperformed IVIg. We also performed them as it related to kind of hospital value-based measures. So we got patients out of the hospital almost 2 weeks earlier than IVIg. We got them off the ventilator almost 2 weeks earlier than IVIg, less than -- we got them out of ICU almost 10 days earlier than IVIg. So really robust outcomes, and it stands to reason. So this is a targeted immunotherapy approach that we're pursuing here in Guill-Baré syndrome, very much like what you see in CIDP or myasthenia gravis, whereas IVIg is a nonspecific mechanism and so their outcomes are a bit wobbly, I guess, one would say.

Why not combine the 2?

What's that?

IVIg and...

No need to do it. I mean you see 90% of patients getting better, one, with our drug. Two, IVIg is 5 courses of treatment over 5 days of infusions. We're a single infusion. So it's super efficient for the patient as well as for the hospital and administration staff. And three, IVIg actually carries a black box warning. And really, when you look at our safety profile in our Phase III program, it looks very similar to placebo.

So the drug is really well tolerated and looks relatively safe. Whereas IVIg with the black box warning, 12%, 13% of these patients get thrombosis in Guillain-Barré syndrome. So we don't want to take that risk given the outcomes we're seeing, and we're a relatively safe compound.

And then sort of what are the expectations from the regulators? What does the FDA want to see? What does the EMA want to see? From the RWE? What are the key analyses each regulator wants for an approval?

Yes. Maybe I'll start with EMA first for the MMA approval since we're further along in those discussions. As I said before, for both jurisdictions, they're very consistent in that both want you to demonstrate substantial evidence on your Phase III program as well as demonstrating this generalizability analysis and your real-world evidence work that we've done. With EMA, we're further along in that we've had multiple discussions with them on the specifics of our programs.

This dates back to our proof-of-concept study, where it was a placebo-controlled study that we went on. There, we saw orphan drug designation in Europe with a higher bar there because IVIg is actually approved for Guillain-Barré syndrome on a compendia, not because they ran a study. And to get orphan drug designation in Europe, you need to demonstrate 3 things in our particular case. We need to demonstrate that the study that we run in Southeast Asia was adequate and well controlled and met the requirements for substantial evidence, which EMA agreed with.

We also need to demonstrate that the real-world evidence generalizability analysis we did was appropriate to establish comparability or generalizability between our patient population in Europe, which EMA also agreed with. And then finally, we needed to demonstrate that we were likely to be substantially better than standard of care IVIg in that Phase II proof-of-concept study. EMA also agreed with that. They wrote a 20-page single space document really detailing the disease as well as our outcomes, both on the efficacy side as well as the generalizability side. So they have a rich background in what we're doing. And that's really important as we move forward there from a regulatory perspective.

Once we got the Phase III data, we then went out and did country-specific meetings with the local regulators across Europe, which really were quite productive. In fact, one of the meetings we had was with the Netherlands, really deep in the GBS space, Erasmus is there, et cetera. They have a lot of research in this space. The meeting went exceedingly well, and the head of the regulatory group there actually raised his hand to be a rapporteur for the program.

And so we were delighted to see that he's been named as the rapporteur for this program. And we, of course, already have a written opinion from the Netherlands and the second chair is Poland. So we're in really good position with regard to where we are in EMA and moving that forward, and we're excited, looking forward to file the BLA or the MAA by Q1 2026. So all systems go there.

Similarly, in the U.S., we've had, I think, 10 meetings with the FDA over the last 10 years on this program alone. This is a first-in-kind program. The FDA had not seen a program in GBS in 50 years, which is, again, different than EMA from that perspective. So we've spent a great deal of care and working closely with them. They've been really engaged and quite productive in the discussions. And just first, understanding the disease Guillain-Barré syndrome and why it's different from most any other disease one will see. And then two, our development program, including the alignment on substantial evidence for the Phase III study in Southeast Asia and the real-world evidence analysis.

So that's what they're looking for. Similarly, we've had good discussions with them on both. More recently, we met with the FDA in June towards the end of the month on the real-world evidence discussion. We'd already talked about the Phase III study. I mean that was really a quite productive meeting led by Teresa, Dr. Teresa Buracchio, who is the office head for the Neuro division. So really strong engagement from UPI, and we really appreciate their collaboration on it. Quite a productive meeting.

Once we got the meeting minutes, however, a bit surprised in the aspect of it in that there was post-meeting comments that reflected meetings that occurred internally within the FDA outside the purview of the company. And so some of the comments we're going back to them on just to make sure we are really clear on what they're thinking and whatever it is that they would be looking for as a result of that. So that's our next steps. We'll be back with them this fall to really address these post-meeting comments that we just weren't a party to for those discussions.

Sort of what's the nature of it?

It's all around generalizability. I'm sorry, I should say that. Yes. So all of those post-meeting comments and even all of the meeting minutes from the June meeting all relate to generalizability, and I can say what they don't say. So what they don't do is call into question what we did from a Phase III perspective or call into question our generalizability analysis. It appears that there could be a larger policy question in terms of what type of information would you want from programs that are run outside of the U.S. under today's kind of FDA leadership.

Is it changing? So I believe there was guidance last year or 2 years ago.

Well, there's been guidance. There's federal registry on this. There's an international guidance that companies follow.

This is from the agency?

Yes. And then we have specific guidance on this program before initiating the Phase III. And so whether it's changing or not, it's too early for me to say before we have a discussion with them.

All right. Have hands switched in terms of dealing with Annexon at the agency?

Well, Dr. Buracchio has been with the program for the past 10 years. She started off, I think, 10 years ago, we first met with them, I think she was the clinical reviewer on the program, and she's matriculated up the organization. So she's been there. But of course, like any -- most organizations over the last 10 years, there's been some ins and outs, I imagine that neuro division.

All right. So you do have the FORWARD study, open-label study conducted in North America and Europe. Just walk us through the design, how many patients you expect to enroll and the rationale for conducting it?

Yes. So the FORWARD study is the first U.S. study. in Guillain-Barré syndrome in 40, 50 years. We're super excited by it. The reason we're able to run the study is it's an open-label study where everyone gets treatment, tanruprubart, and that's on the basis of the strength of our Phase III data, where the physician population, the IRBs, et cetera, are really excited to give patients an opportunity with this drug in the U.S. Our purpose for doing the study is twofold. One is to get patients and physicians in the U.S. experience with our drug prior to launching in what we think is a very meaningful commercial opportunity.

The second is it checks the box of we expanded the study to allow pediatrics into the study. So it allows us to pick up patients earlier, which is an important element for an EMA filing that you actually have a study ongoing that allows pediatrics to be treated as well.

So twofold. We love what we're seeing so far in the study in that we are really bringing sites online and really helping to harmonize their approach to treat GBS. GBS is very different than any other acute disease you will see like stroke, or something or another where there are really robust protocols and consistency in how it's dealt with in institutional level and across the United States. That's not the case at GBS. We see that every institution does it differently.

And so being able to harmonize how you treat GBS is important. In fact, 1 out of 4 patients are diagnosed with GBS upon first presentation. And time is nervous. You need to treat this disease as quickly as possible. Part of that is that there's never been an approved drug with sales reps, MSLs and companies coming in to educate and to help assist in kind of harmonizing how it's managed. So we're doing that as part of this study, and it's been really great to see.

Have you enrolled any patients yet?

We're going to just hold off. We've initiated our sites. We will do an update on the patients. Once we have a cohort that answers the question for us. The questions we want to answer is PK/PD, one, does tanruprubart perform the same in the West as it does in Europe, in Southeast Asia, antibodies perform 99% the same. Geographically, it doesn't really matter. But we need...

So not disease-wise but I mean, you did run the Huntington's disease.

We've run multiple programs here in the U.S.

Would PK/PD be any different?

Well, this is an acute disease. So the studies we've run here in the U.S. historically have been chronic diseases. So we don't anticipate it will be different, but it's a box checking, and we want to make sure we do that the PK and PD. We'll also look at efficacy. We want to carry through what we've seen in the 2 prior studies of 90% of patients getting better at week 1. It's a really important finding and it certainly will help as we commercialize this drug post approval. So those are the 2 primary things we're looking for out of the FORWARD study in addition to the experience aspect of it.

All right. Does any of this have to do with generalizability with the FDA?

It hasn't yet, but we will see. TBD.

Did you initiate it? Or did the agency?

We initiated it. Yes, we had no interaction with the FDA with regard to the FORWARD Study. We did that on our own. Of course, we went through the normal channels of submitted the protocol, et cetera, received no comments or anything, but that was not a mandate when we initiated the study, yes.

All right. Commercial prospects. run us through it?

Really excited about this. So there's a minimum of 7,000 patients treated every year. And I say a minimum because we're just completing our health economics work, which we will release in the fall. No one's done this extensive analysis of Guillain-Barré syndrome ever forget about it, bar none. And we're seeing that it's likely more than that. We're also seeing that the cost of the health care system is dramatic. I mean it's in the neighborhood of $3 billion to $4 billion a year to treat 7,000 to 9,000 patients. So a really significant burden.

