Good morning, everyone. Thank you for joining us on day two 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. And to start here, perhaps a snapshot of how to think about the second half of 26 and beyond. You know, this is a potentially transformational year for the company with pivotal data and 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 three study success.
Yeah, happy to do so. And thanks, Kim, for having us. It's delightful to be out here in Miami with you all. So look, we're really excited about the phase three asset of on-approvement for the treatment of geographic atrophy. I would say it's differentiated from the first generation asset in three 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 vonoprument 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 fragment. It's 50 KD, no pegulation, 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 a quarter 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 the pressure, so really excited by that. And then finally, we're really excited about the data to demonstrate significant preservation of the photoreceptor retina neurons that are responsible for visual acuity. It had an even more pronounced impact in the central macula of the eye, which is principally responsible for ingiographic atrophy. And that translated to significant preservation of vision on all of the measurements in our Phase II study, and, importantly, best-corrected visual acuity. We differentiated outlook from the prior therapies, and we're excited.
Maybe to jump a little deeper here into the Phase II data, with regard to what we saw, the study did not meet the primary endpoint of GA lesion growth, but showed vision preservation for BCBA, as you mentioned, how do we reconcile the benefit on vision preservation with the lack of impact on anatomical markers?
Yeah, 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 cells or lesion growth. And the reason for that is you actually now lose, 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.
Yeah, so, you know, as Doug said, it is well we know from our work as well as other groups that photoreceptors are lost first in dry MD 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 is a C1Q inhibitor. C1Q is known to localize on photoreceptors that are lost in geographic accuracy. So by inhibiting the function of C1Q, we protect photoreceptors first, which then protects RP cells down the line. And from our data in the phase two, we did not show a statistically significant benefit in RP lesion growth, but we saw a 10.5% reduction in the final six months of our phase two program. we expect to see further protection of RPE in our Phase III program out to two 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 arms 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 the data that we've pulled forward is our definition with confirmed 15-letter loss at two visits. That number in our phase two 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's 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, you know, 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 directional benefit with Vaughan improvement in the fellow eye analysis, as well as a dose-dependent benefit, the 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 aisle.
Yeah, 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 see in our data, we put out all of the data related to vision preservation, 10-letter, 15-letter, 20-letter, fellow eyes, another sensitivity analysis, as Boyd said, 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...
Maybe looking forward to the Phase 3 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.
Yeah, maybe I'll start, Lloyd, and then get you in on the sham arm. So a favorable outcome is statistical significance on BCBA 15-letter loss. Again, it's the gold standard. It 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. And so any statistical significant demonstration on BCBA 15 letter and talking to the regulators as well as the physician communities deemed clinically relevant and sufficient for an approval with regards to kind of what we're doing?
Yeah, and in terms of the performance of the groups, I think it's 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 review.
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 regard 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 power 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 a neurodegenerative disease.
And given geographic atrophy is initially phobia sparing, how, I guess, how confident are you that this DCVA endpoint is achievable in the context of this disease, just given what we've seen with the other two drugs?
Yeah, 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 two.
We expect we'll do it in the phase three, but it's a delivery.
It boils down to patient selection. There's really three phases of disease in geographic atrophy. Early disease, there's several years of progression where patients lose no vision. And then towards the end of disease, once patients develop large subphobia 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 we know that our drug is beneficial to all patients with geographic atrophy and dry MD 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, is statistical significant benefit on GA lesion growth rate reduction at the 18-24 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 the phobia?
Good question. I'll start, and please dive in. So first, we think it's quite likely, well maybe even before, let me just back up on RP and lesion growth.
So it's just really a debunked hypothesis, and I just need to say it that plainly.
There is zero 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. What, as Lloyd alluded to, if you look in the second six months of our study, in the Archer study, what we showed is that we protected against lesion growth at a rate more than three times 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
You know, I guess, how much data is there or just literature to kind of support this neuroprotective dynamic that's playing out with C1Q?
Yeah, great question. Yeah, 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 states. 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 200 times 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 viable mechanism and central for protecting neurons as well as photoreceptors.
I'm glad you referenced the preclinical data. We invite folks to go in and look at the package. Different, again, from the RPE story, we actually demonstrated pre-clinically 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 pre-specify BCVA15 as a key secondary end.
What are your thoughts just long-term on immunosuppression or just overall safety in the context of targeting upstream in the 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, so I have 20 years of experience in development of these drugs as well as using them. And our drug has all the same characteristics of the important drugs in the exudated 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 vonopruman systemically in our patients in the phase two.
And on a regulatory standpoint, the Phase III trial has been designed to be evaluated as two independent sub-studies. Speak to your confidence in the powering of these individual sub-studies.
Yeah, first maybe just to clarify kind of regulatory status. So, status. A single pivotal study is all that's required for approval in Europe with EMA. With the U.S., we have a single protocol, two sub-studies as you alluded to, both are powered at high Phase III, greater than 90 percent at the sub-study level.