What we like about it from a commercial perspective is it's a super efficient commercial footprint. 175 physicians or 175 hospitals control 60% of the patient population, which we love. So this is an incidence-based disease. It's really driven by population. So we know exactly where to go. In fact, 26 hospitals control 20% of the population. So with a really crisp sales force and MSL group and then field managed care, we think this is a real blockbuster opportunity.

One thing I left out is 90-plus percent of patients get treated with GBS. Many of them are getting treated too late, so we need to move that up, but everyone is getting treated. So it's a ready market right there for you. The other thing I will note is that from a payer mix perspective, while this is a hospital-based disease, 2/3 of patients are reimbursed with commercial payers. That's really, really important. When you think about CAR-Ts, for example, that charge in the millions of dollars in the hospital, how does that work economically? They're commercial payers. It's the same paradigm for GBS. We do not anticipate charging anything near that, but we like that we have a real robust path to reimbursement with regard to this program.

Okay. We have about 6 minutes or so left.

I'm sorry, I'll go quicker.

Let's quickly just touch on a molecule, which is I think there's a lot of interest in it and the pathway, 1502.

Yes, ANX1502. Yes, first small molecule program, the classical pathway. I'll be quick about this. This is a program that we started 8, 9 years ago, really to bring forward kind of the first oral approach to a host of autoimmune diseases. When you think about, for example, rheumatoid arthritis, MS, you can see how those fields evolved where they started with monoclonal antibodies, infusions, they move to subcus and ultimately to orals as competition is exploding. We're seeing that in MG, CIDP and other indications where you see a lot of players that are trying to differentiate on the margins between an infusion or a subcu.

We've gone hopefully towards the front of the pack with an oral, full stop. We started a preclinical program where we did a CH50, where we compared our molecule with approved drugs targeting C1S in the space, sutimlimab, in particular, to really establish our target drug levels and exposure we need to see to demonstrate efficacy. From there, we ran a suspension study in Phase I to show PK tolerability. That went well.

We then moved to a film-coated tablet. We ultimately want to be in a pill form. That also went well from a PK exposure perspective, saw some tolerability in that study that we thought was related to MSS and nausea that we could bypass with an enteric-coated formulation, which we were able to successfully do. So we moved to enteric coated, ran another healthy volunteer study. There, we demonstrated similar or better PK profile, but really more or less minimize the tolerability topic. So that was really quite encouraging.

We are now in our first proof-of-concept study in patients. What's important about that, these are patients where complement is really highly elevated. This is also the first group that we've run a study in where patients are not fasted. So in the healthy volunteer studies, all of the subjects were fasted. What we've seen thus far in the proof-of-concept study is in patients who are fasted, our exposure levels are fivefold higher than what we want from a target perspective, like we're super excited about what we're seeing.

On the other hand, when patients are taking the drug with food, it's washing out the drug in the stomach before it gets to the intestines. And so as a result, our exposure levels are minimal. And this is BID dosing so every patient is their own individual control, if you will, with regard to that. Notwithstanding that, we're still seeing very nice trends on bilirubin, et cetera. So what we are doing is we're taking a handful of patients, retreating and a couple of new patients as well. And we're looking at them fully fasted on both doses to really confirm what we've seen thus far.

Once we have that data, we'll release it. And hopefully, knock wood, everything plays out. We're just walking the down. It's a first-in-kind approach. I tell people all the time, it is not off the shelf. People talk about time lines, et cetera. You can't really do that with a translational program of this nature. I think the question we should be asking is, why isn't everyone going after appeal in this space? And they are not. It is not for the faint of heart, but complement is what we've been doing over the last 10 years, and our research goes back 25 years. So we know complement pretty well.

Right. So are the patients that were originally on it staying on? I don't know if I just missed it.

It's 4-week study. So there is some of those we will bring back retreat with this new fasted for both doses paradigm for 4 weeks.

All right. I know you just said time lines, the time lines.

No, listen, we're taking learnings along the way, which we're excited by, and we anticipate updating on this by the end of the year.

Okay. I guess what indications would you go after?

We like other neuromuscular indications, of course, but we like more than that. I think with an oral gives us an opportunity with the dosing flexibility and other aspects of it to go into a range of diseases that some of the programs from an IV perspective aren't in yet.

All right. when you think about like the need to inhibit complement for different diseases, it's to a certain degree, right? So for MG, you can get away with 90% inhibition and so forth?

Our approach is full inhibition. I mean, if you can get away with less, we will be able to do that with the pill because you can titrate the dosing. But we're starting off with full inhibition because typically, complement-mediated diseases, you want to knock all the way down. We are seeing some more recent data that suggests maybe that's not required. And we saw some data released last week with regard to that, which...

I was going to ask what's your take on that.

It's a little tricky.

Or is it actually...

It's hard to know whether they have 75%, 78%.

74%, I think it was.

74%, yes. So it's a little hard to know. I mean that aspect of it is not complement though, right, from an inhibition perspective. And I mean, the question I'm still asking is, how much better do you need to see from an efficacy perspective with a second, third, fourth, fifth subcu program in this space to win from a commercial perspective. I think we're not having the right discussion.

I think that these drugs are going to have similar efficacy. I mean, that's the hope anyway. It's been validated with the prior targets. But how are you going to win on the commercial side as the third or fourth subcu? I don't know the answer to that, but that's going to be the fight. I've seen how that's played out in RA or MS, and you need an oral if you want to win it is what I've seen.

Oral and I think like what you're inhibiting, no black box.

And no black box. Safety is very important. Absolutely agree.

All right. We got 1 minute left. Just 007 timeline.

I got to talk about that in 1 minute. So this is the Phase III program in geographic atrophy, world's leader, it's a blockbuster. We love it. We're super excited on the data on the functional side as well as on the structural side. The Phase III enrolled 2 months ahead of schedule, more than 30 patients over enrolled globally, physicians are on board. We well-run studies tend to do better. So we're super excited by that. We'll have data in second half of next year and hopefully get this out to the 8 million patients around the globe impacted by this disease.

Got it. Are you thinking about keeping it in-house or...

We're keeping this thing as long as we can keep it. Look, and there's a paradigm. I mean, there's precedent for that, right? We saw with the other approved GA programs, which has really helped make the market. So coming in now will be a bit of a more efficient approach to commercializing with a very differentiated profile.

Okay. And if we're sitting here a year from now, what do you want to say that you'll accomplish?

Well, listen, GBS needs to be approved. Let's get that out to the patients around the world. I mean, these patients are really suffering from that disease. GA, let's turn over the cards and crush that thing, right? Like again, we're preserving vision in an elderly vulnerable population. Don't get me going on that, but it's really important that we protect this population and the world is aging, right?

And then we want to get this small molecule going in a range of different diseases. We think we can help a lot of people in a way where they can take this from their home in a very comfortable, safe way where they don't have to deal with needle phobia. They don't have to go get an IV, et cetera, and get them back and helping them live their best lives as well.

All right. Well, thank you very much for attending our conference and the fireside chat, and look forward to all the updates.

Thanks, Peter. Thanks for having me.

All right, everyone. We'll get to the next fireside here. My name is Derek Archila, I'm one of the Senior Biotech Analyst. I'm very excited to have Annexon. From the company, we got Doug Love, President and CEO. Doug, good to see you.

Good to see you as well, Derek. Thanks for having us. I'm happy to be here.

Yes. I know you just hopped in here because some bad, bad directions, really by the bankers, probably. But well, a lot of exciting things going on in Annexon. Maybe it'd be great to kind of get the overview and then we can kind of dig into the Q&A.

Yes, absolutely. Great time to be at Annexon. For those of you who don't know us, Annexon Biosciences, focused on classical complement, and we love it. We're having a great deal of fun and it's really a great time to be at the company. So what we're doing at Annexon is we're targeting the most proximal target for immune inflammation in a host of different diseases across the body, brain and eye. The reason I start there is all of our programs are first in kind in which we're pioneering. And after 10 years of the journey, we're really excited about where we are today.

Firstly, starting with Guillain-Barré syndrome, the first and only program in the last 50 years in this space, we really demonstrated landmark unprecedented data and getting patients better in this debilitating disease. By week 1, 90% of patients get better. So we're really excited about that.

Following that is our geographic atrophy program. It's a beast, if you will. It is the only vision-sparing program in the world. It's received prime designation among other things. We've just recently completed a large Phase III program, 650 patients enrolled ahead of schedule, and we're excited to bring that study or data forward. Now last but not least, the first and only small molecule approach in the classical complement space, targeting a host of neuromuscular and other antibody-mediated diseases, really has the potential to disrupt the market that's already well made with antibodies by bringing forward a more convenient pill form.

So Derek, I'm sure we're going to dive in and I'm looking forward to that.