No, I mean, we're well aligned with FDA in terms of our two-sub-study 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 pre-specified plan where we'll split at the site level to identify two very, very similar patient populations, which should increase our PTSD.
Perhaps jumping over to the commercial opportunity here, maybe frame how you view the opportunity We have two 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 from lesion growth, which, to 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. 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 on 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 are 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 EZOCT, where you can assess damage to your photoreceptors earlier, even before you've lost significant vision, we really think we're going to open this market up, and it's a real opportunity.
Yeah, one other comment. You know, 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 specials 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 physician activation will be increased and that will be key to utilization. So the market's significantly underdeveloped.
One other just quick thing is sometimes we have 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 six months, not only on 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's having a disease-modifying effect, and that's why we built our study with this off-treatment period where we could follow the patient. and 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 markets penetrated and only 20% of the doctors are 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, you know, is it, I guess I'm just trying to understand.
Yeah, the headwinds. The headwinds, yeah. 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 brisk, 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, you know, to me, I think there's a fair amount of fatigue based 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, you know, 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.
What do you think about the competitive landscape here in terms of drugs in development? There's a systemic CERNA drug from Regeneron, among others.
Yeah, for me, and I'm confused by the follow-on approaches in development because you're still starting this RPE lesion growth story. 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 in the U.S. market because physicians and patients aren't 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 what you're saying.
No, I agree. And the other issue with 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 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 in.
Speak to the commercial strategy here in terms of whether you'll go at it alone or look to a partner.
Yeah, we like it. We're going to go at it alone. It's a super-efficient commercial. We're putting 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 them. We're 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 ourselves.
Switching over to your drug, Tan Rupert, for the development of Guillain-Barre 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.
Yeah, we're really excited about this asset. Really the first clinical demonstration of blocking upstream classical complement in a neuroprotective way in Guillain-Barre syndrome. In our Phase III study, what we saw is roughly 90% of patients benefited by week one, which translated to a two-and-a-half times greater likelihood of improvement by week eight, which was the primary endpoint, and a two-and-a-half times greater likelihood of being normal by month six, which are whopping effects in this disease that has not been studied in more than 40 years by anyone's first randomized study program. We're really encouraged by that. We ran this program ex-US because it was deemed unethical to run placebo-controlled studies here in the U.S., and we run controlled studies, natural history, whether it's a rare disease. So we ran these in Southeast Asia with alignment of the regulators, both in Europe and the U.S. on patients in our study with patients clearly have satisfied the first box and so we're really pleased by that. We also feel like we've 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, their outcomes versus placebo as we're in. 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. 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. They cross every T, if you will, dot every I to ensure themselves that the patients were comparable. So we initiated an open label study here 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. It really shows the impact of Tamron for Bart in the West, which is...
Just going back to the Phase III studies, they were conducted in Bangladesh and the Philippines to speak to the translatability of this data to the U.S. and European patients.
Yeah, the most important part is GBS is GBS. So GBS is an antibody-mediated disease. That's been widely studied. We have every KOL in the globe disease presented. Secondly, with regard to the patient populations, an antibody-mediated attack, and the question is whether you can stop soon enough to show protection to your peripheral nerves and recovery from therefrom. And so we've seen that now.
What is the regulatory risk? Until we go back to the regulators, we don't know.
And that's in three regards. One, the PKPD profile. So if they were different profiles, that would be an area. The 50 profile is really akin to reported. And I alluded to some of the efficacy outcomes that we're not really seeing anything that's different. Absolutely, yes. So it's a rare disease, and it's just really not our baby week to partner it. In the U.S., however, there are about 50 or so health care centers that see more than 50% of the patients. Your very targeted footprint is a field force. You need MS sales, and you're really excited. The other 95% of those patients, even though it's unapproved and its treatment effects are mid-LIN, when you look at the outcomes in our study. So we're excited to really...
You also have a pipeline behind these two programs, and how do we think about 1502 and when we could get proof of concept from that oral small molecule?
Yeah, we like it.
So this is the first line to target active.
It's a target that's been clinically validated by multiple antibody approaches and opportunity to capture a market where about 70% of the patients are currently on oral. So we really like this proof-of-concept study, really a translational stage to engage this activated complement.
We're getting drugs in Mycenae Gravis, for instance.
Well, importantly, as I said, the big differentiation is I think we reported 225, which gives us runway into all of the key GBS filings and the proof. So we are really comfortable from that perspective. That being said, we're engaged in a lot of our wholly owned. We're not commercializing GBS, for example, outside of the U.S. So we'll look to do something.
Maybe it's a last question here. Anything else that you want to highlight about the company's strategy and as you look to these, you know, big data reads that are all.
Yeah, listen, we're excited. We call this a win season for us. Like, we've been at it now for 11 and a half years out of 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 and downstream approaches. And folks talk about GA. At GBS, I mean, Alexion ran a phase two and a phase three. They're dramatically different. We're seeing it in GA. So for us, this is a period of execution. 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 complements, not the same. And we're looking to return people's lives by really, I mean, we appreciate.