Yes. Awesome. Well, maybe we'll start off with tanruprubart and GBS. So on the quarter, you provided some kind of updates around kind of meeting with the FDA, actually also with the EMA, right? So some of the regulatory bodies. And maybe just kind of give us a sense of how those discussions went. And I know there's kind of this addendum component to the minutes. So maybe any additional color there in terms of when we could get an update, a clarity on when you can file in the U.S.

Yes, absolutely. So tanruprubart for Guillain-Barré syndrome, as we said before, first and only program in 50 years. And what's unique about this program, this is a program we had to conduct outside of the U.S. and Europe because we were required to run a placebo-controlled study. The standard of care here, IVIg, is an unapproved drug that has never been studied in adequate and well-controlled study. So it was thought to be scientifically unviable as a comparator. And so we took all the kind of herculean task of running this placebo-controlled program in Southeast Asia, and we've run multiple studies now. So we have a placebo-controlled proof-of-concept study as well as the placebo-controlled Phase III study. We've done a drug-drug interaction study with IVIg and a real-world evidence study comparing our drug versus IVIg in a mass patient population. So it's a really robust package, particularly in the context of a rare orphan disease, rare and acute orphan disease.

With regard to regulatory on the EU EMA front, we've had significant progress there. We're really pleased by that. Maybe I'll just start as a backdrop that EU and EMA, in particular, understand and have been involved in this program differentially from other jurisdictions around the world. In Europe, we were able to secure orphan drug designation based on the proof-of-concept study. That's quite a high bar and different than what you see here in the States. Their IVIg is approved.

And so what we had to demonstrate to get orphan drug designation in Europe is 3 things. First, we had to demonstrate that the proof-of-concept study was adequately and well-controlled and sufficient for which a regulatory body can make a decision on that data set. Secondly, they had to review our first real-world evidence analysis that we did based on the, say, proof-of-concept study and determined that, that was effectively done that we were able to match patients from Southeast Asia to patients in the U.S. and Europe and that the outcomes were consistent. And then thirdly, they had to determine that the comparison of our drug, tanruprubart versus IVIg was likely to be substantially better with our drug. EMA made all of those determinations in our favor and in fact, wrote a 20-page single space document.

So it's with that backdrop by which they are reviewing now our Phase III program as it's come through. We did multiple country-specific meetings with regard to our Phase III program, both with the Phase III data as well as our Phase III real-world evidence package. One of the countries that we met with was the Netherlands, a really quite productive meeting with a written response from that meeting as well. And that person who led that meeting is now subsequently been named the rapporteur for the program in Europe. And so we're really pleased that we are interacting with a really engaged regulatory body who has a deep understanding of GBS generally as well as our program more specifically. And so we look forward to moving that forward along and we anticipate filing for MAA approval by Q1 of 2026.

In the U.S., similarly, we've had significant engagements with the regulators over the last 10 years. I think we've had an order of magnitude of 10 or 11 meetings over that period of time with U.S. with really strong alignment on what's required for an approval here, which is, of course, both substantial elements demonstrated in the Phase III program and a demonstration of generalizability, that is, again, the data or the patients in our Phase III study are comparable to the U.S. and in Europe.

We had a very productive meeting with the FDA on that where they were highly engaged and informed and really partners with Annexon in those discussions at the end of June. We got a meeting minutes back a month or so thereafter. And meeting minutes read reasonably well. However, there is an additional addendum attached to the meeting minutes that relate to post meeting comments that were made by the FDA in discussions that were had on our program without us at present. So the sponsors were not there. And there were some things raised in those meeting minutes as it relates to generalizability that we want to get a better handle on and make sure we understand before we communicate specifically where we are with regard to the FDA going forward.

Some of the things I will note is that what was not raised was anything with regard to our Phase III program or the real-world evidence analysis that we did ourselves. And so exactly what they're looking for. If anything, we will get elucidated. Our timeline for doing that is in and around this fall in a Type C meeting and then we'll update the market thereafter.

Okay. So now, you see, you do have a Type C meeting on the books. Is that it?

We have submitted, but we have not -- but we anticipate we will get one because in the post meeting minutes, they did ask for us to have a meeting with them. So we anticipate that, that should go well.

Got you. Okay. I guess so, I mean if we get perhaps some clarity in the fall. I mean I guess, how would you communicate that? Would that just be kind of a press release or would you...

That's a really good question. Yes, depending upon the nature of the meeting, the minutes and the alignment there, it could be anything from a management call to a press release or something or another.

Got you. I mean I guess you kind of told us what it isn't about. But I guess in terms of like you kind of are running this current like PK trial in the U.S. Some folks have kind of seen this is like, are they kind of like hedging against something? But I mean, is that part of this in this respect? Or is that mostly separate and more for like kind of informative marketing purposes, as you guys have kind of stated in the past?

Really good question. So when we initiated the study, really important to know, we have not been requested to run the study, and we did that without kind of discussing or aligning with the FDA on. We did submit the protocol, of course. We did all the normal kind of box and the bells and whistles and checked all the boxes with regard to that.

The study really was set up to meet 2 principal requirements. One, for EMA to meet the pediatric requirement there, you need to have an ongoing study in which you were able to enroll study patients who are pediatric. So the studies that we run in our Phase III to patients, I believe, were 16 and above. In this study, I believe they are 5 and above. So it really checks the box for pediatric for Europe. So it was important from that perspective. Two, and as important, candidly, particularly in the U.S. is that there are no consistent processes, protocols or approaches for how to treat GBS in the U.S., really, really important, and we've learned a lot about this just in the context of running this U.S. study, we call it the FORWARD study.

So every hospital and every system handles GBS differently. And that's because there's been no approved drugs. There's been no sales reps, MSLs, managed care folks to go in and work with physicians and hospitals on how they are triaging and managing patients GBS patients. GBS patients show up everywhere. They can show up in urgent care, they can show up at the emergency room, they can show up in a larger tertiary center. How do you enroll them through the system varies hospital to hospital.

So being able to gain experience on how the patient journey actually happens in real life, really, really important for us. And working with these key centers on how to streamline that and do that in the most efficient, effective way. So that's the purpose for the FORWARD study, and it continues to be the purpose for the FORWARD study. The FDA has not required us to do that as of yet. Whether they do so or not is to be determined.

Got you. And do you -- that trial, how has it been enrolling? And I guess, give us a status update, like when -- is that something that you'll produce data like a medical meeting, like what?

Yes. Really good question. Yes. So we've got sites up and running here in the U.S. We will soon have sites up and going in Europe as well. And what we will do is, it's an open-label study that's currently constructed is we will compile cohorts of data where we feel like we can answer questions. Some of the key questions for me in the study is, one, just really demonstrating that the PK/PD that we see in our Phase III study is replicated here in the U.S. We think that's a very low bar. This is an antibody, tanruprubart that's been dosed in the U.S. in multiple other diseases and in any event, antibodies translate very well region to region. There's a high 90-plus percent translatability effect.

The other, which I think is really important from a commercialization perspective is to demonstrate really rapid benefit on GBS patients treated with tanruprubart in the U.S., similar to what we saw in our Bangladesh and Philippines study. The reason why I say that is 90% of patients treated with our drug in our Phase III study got better by week 1. That is a strikingly significant number. We know that with IVIg, patients are still declining at week 1.

And why week 1 is so important is health care professionals are making decisions about what patients are going to go to, ICU, beyond ventilation, stay on ventilation or be it, perhaps, be transferred to skilled nursing facility, et cetera. So real-life treatment decisions are made at that point in time. Secondly, week 1 is the most prognostic factor for outcomes for GBS patients when you look out to 6 months. So how you do early in this disease in terms of protecting peripheral nerve damage is everything to how you fully recover.

So being able to replicate that here in the United States and being able to educate on that in concert with really developing robust, consistent protocols and systems for managing GBS here is really important. When you think about stroke, for example, everyone knows how to handle stroke now. It's an acute disease, it's debilitating. All hospitals handle it very similarly. We need to get that in place for GBS so we can make sure we can bring our best to these patients here.

I mean are you surprised by like how the different regulatory bodies have looked at this? I mean, obviously, it's surprising to me, I guess, like that the EU, they have IVIg. I would think they'd be like, oh, you know what, like -- but I'm not saying that, that's what the FDA is doing. But are you a little surprised on how this all kind of played out a little bit?

It's a fair question. Yes. I mean we certainly thought it would be smoother sailing on one hand. On the other hand, from day 1, we knew that this was a case of first impression for everyone, not just regulators, but certainly for investors and everyone else we've been interacting with for 10 years because GBS is a disease that's never been studied. No one had done any research on it. In fact, there are no institutions in the U.S. currently studying GBS, whereas in Europe, there are several institutions studying GBS. So there's just a different knowledge base. And so we've always kind of thought about that a little bit. So that's one.

Two, we just always knew that. We've not and nor has anyone ran a ton of studies in Southeast Asia. So there's a bit of the unknown there that you just know you have to navigate through. But that's who we are. Like our core value is built in and around warrior spirit. We knew we were pioneering when we ran that proof-of-concept study, and we learned that patients were getting out of bed by day 2 or 3 for disease that otherwise robs people of their lives. We're just fully committed to bringing it forward. Like it's something that serves our mission. And then we think it happens to be that it's a really significant commercial opportunity, which I'm sure we'll touch on as well.

Yes, I was going to say, like, I guess, as we think about the opportunities here, EU seem like it's come up first. I mean I know you've talked about monetizing potentially the ex U.S. rights to GBS or potentially even the whole program. So where do you kind of stand on that? And obviously, with the caveat that you need to clarify some stuff with the U.S. regulatory agency, again, where are you kind of landing on what you want to do with this program?

Absolutely the right question. Yes. So we're fully intentional about not commercializing ex U.S. And in fact, maybe I said that in a negative way. The more productive or positive way to say that is we're fully intentional about putting this in the hands for people who already have a hospital-based neuro business and the wherewithal and understanding on how to do this in multiple countries across Europe and beyond that. And we're really excited about that. We've been involved in multiple ongoing discussions. There are quite a few players around who have a real track record at hospital-based businesses in Europe, which is a different commercialization animal than what we deal with here in the U.S. and would take Annexon's eye off the ball a little bit if we decided we were going to go out and try and commercialize this in Europe on our own. So we are looking to monetize that. And we feel like we've got really good traction on that. We look forward to what's ahead with regard to that.

The U.S. is a different piece. So in the U.S., it's a highly concentrated market, 175 hospitals control 60% of GBS patients year-over-year because it's an incidence-based disease. In fact, 26 hospitals account for 20% of the patients year-over-year. So with a very concentrated commercial footprint, you can go in and get after this. And what's really key is that you do some level of education and really making sure you iron out the processes and the patient flow with hospitals here in the U.S. is one aspect of that. And we're underway with regard to that predominantly in the media type activities where we're sending information out electronically to folks who've opted in for that, and it's thousands of physicians already. We're really pleased with the way that's jumped off.

Secondly is just making sure the drug is available, and that's a formulary thing. And what's really most important about this. We get a lot of questions on commercialization in the U.S. in the context of a hospital-based business. It's not how we think about it. We think about this much more akin to a CAR T type business where the predominant payer for GBS is currently commercial payers. About 2/3 of GBS patients have commercial insurance. And so that's what allows you to really be able to get the pricing and reimbursement that you would like, and it makes sense for the payers. We bring a value proposition. We're getting you out of the hospital sooner, out of ICU, out of the ventilator, best skilled nursing facility. Commercial payers pay for all of that as well as lost time and wages from work, whereas the hospital is only really just kind of paying for the drug cost and in and around kind of the hospital-related costs.

And so being able to work predominantly with the payers really makes us attract commercial payers and attract commercial footprint. So we're really active on that as well. So as we sit here today, we're thinking we're going to commercialize this in the U.S. We've got a good team up and running, doing a very nice job with regard to that. We'll see how that plays out.

I guess how do you think about the overall market opportunity both in the U.S. and EU. I guess, if we're trying to like shoehorn like what type of deal economics you could get in the EU, what does that opportunity look like as well?

Yes. No, that's a great question. So 15,000 patients a year in the EU year-over-year, very, very consistent, mid- to high 90% of those patients currently get treated with IVIg. So again, working with a partner, it's making sure that the drug is available and usable for patients there at all of these hospitals. The drug has a 4-year shelf life, but you can put the drug on the shelf, and physicians or hospitals can pull it off when they use it, they could do that through buy or bill or they can do it on consignment or we can do drop shipment through some of the large areas like McKesson or Cardinal Health.

And so with that opportunity plus with the value-based proposition, we will be releasing our health economics analysis later this year, dynamite. More patients than what people think, and the cost of the health care system is more than what people think. The last time this was done was 20 years ago and a little bit -- and it was academic work. We are doing this in a commercial way where we're going deep and we're really excited to show that there is a real commercial opportunity.

And I guess the last thing I would say is that as we're having discussions with potential partners on the EU side, they're valuing it similarly to where we are. Still some negotiations to be done there, but we feel like that's going to be an accretive deal for us.

Is that something that's like very near term? Or like how are you...

I don't want to put a timeline on it because we think it can be tricky. But we're working on it. It certainly has our attention.

Got you. So it's definitely front and center. Got it. Anything else on GBS that we didn't touch on before we...

I think we've covered it. Look, we're excited about the program. We think from our perspective, from a regulatory perspective in the U.S. and Europe, but U.S. more specifically, it's a question of when and not if. So the data is robust. We've got the most robust package you can hope to have for a rare disease, as I said before, 2 placebo-controlled studies, drug-drug interaction study, real-world evidence and now we have some additional data coming in from the U.S. on that. So we -- and the drug is super safe. I mean when you look at our safety profile, it looks very much similar to placebo. So a benefit risk analysis checks all the boxes on that. I want to make sure, of course, that our partners, the FDA, are comfortable with the generalizability analysis and get this patient -- this drug out to patients to help them benefit as soon as possible.

Got it. Maybe we can shift to GA. Couple of years ago, it's like, okay, yes, we've got the data coming along in like '26. So like here we are. We're on the cusp now probably within a year, hopefully. So maybe just refresh us on the excitement around this program. Obviously, the Phase II, some folks think mixed, but you also were the only drug ever to show an improvement on BCVA. So that's highly relevant and important. So how should we kind of start teeing up how we should think about the Phase III?

Absolutely. Listen, we love the GA program. The thing I would say about GA, maybe just taking a step back, GA is the thesis of Annexon. Annexon was founded on the neurodegenerative mechanism of action of C1q and targeting upstream classical complement in the eye. By the way, Dr. Ben Barres, Annals of Medicine, Chair of Neurobiology at Stanford, that is who we are, what the company.

So it is our flagship program in the neurodegenerative space. And for anyone who thinks the Phase II data are mixed, they should dive a little deeper back into the data and GA itself. I recognize that people have said that because they're focused on lesion growth. I'm here to tell you that lesion growth is irrelevant to visual outcomes. Not me saying that, it's the data. You have 2 approved drugs out there 2, 3, 4 years' worth of data, no association with vision. You're not going to see it preclinically or anywhere else. You have regulatory bodies like Europe who've looked at it and said, no scientific relevance for vision. And in our Phase III study, the FDA does not require us to study lesion growth as a measurement in the study.

So it's important that people understand our data in that context, what have we shown. In our Phase II proof-of-concept ARCHER study, 270 patients, sham-controlled, we showed 2 really important pieces of data. On vision using BCVA 15-letter loss, which represents 50% of your vision loss in a 1-year period of time, you have to turn in your driver's license. You lose your independence. You cannot see. We show statistically significant preservation against the loss of vision at 12 months and over time, which is really important on what is the gold standard endpoint for visual acuity. It's used for wet AMD, diabetic retinopathy, retinitis pigmentosa, et cetera. This is the gold standard for vision.

We also showed it on its sister indication, which is low-light visual acuity, which is assessing visual acuity in low-light conditions. Really, do we have perfect light, statistically significant, statistically significant whether we looked in foveal patients, nonfoveal patients. When we look at patients earlier in the disease process, 0 out of 56 patients lost vision versus 17% with sham.

Why is that really important? If you're looking at a neuroprotective neurodegenerative disease, you should always do better in an earlier treatment patient population. The more damage you have to your neurons or death to your neurons, the worse off you are in neurodegeneration. So by treating earlier, you should have a better effect. We see that in a pronounced way. It's been recognized by the regulatory bodies on both sides of the pond, if you will. And so we're really excited about the comprehensive nature of what we see on the functional side.

Turning to the structural side, the key assessment for structure as it relates to vision in geographic atrophy and frankly, all neurodegenerative eye disease is damage to your neurons in the eye. In geographic atrophy, those are photoreceptors. We are the only company to show significant preservation of photoreceptors in the central retina of the eye. Our focus on the central retina versus the pan-macula where some companies have produced data showing the impact on photoreceptors in the pan-macula. It's only the central retina where vision is housed and you have an impact on visual acuity. Our protection there is in the neighborhood of 50% to 60%. Imagine that. We are preserving the function of neurons in the neighborhood of 50%, 60%, versus the drugs that have been approved for RPE lesion preservation at, what, 14%, 17% on something that doesn't relate to vision.

So when I hear people say the Phase II data are mixed, we're saying, go back and study geographic atrophy. See where the field has progressed over the last 18 months because everyone's focused now on easy and photoreceptor preservation. So it's those 2 data sets combined that when we went out with our Phase III study, which is very closely designed to replicate what in the Phase II did, 659 patients enrolled. We enrolled that study, the fastest enrolling Phase III study we're aware of in geographic atrophy. We enrolled it 2 months ahead of schedule, and more than 30 patients over enrolled. And so the physician population who understand the disease in a very sharp way have really grabbed on to this program, and we're excited about it. It's been really fantastic in the U.S. and Europe. Of course, we're watching it very, very closely.

And the last thing, I guess, I'll say, and I said it before is that we ran the study to really closely mirror or replicate what we did in the ARCHER study. We made very few changes. One change that we did make, I'll just call out quickly is we did enrich the patient population based on your baseline vision or BCVA levels. What we observed in our study, and then looking at lampalizumab, which is the world's largest Phase III program run by Roche as well as the SYFOVRE and other data set is that patients who are too far gone in the neurodegenerative disease process, you really can't save their vision or preserve their vision. It's just they've lost too much. And you can think about this in Alzheimer's or other neurodegenerative diseases, patients who've progressed too far, you can't help. So we've really honed in the sweet spot on patients who will lose vision over the course of the study but in a manner in which we can stop that and show a delta. So it's really, really important for us to be able to do that. And so that's how we've constructed Phase III study.

What's that entail in terms of the enrollment criteria? What specifically?

Just really a cutoff on your BCVA , baseline level, which we have not shared publicly. We think it's proprietary. We're one of the only companies who could do this type of work because we were able to demonstrate vision in our proof-of-concept study. If you don't have a database to be able to do that, that's difficult to do. So we were able to do that. So we've kind of held that a little closer to the best.

I don't know how much this is really going to matter. But I mean, obviously, we get questions like, oh, how do they show a slowing of -- or basically a benefit on BCVA preservation, but they still showed -- they didn't show any like signal on lesions, right? Although you already just said like the regulators aren't even -- it doesn't matter in trial. But I guess like can you explain, can you talk about that?

Yes, yes, yes. I can absolutely say. So the way lesion growth or RPEs, which is when you lose your RPE cells, RPE cells provide trophic support underneath your photoreceptor. Photoreceptors are where light comes in and that's where you have vision. When you lose RPEs, the thought was, the hypothesis was, if you lose your RPE cells, you're going to have damage or loss to your photoreceptors, and that's going to impact your vision. What the key step that was left out of it is that you actually lose photoreceptors before you lose RPE cells.

So RPE loss is a lagging indicator. It doesn't -- once you've lost RPE cells, you've already lost your photoreceptor synapses and your photoreceptors. So it doesn't matter really what -- I shouldn't say it doesn't matter. I mean, of course, you want to keep all of the structure in your eyes, so I don't want to kind of demean that. But it doesn't translate to vision. And so that's the answer is that, so that's one.

Two, by protecting photoreceptor integrity, you will protect RPE integrity over time. And so when you look at our data, if you break it up into 6 months intervals. In the first 6 months, very limited impact on RPEs and slowing of lesion growth. In the second 6 months, we double that. So we double the rate of RPE preservation and slowing the lesion growth, which what that tells you, go out to 18 months, perhaps 24 months, you're going to probably be stat sig and showing preservation of RPE.

And by the way, that's not too dissimilar to what we saw in the Phase III SYFOVRE study. You remember the DERBY study. At 12 months, they weren't stat sig at 12 months in RPE preservation. They had to go out to 18 months to get there, right? So it takes a little bit longer. We're coming top down preserving photoreceptors and then RPE. The downstream complement approaches are going bottoms up. They're preserving RPEs. But unfortunately, by the time you do that, you've already lost your photoreceptors. So that's the distinction between the 2 approaches.

Understood. I guess -- and going back to kind of your comments about the agencies, I mean it sounds like, again, at least with prime designation in Europe, which is you're alone in that. No one else has gotten that. But I guess, how is the FDA looking at basically your endpoint versus the others? And obviously, this would probably result in a different -- differentiated label, right? So like, I guess, put that all together for us.

Yes. So the label would be in U.S. and Europe would be the preservation of vision for the treatment of dry AMD that causes GA, and FDA has been fantastic. Optha division, really strongly intact, really super collaborative. We just had a face-to-face meeting with them recently, really completely signed off on the Phase III program, the design of the program, the analysis in the program. And BCVA 15-letter loss is the gold standard for the FDA. So as we come in with another vision endpoint, we would have had an issue. There was no discussion at all. It's just we agree with your endpoint. So it's all completely reconciled on both -- in both jurisdictions, which we really like. And so replicating this data gives us an opportunity for the first global approval for GA for the preservation of vision, which we think is just a complete game changer for these 8 million patients affected around the world.

Got you. And so you've highlighted data in the second half of '26. Any like early -- like what do you think, I guess?

Still too early for us to say.

And you give updated guidance like the beginning?

We may. And I'll tell you why. What we're looking at is the events of BCVA 15--letter loss in a blinded fashion. So we're not obviously unblinding the study, but you want to have a certain level -- number of BCVA vision events -- it's not a loss, of vision events over the course of the study. For us, it needs to be on 2 consecutive visits, we don't know all that. But once we hit that threshold number, we'll have a good sense of where we are with regard to things from a timing perspective. So it's still too early for us to say that. That's something that's naturally monitored as part of your Safety Monitoring Board, which, by the way, is going really well for us at this stage, knock on wood.

Yes. Got it, okay. Maybe last up, 1502, oral C1s. So you guys have been developing this for quite a bit. It's gone -- it seems like an iterative process. Maybe just kind of walk us through where you are today with that program? I know you've highlighted data by the end of the year. What should we be expecting?

Yes, a really good question. So I'll just say at the outset. I know folks have probably been a little frustrated in this program. This is not a program for the faint-of-heart. As I said at the outset, we are only focused on first-in-kind innovation, game-changing programs. GBS is game-changing, GA is game changing. 1502 is going to be game changing. So this is an early-stage translational program. And I think it's important for people to understand that. We didn't really go out and tout this disease. People picked it up in various forms and started asking us about it, so we've been responsive to it. But we're learning how to bring forward the first-ever small molecule in the classical complement space.

And it's important that people think that through because you would think when you look at industries or diseases like MS or RA, et cetera, they start antibody and they move to small molecule in the market. We thought that 8, 9 years ago when we started the small molecule approach, and it's a little bit curious because you would think some of those who have a big, large antibody, multibillion dollar franchises, they went from IV to subcu. They didn't go to small molecule. So we have an opportunity to really jump in a really strong position in this with data.

So what have we learned? We've learned something every step of the way. We started with crystallography preclinical approach, did CH50 and everything there to really elucidate what are the target drug levels we need to show that our small molecule are comparable to the antibodies that are already in the clinic or have been approved targeting C1s. So we had a really good barometer on how to do that. And we had our own C1s antibody. So we were able to compare all of these head-to-head.

That said, our target levels for the clinic, we started with the liquid suspension. We were able to achieve those target levels with the liquid suspension then quickly move to a film coated tablet, worked very, very well from a PK perspective, also saw some nice hints on PD, which was unusual. And patients who had any elevation in complement, we were able to knock it down. But I'm sorry, these are not patients, these are healthy volunteers. So they have generally low levels of complement or normal complement, but if they had any elevation of complement, we knocked it right down. So it gave us some hints of PD. We were really encouraged by the film coated. We did see some tolerability in that, saw some nausea, a little bit of emesis in that program.

And so our thought was we needed to get the drug past the gut and to release into the intestine so that we could see its effect without having nausea. So we developed enteric coated. Now each one of these steps, we're learning, it's first in kind. Every time we learn something new, people say, you guys are delaying the program. We're like, we're doing drug development. We're not cutting corners, sorry. Like we can't be a slave to a timeline on something that's never been done before, right? I just think people should understand that. We're not going to listen to that. So in any event, we did the enteric coated, it worked beautifully. We did it first in healthy volunteers, matched what we saw in the film coated from a PK perspective, tolerability immediately improved. So really like, hip, hip, hooray, we're rolling.

We're now in a Phase II proof-of-concept study in patients, first ever with elevated complement and they're taking food. And what have we seen is a few things. One is very pleased with the PK. In fact, the target exposures in these patients who are in a fast, that is without food, are well exceeding what we were hoping to see. So we're really excited by that. This is BID twice a day dosing. However, in that same patient, if they eat food, the food -- the drug gets washed out in the gut. So the gut needs an acidic environment for the enteric coated to go through if they eat food, the acid goes with food and washes out the drug, so you have no tolerability. And each patient pretty much serves as their control with BID dosing, we see consistently in all of the patients without food, exposure levels well above target, with food, not.

So what are we now doing. And it took us a few patients to understand what was going on because notwithstanding that, we were still seeing very nice trends on bilirubin reduction. So we were still seeing an effect. We thought it could be bigger. And so we really dove into this and we saw the different exposures depending upon whether you ate or didn't ate -- eat. And so what we're doing in this next set of patients, just a handful of patients to confirm what we've seen is they'll be fasted at both doses. And the fasting that we're talking about is you need to be without food an hour or so before you, an hour or so after you eat. So it's not an all day fast or anything. So in the morning, what we're saying to people is take your medicine when you come -- when you wake up, eat your breakfast an hour later. In the evening, have your meal, take your pill before you go to bed an hour or so after you eat or later, right? And so it's that type of kind of fasting scenario they're on.

Once we have that data, we feel like we'll have an answer, yes, no and go from there. I will tell you, it's a high bar for us to move this forward in Annexon. We've got a lot of programs, and we're seeing a real consistency in this mechanism. And so to move it forward, it's got to pay for itself, it's got to meet that bar that both doses are clean. It meets our tolerability levels, obviously, and it meets our drug exposure levels to really demonstrate that the potency is equivalent, if not better, to the antibodies, and we'll move that forward from there. That's where we are. It's been a journey. We're having some whistling with it. I mean, if you're not whistling while you work, what are you doing.

Got you. I mean how like intently are you watching, like, again, the Dianthus data and some of these other C1s molecule? And ultimately, like where would you want to even take 1502, presuming that the data look?

Yes. We're watching it really closely. And we think we're pulling for those guys. We pull for everyone candidly. I think that it should work. Look, I would expect that C1s should work in MG for these guys and their other diseases. I think the question for Dianthus and some of these others is not the science or clinical, it's the commercial. How do you differentiate commercially against the big boys who are well entrenched with billion-dollar franchises, they're not going to roll over very easily, versus if you think about MG, for example. Patients come in with MG, they all get cholinesterase inhibitors. These are orals. They're trained on orals. It's once they break through, they then move to these IVs or subcus.

We want to bring you right back to an oral. We think it's a real differentiator. Because it's an oral molecule, we can titrate dosing. We can do different things. We think the penetration in the tissue will be greater, et cetera. There's a potential for it to even have better efficacy. But at a minimum, we know it's going to be meaningfully different from a convenience perspective.

And these are diseases that have severe neuromuscular impact. I mean, these patients are not in great shape and have to kind of schedule their life around going to get an IV or doing this needle phobia circumstance and overcoming that. It's not trivial, particularly given that these patients were trained on orals. So we really like the opportunity for this drug, but we've got to prove it out. And so we're just going to walk it down. And hopefully, knock on wood, we'll be able to present data by the end of the year and move on from there.

Good. Well, Doug, we'll leave it there. Thank you so much.

Thank you. I really appreciate it.

My name is Andrew Tsai, senior biotech analyst at Jefferies. Thanks for coming to our day 1 of the June Healthcare Conference. And it's my pleasure to have to my right, Doug Love, CEO of Annexon. Welcome, Doug.

Thank you.

And maybe to start, give us an introduction about Annexon briefly. I do have a lot of questions for you. But what are you trying to achieve? And just walk us briefly through your milestones over the next 6 to 12 months.

Yes, absolutely. Well, firstly, thanks, Andrew, and thanks, Jefferies. We're happy to be here. Again, I always enjoy this conference. It's an exciting time for Annexon. For those who are not familiar with us, we're focused on complement and specifically classical complement C1q, which is the initiator of the classical pathway. And why that is relevant is that is the key target in the complement system that binds disease tissue, activates this inflammatory process and drives disease in a host of different neurodegenerative diseases in the brain and in the eye as well as autoimmune conditions in the body.

After 10 years of advancing the company, we're at an exciting stage where we have a late-stage program in Guillain-Barré syndrome on the basis of a pivotal Phase III study, and we will be shortly speaking to regulators about our BLA filing upcoming later this year. We also have a very large program, a Phase III program in geographic atrophy. It's a 630-patient study. Just for background, this is the only program that has shown preservation of the loss of vision on multiple endpoints in geographic atrophy. And so we're excited with regard to this Phase III program and the potential to treat 8 million patients worldwide.

And then finally, our small molecule program, first and only in the classical pathway. Really excited about this program as it continues to matriculate through a proof-of-concept study. Our aim there is to complete this program this summer and then provide data and advance this into a host of different neuromuscular diseases.

Great. I would like to talk and start off with GBS and then the oral program, given there are some catalysts this year. And then if we have time, we'll talk about the GA program. But going back to GBS, taking just a big picture view, remind us the drugs that are approved, if there are any in the U.S. and the EU, and frame the market opportunity in both regions.

Yes. Really good question. So GBS is a devastating neuromuscular disease. It's an acute disease. It's the #1 cause of acute neuromuscular paralysis. It impacts 150,000 people every year worldwide, 7,000 in the U.S., 22,000 in Europe. And unfortunately, there are no approved therapies in the U.S. for this disease. Standard of care is IVIg, which is nonspecific for the disease, but has some effect. However, there's never been a randomized controlled study there. So substantial evidence has never been demonstrated in this disease. And so our program is the first advancement from an innovation perspective in 40 years in this disease, which we're really encouraged by.

The marketplace is really quite robust with the market opportunity. 90% of the patients -- 90-plus percent of patients get treated for Guillain-Barré syndrome because of its really devastating nature. And as a result, you have a ready-made market to attack with a really effective therapy. And so we're well underway in preparing our commercialization activities with regard to that. And we look forward to bringing this drug to market and helping patients.

Excellent. And so what -- going back to the Phase III, what would you say are the key efficacy measures that lead you to believe this is better than off-label IVIg in the U.S.? What are the most important endpoints to the FDA in your view?

Yes. Really good question again. This was a landmark win from a Phase III study perspective in that we won on all of the key measurements with regard to Guillain-Barré syndrome. First and foremost, we won on the primary endpoint, the Guillain-Barré disability scale, where we showed patients had roughly a 2.5x better likelihood to get back to a state of normal -- or better health at week 8 and then normal health by month 6. So winning on that was, first and foremost, critical, and it was highly statistically significant and certainly clinically relevant.

But beyond that, we won on measures that are really important to the marketplace. So what we showed is that by taking ANX005 in a single infusion or tanruprubart, its now marketed name -- by taking that with a single infusion, we were able to get patients back in healthy -- or back to a better state of muscular strength by week 1. So we had a very rapid effect on muscle improvement. That translated to a better outcome on multiple measures.

From a marketplace perspective, when you talk to patients and physicians, our ability to get patients out of the ICU, off of the ventilator 30 days earlier, getting them back to walking without assistance 30 days earlier, really, really important. All of those measurements were against a placebo-controlled population, so the gold standard, if you will, from a study perspective.

However, we also studied the effect of tanruprubart against IVIg in a real-world evidence study. And there, too, we showed a 2.5 greater likelihood of getting patients back to a state of health versus IVIg at week 4 and at week 8 and similarly out to week 26 or 6 months. We also showed improvements in getting patients off of ventilators and out of the hospital and ICU and walking roughly 10 to 14 days sooner than IVIg. So again, on every measure that you look at with regard to this disease, we had a better outcome versus placebo as well as standard of care.

And if I remember correctly, in the Phase I dataset, the EMA even gave you an orphan drug designation. What did they -- how -- why did they give you that orphan drug designation? What specific measure? And how does the Phase III overall compare to the Phase I results?

Yes, really important. So one of the things we love about this program is the consistency of the data that we're seeing from study to study. So as Andrew alluded to, in our Phase I proof-of-concept study, there, we showed patients got better more quickly at week 8 versus placebo, this was a placebo-controlled study as well, as well as improvement on all of the other measures that I alluded to in the Phase III.

On the basis of the proof-of-concept data, we were able to get orphan drug designation with EMA, which is a high bar candidly and certainly higher than what we see in the U.S. There, you have to demonstrate a likelihood of being significantly better than standard of care. So that's where we did our first real-world evidence assessment based on the proof-of-concept data where we compared tanruprubart versus IVIg standard of care. EMA did a detailed assessment, wrote a 10-page single-space response to our application granting orphan drug designation. That, of course, allows us to have great deal more interactions with EMA as we go through the approval process with them, which is going really quite well there.

Okay. And some investors, unfortunately, just a little bit stuck about how this is just a somewhat unusual pathway, pursuing the Phase III in Southeastern Asia. Can you just give us a yes or no whether you did get buy-in from the FDA as well as other agencies to do a placebo-controlled study, that's number one, also in the Southeastern Asian region?

Yes is the short answer.

Okay. And then you also had FDA agreement that you can do an IGOS, like a third-party comparison analysis to support an approval.

That's correct as well.

And then also on top of that, the Phase III did have 2 doses. The low dose did look a little bit stronger than the high dose, but you got blessing that either dose can succeed.

Yes, that's correct as well, prespecified. But maybe if I could just talk a little bit about the 2 doses. So people refer to them as high/low. We actually refer to them as short and long duration. Both doses fully suppress complement. It's a question of how long you suppress complement. GBS is a rapid neuromuscular disease, as I alluded to previously, and you really want to only suppress complement through the disease phase and then allow it to come back and be part of the repair process.

In the proof-of-concept study, we had multiple doses there. And what we observed is that the lower dose or the shorter-duration dose actually outperformed the longer-duration dose. So as a result, we took both doses into the Phase III, prespecified both, and we took alpha on both doses so that you could win on either one in the Phase III study. The Phase III study replicated exactly what we saw in the proof-of-concept study. That is the shorter duration dose outperformed. So it's a window in which you want to be able to block complement activity, as I said, and allow it to come back. We've now defined that window very nicely in 2 respective studies, and we had approval to be able to do that with regulators.

And to ask this just out of full respect, but I just want to pry just a little bit because the Phase III study was produced in June of last year. We're nearly 1 year from that Phase III result. So the natural investor question would be, is there something wrong with the filing? What would be your response?

Yes. I mean it's the right question, right? So typically, you get Phase III data and you're filing within 6 months. We understand that fully. In this instance, we also had the additional requirement of demonstrating that we could match the patients from our study with patients in the Western world to demonstrate comparability or generalizability. So as Andrew alluded to, we ran our studies in Southeast Asia because that's the only jurisdiction where you could run a placebo-controlled study. IVIg, because they had never run randomized blinded studies, is not -- it was thought not to be an appropriate comparator to ANX005 to establish our efficacy.

So we had to do a placebo-controlled study. We had to go to jurisdictions where they did not have IVIg. That being said, given that the study was run exclusively ex U.S., we also have the additional requirement of demonstrating that the patients in that study and the work that we did there is translatable to the U.S. So upon completing the Phase III study, we're working with IGOS, international Guillain-Barré outcomes study. It's a 2,000-patient prospective registry housed out of Erasmus. Erasmus is actually responsible for doing the analysis on generalizability, that is the patients in our study are comparable to the patients in the West.

And to do that, they looked at the patients in the Phase III study, compared them with match patients from the IGOS dataset. Again, they own all of this data. This was done in-house there, completely independent of Annexon, although we have, of course, advised or counseled on their analysis. And that took them a while to do. So they completed that. We got the first pass of the data at the end of December or in December. They just produced the final analysis of that data at the Peripheral Nerve Society about 2 weeks ago. So now we have the full package for which we can go in and submit for BLA.

Got it. And then to be clear, after the original Phase III dataset, have you had the chance to talk to the FDA in the second half? And what was it about? And then you're having this pre-BLA meeting. What are you talking about that's different?

Yes. Good question again. So yes, the first meeting we had with the FDA was our -- kind of the standard end of Phase III meeting with the FDA, something you want to do on how do you perceive the data from our study, how do you consider the study, the conduct of the study, et cetera. We had that in December of 2024. Good meeting with the FDA. A lot of feedback in and around that. We had just got in the RWE dataset. It was the initial dataset. We submitted that, but not in time, for a full discussion or any discussion with them on the RWE dataset.

And so this upcoming meeting that we will be having with them this quarter, shortly actually, will be really principally on 2 topics: one, on this topic of generalizability and the use of all of the information that we've gathered to show that the patients in our study are comparable to the patients in the West and the data are translatable; and then two, just kind of the specifics around the BLA filing, kind of what they want to see in the package, how we list -- do the tables, listings and all of those things. So those are the 2 key topics upcoming with the regulators.

That's very clear. And could a filing occur in the second half?

Yes, certainly.

Okay. Certainly, okay. Good.

Yes, absolutely. I mean, obviously, the meeting is important, so I don't want to get ahead of FDA on that. But that's certainly our plan.

Okay. And then does it make sense -- just because to me, the data does look quite compelling, especially after you've compared it to IGOS, does it make sense to file for breakthrough designation?

Yes. Great question again. Yes, I mean, look, we want to have the first discussion with them just so that we stay on the right path for a BLA. Breakthrough therapy designation is obviously always a nice feather in one's cap. For purposes of where we are now with Fast Track designation, et cetera, it doesn't really help us from a regulatory engagement perspective. But that being said, the market likes breakthrough, and so we recognize that as well. So we'll make that determination after we meet with them in this upcoming meeting.

Great. And then earlier in our conversation, it seems as if you really like the rapid improvement that you saw in the Phase III results at week 1 benefit. Some investors then will ask, because this was a 26-week study, correct me if I'm wrong, is that "enough" to justify a higher price ultimately? Does it make sense to follow out for longer to convince payers to pay for this drug? Because maybe...

Yes. Really good question. Yes. So firstly, no company or no study in the history of the world has studied GBS patients out to 26 weeks. So this is the longest-duration study that's ever been done in GBS and with full alignment with the FDA. And just important to note a couple of things. One, the primary endpoint is week 8. So the 26-week is the follow-up period, so out to 6 months, which we did. And we think that's more than sufficient for both an approval and for pricing and marketing perspectives.

The thing to bear in mind with regard to GBS is the cost associated with this disease is not in drug costs. I mean the treatment of the cost is what it is. Really, it's the fact that these patients are in the ICU. They're on a ventilator. And after that, they're in skilled nursing facilities, and they have long-term physical therapy. I mean at 1 year, 20% of patients still do not have the ability to walk unassisted. 1 in 4 patients are going on a ventilator right out the gate.

So those are the costs. And so we are in the course of doing really robust health economics work on that. We will have that later this summer. We've started the engagement from a market access perspective with formulary committees and others in and around that just based on the information that we already have. We know that these patients cost hundreds of thousands of dollars to the health care system, up to millions of dollars depending upon how long they're ventilated, et cetera. And so that's really the key to really driving market opportunity here and premium pricing. Getting them off of the health care system sooner is the key to being able to price this drug.

Makes sense. And are you ready to give us a price range for this drug? I mean you did allude to the alternative being hundreds of thousands just now. But...

Yes, right. And that's absolutely right. So without treatment or even with IVIg, we know it's hundreds of thousands to millions of dollars to treat these patients. We are not ready to announce pricing. What I will say is that the analysts have somewhere between $75,000 to $150,000 for course of therapy. That's not unreasonable and certainly reasonable in today's world of rare disease -- drug diseases. And so we'll just kind of guide people to that at this stage.

Got it. And then -- I'm flip-flopping a little bit, but just going back to the FDA, could they -- even though they gave you buy-in around this whole program and how to go about it years ago, could there be a risk they flip-flop with the new changes going on? I mean what's your sense, especially after talking to them in the second half of last year?

Yes. Well -- so 2 things. One, I wouldn't call it flip-flop because we love the regulators. I mean these folks are doing yeoman's work, I think it is worth calling out. This is a program that they have never seen before. They have not done a full review of a GBS package other than IVIg almost 50 years ago, which is not -- again, not a randomized study. So they really are learning the disease and our data and what is necessary to succeed or to effectively treat patients, and they're doing a really nice job, and they've been great.

Our interactions with them were in December, prior to many of the changes that have gone on with the FDA. So those will be new learnings. That being said, we're pleased that many of the folks who are involved with the program when we first got kind of the green light to go forward into our Phase III are still involved in various ways, not maybe day-to-day, but at higher levels, office head, et cetera, et cetera.

And so -- but to your question, could there be a surprise in the meeting? Obviously, we prepare for all scenarios. And if there is one, I think we're prepared for it. I think -- just to be candid about it, if they ask for anything other than what has been previously asked for, it would be just some experience with Western world patients with our drug. So just, ensure us that when you treat patients in the West, if you look at the PK/PD, for example, tanruprubart in Southeast Asia, does it look like in the West? So that's a scenario that we have. We don't think that's the scenario, but we're prepared for that, and we can talk about how we kind of belt and suspendered for that approach.

Sure. And then -- we'll get to that in a bit. And then are there precedents where a drug was studied ex U.S. and ultimately got approval in the U.S.?

Yes, several. So if you look in the literature or you look at what's the precedent that's occurred with the FDA over the last 10 years or so, you'll see multiple examples of this in multiple therapeutic areas, whether it's oncology, infectious diseases as well as in the neurology division. One of the examples we like to point to is the Radicava example, which is for ALS. This was a program that was conducted in Japan in roughly 80 to 90 patients. Single study where they won on the primary endpoint, but minimal supportive evidence, but no patients in the West.

And they used that -- the neuro division was able to find that, that patient population was translatable to the West. That's not always the case, but you have to do that deep analysis. They did that. We think we've got a very robust package in the way we've done that as well. But yes, there have been multiple examples.

Great. Great. And then -- so you're meeting with them again in Q2. Presumably, you get the meeting minutes back. And then do you come back to The Street about anything? Or what's the news flow like?

Yes. Really good question. Yes, I think we'll update The Street in some form or fashion on the go forward. I mean, again, we'll be looking to file our BLA and move forward on that. So yes, we will update in some form or fashion.

Okay. And is it safe to assume that there would be an AdCom during the review process?

Hard to know. I mean when you look at the prior programs where they were -- used ex U.S. data for approval here, half of them have had AdComs, half of them have not. So there's no clear precedent with regard to that. Candidly, from our perspective, given that there's not been a lot of experience with the drug, at least in GBS. We've used tanruprubart in other diseases like ALS, HD, et cetera, here in the U.S. to dose Western world patients. But given that there's not been a lot of experience in GBS, an AdCom may not be the worst thing for the program. It may be an opportunity to provide additional education in advance of launching on GBS and the effects of our drug on GBS.

One of the things we talk not enough about is the safety profile of this drug in GBS. I mean the safety is -- it was really, really quite compelling from my perspective. These patients looked similar to placebo in the treatment arms across safety. Tolerability was a little different but not unmanageable at all. And so it's a really effective and reasonably safe program with a single infusion. So we'll be making all of that clear. An AdCom would help kind of illuminate that even further.

Got it. And as this is going on, you've decided to start the FORWARD study on 30 patients we just alluded to, enrolling Western patients. What are you trying to achieve here? And was this informed by FDA discussions? Or was it more of you just hedging a little -- I don't know, just being prudent about things.

Yes, super proactive. Yes, it really serves 2 things for us, which -- look, we're super excited by the FORWARD study. I mean I cannot deny that at all. And it's been something that we've planned for, for quite a while now. So for those who are following us closely and you're looking at our runway, et cetera, and where we're allocating dollars, you can see our runway never changed or anything like that once we announced the study. So this study has been planned for quite a while.

What we know is that when we talk to physicians about GBS and tanruprubart and we take them through the data, they're all super compelled by this data, particularly again, this earlier treatment effect by week 1, patients are getting better. Such a critical junction because that's when you're making decisions about longer-term ICU use. Are you keeping them on ventilation, et cetera? So week 1, we're seeing patients get better across every study that we've done in this disease. So really, really important. But the pushback that we hear from time to time in our market research with physicians is, but have you treated any patients in the U.S. in Guillain-Barré syndrome?

And so that is a reasonable question that we get. It would make folks feel a lot more comfortable to get some experience with the drug and understand its treatment in the U.S. population. And so starting this FORWARD study now with key centers around the country is allowing for that. It's an open-label study. We'll be able to provide data kind of real time to the physician population, patients and the marketplace as well. So we love that from that perspective because, again, that is the #1 question we get on this program for physicians in the U.S. is just experience in the U.S. with the drug.

And then the second piece is just what you were alluding to, Andrew, which is that to the extent there is a question with the FDA on just, we'd like some patients dosed here in the U.S., it answers that as well. So it's a belt-and-suspenders approach. So it's kind of 2 birds, 1 stone. We purposely designed it where the primary endpoint is PK/PD and then week 1 efficacy and then, of course, safety, et cetera. So it's designed in a very limited fashion to kind of do -- meet the objectives that we have for the study.

I see. So presumably, the data could be pretty fast.

Well, we expect it on a rolling basis. And so if the FDA wanted to see something while we're reviewing the BLA, we would be able to do that. Obviously, GBS is episodic, but we did start at the centers where we know they see x amount of GBS patients on an annual basis. And so that's how you try to do this in a way where you can do it efficiently and effectively.

Right, right. And then going to the EU then, how are EU -- EMA discussions? And when could you file?

Yes. Love the discussions with EMA. I would say on some level, they're a bit more advanced than what -- where they are with the FDA. I mean starting the discussion on the orphan drug designation in Europe is a really good question, and we don't get that enough. We probably should talk about that more. But that's allowed us to have more interactions with EMA earlier. We've started with country-specific meetings. They've gone really, really well. We have an upcoming meeting with EMA before too long as well, I guess I will just say that.

And so we're very much on pace to be filing in Europe. By the end of the year or first part of next year is kind of where we are targeting for that. Upcoming meetings will clearly define that, but that's our kind of base position today.

Okay. That's very helpful. Maybe let's shift gears to the small molecule program because there is a data readout -- is it mid-2025?

Yes, correct.

Okay. I guess big picture for people listening, why is this a game changer in your view?

Yes. Well, listen, the role of complement has been validated clinically in a host of neuromuscular diseases. So you see that with C5, C1s types of approaches. These are done with monoclonal antibodies that are dosed everywhere from every other week to once a month. You're now seeing the advent of subcutaneous approaches that are coming forward. And whether or not they're better than the infused monoclonal antibodies or not, TBD.

Coming forward with a small molecule in these conditions is really, really important. So for example, if you look at myasthenia gravis, all patients or most all patients start off with [ cholinest ] inhibitors. These are orals. These patient populations are already trained to take orals. It's only after that when they move forward into kind of infused therapies, et cetera, et cetera. And so bringing them back to an oral feels like a really straightforward marketing approach from our perspective.

And just the convenience of it -- again, these neuromuscular diseases, they all have their respective titles, MG, CIDP, et cetera. But to actually know the patients and what they're going through is really, really significant. There's a significant amount of pain, fatigue, lack of mobility associated with these diseases. For a person to go to the grocery store, they really have to schedule their week to do that because for 2 or 3 days after, they're wiped out. They can't do anything.

So having to go in and get infusions in a chair, et cetera, or finding someone to administer it subcu in your stomach multiple times over the course of a week or every other week, whatever, is not trivial. So the ability to give them an oral and help them get their lives back more fully, we think, can be very disruptive in this space. And we're encouraged by that. We continue to mention the neuromuscular diseases, but because it's an oral, we think it gives us an opportunity to pursue other diseases outside of that space that you can probably more attractively run clinical studies in as well.

Great. And so now you're in a Phase II program. And originally, it was supposed to read out year-end of last year. You pushed it back a little bit. What exactly happened? And can we feel confident it will not be pushed back again?

Yes. Two things occurred there. One, our initial read was done with a film-coated version of the drug. What we saw in our healthy volunteer studies, which -- healthy volunteer studies went really well. We got the exposure levels that we wanted to get there, safe, generally well tolerated. But we did see some tolerability topics with regard to nausea in the [indiscernible] in the gut. And what we saw with the film coated was it was releasing in the gut and causing that issue.

So late in the year, we were working in the background on an enteric-coated tablet, which we have now completed. And what that allows the drug to do is to bypass the gut and then release the drug. And what we saw in the healthy volunteer study, we ran an additional healthy volunteer study with the enteric coated, we saw a significant reduction in that tolerability topic. Still achieved the same kind of exposure levels that we wanted, et cetera. So we're really pleased by that. So we thought, again, made great sense to push back the program.

I didn't say this, but I think you guys all know this. This is an early-stage translational program for the first oral ever. It's really not a program we probably should even be talking about publicly. I can tell you, if this were in the hands of J&J, you wouldn't even know about it, right? But we're a small biotech. We know we've got to keep things interesting. So we're doing that, but we're taking you on the journey of how you actually develop drugs that have never been developed before. I think it's important for people to put this into context. This is not an infused monoclonal antibody.

So that being said -- so we pushed back because of the enteric coated. And what we've also done is we've added to the size of the study. The study was initially only going to be 3 patients. We determined that's probably too small in today's market, that people would want to see a more robust dataset. It also gives us an opportunity to better characterize kind of just the dosing properties with more patients. So we're saying roughly 7 patients or so, and we're on track for that.

The key topic for this, just so people understand, is we're doing this in cold agglutinin disease. And in cold agglutinin disease, you want to treat patients who are in hemolysis. The variability on that is really quite large. All of these patients are being taken off whatever standard treatment they are on. We wash them out. They then go into hemolysis and then we treat them. That path to hemolysis is quite variable between patients. It could be a month to 6 months.

So you have your patients identified, lined up, enrolled, but you're waiting for them to get to a state of hemolysis before you treat them. That's just biology. Again, early translational stage program that -- hanging on every topic, but it's important that people understand all of these kind of nuances in development.

Makes sense. And then maybe in the last minute then, in the data readout, what is the go-no-go threshold for you? What biomarkers are you looking for to make you...

Beyond safety and tolerability, given you got to achieve that, very, very important, obviously. But after that, really want to show impact on 2 things: one, complement. So we want to be able to show that we can reduce or bring complement down to its normal state. Complement really spikes in these diseases, as you guys are probably aware. And then the second is bilirubin, really objective measurement of hemolysis. And so we know that now from multiple other studies that have been done in cold agglutinin disease, including a study we did with tanruprubart so that we could understand the disease on that. We will -- so those are the 2 primaries.

We will also look at hemolysis. But the thing I would tell you with hemolysis is it takes a while -- or hemoglobin -- sorry, hemoglobin levels. And hemoglobin levels really vary among patients and whether we will see that in a 4-week study or not, likely to see some levels of trends. But that's why we made it a secondary as opposed to a primary.

Okay. Very good. And we didn't even talk about the GA program. But...

I got to come back and talk about GA [indiscernible].

Next time. In second half of next year, we'll have data. So -- but thank you so much for giving us an update. It was very helpful today. And thanks, everyone, for listening.

Thank you all. Appreciate it.