Good morning, and welcome once again to TD Cowen's 44th Annual Healthcare Conference. I'm Phil Nadeau, one of Cowen's biotech analysts, and it's my pleasure, along with my colleague, Joe Thome, to moderate a corporate panel on ophthalmology. We have with us today, from Adverum, Linda Rubinstein, the CFO; from Annexon, Doug Love, the President and CEO; and from Apellis, David Acheson, the Senior VP of North American Commercial. With that, I'll hand it to Joe to maybe ask the first question.
Thanks, Phil. So I guess the first one is overall, with several agents already approved in certain spaces like Wet AMD, and obviously, a lot of development coming behind, safety is definitely one of the issues that's in the forefront. So, I guess, can you just talk broadly overall, the bar for safety, both from your perspective as a corporate company, but then also, what are the agencies looking for? Is the bar for safety higher in areas maybe where there is an approved standard of care? Maybe, Linda, you can start things off, and then we can go on.
Sure. In Wet AMD, and frankly, for all products, you need to have an acceptable safety profile, full stop.
There you go.
You know, our view is that for Wet AMD and for other therapies, you need to also take into account the benefit-risk profile. So, for gene therapy, where you're delivering an agent that can potentially provide lifelong benefit, you need to have good safety, but it needs to be well understood and manageable in the context we think of optimizing for efficacy because you have only one shot to deliver that gene therapy. So for us, you know, we've wanted to show. We've been very pleased with the data in our OPTIC study now for three years and our LUNA preliminary data that we put out last month, that it fits within that envelope of having manageable and acceptable efficacy.
When you look at the benefit-risk profile and look at trying to optimize for efficacy, our view is that if you have prophylactic steroids for six months, maybe longer, you might have some supplemental injections, you might have a little bit of inflammation, even, you know, AC cells, if they're treatable with local steroids. Those are acceptable to get the potential, you know, lifelong benefit of having an Aflibercept on board, getting potentially better vision over time and dramatically reducing the treatment burden.
You done?
Yeah, I agree with everything Linda said. So I think, you know, GA is very different to Wet AMD, in that we don't yet have gene therapy, so all of the agents in the GA space are short-acting agents, or you're dosing monthly or every other month, which gives you a different opportunity on how to manage safety, but it all starts with a benefit-risk analysis. And so what we've seen thus far is benefit is shown on biomarkers and a tolerable safety profile. We think that benefit on things like functional, right? So vision, which gives you a little bit more latitude. What we've seen historically in the GA space is a bit of conversion to Wet AMD, which may be not the worst thing in the world because you do have Wet AMD agents to deal with that.
We're seeing some other types of infection, types of risk that seem to be at a low, manageable rate. If that grows, obviously, that'll have to be in correlation with your functional outcomes, it seems to us. So, as we sit here today, we're really pleased with the safety profile that we've put together. I guess we'll talk more about that in time.
And then, I guess, just overall between the agencies, the FDA and maybe Europe or ex-U.S. agencies, is there a different bar or a willingness to, I guess, advance clinical investigation, tolerability, kind of those? And maybe, David, we can start with you, and then I know I want to go back to Linda because the gene therapy component, too.
Yeah. So look, look, we, we actually worked with the FDA, and this has been kind of a standard set where lesion growth reduction is the standard that will be looked at with GA products, specifically, right? Now, Europe, as you know, is going to be looking for potentially more functional data, which we all know is something to work on, and that's one of our goals is to help with that. But that's really the focus. So I wouldn't say the bar is higher or lower.
Right
... it's definitely different, right? It's moved in the direction they're going to ask for some data that we'll have to continue to produce over time.
Linda, maybe as it relates to the gene therapy component, specifically in the field of genetic medicines, we have seen maybe a little bit more separation between FDA and EMA. I guess, in your interactions, have you had any sort of differing opinions between Europe and the U.S. in terms of willingness to advance studies or conversation?
The short answer is no, but you know, there are no gene therapies that have advanced to phase III, right, in the space. But we were ready to advance to phase III on the strength of the OPTIC data back in 2021. So we did have significant regulatory interactions and cleared a lot of issues with them. And I think that the profile that we saw in OPTIC, we thought would have been enthusiastically accepted by regulators as well as patients and caregivers and even healthcare systems. So potentially doing better by exploring different doses and regimens, as we're doing in LUNA, can optimize it, but we think there's an appreciation of that benefit risk across both agencies.
David, maybe I'll direct a question on commercial to you. There seem to be two aspects that are unique to ophthalmology. One is, historically, physicians have been sort of cowboys, wanting to try new treatments, pretty readily. And then, two, private equity owns a lot of these practices. How do those dynamics factor into a product launch, and, and what is Apellis doing to, either capitalize on them or, or counter them?
Yeah
if they're heading into it?
Great question. So certainly in the U.S., private equity is a significant player in the ophthalmology space, probably more so in any space that I've been in, and very important to the launch of any product in retina. I will tell you from an Apellis perspective, we took that to heart. We got to know all the private equity groups incredibly well. We've got some great relationships there, and they've helped us launch the product incredibly well across the country. One of the things you'll know, if you don't know, is that the private equity groups are incredibly well organized, and they are able, in some cases, to even move faster on education among their own groups than we can actually get to all their offices in a launch.
So you kind of start at the top and let them help educate along the way, which is what we did with some of the biggest ones in the country. Hugely helpful in a launch, especially as fast-paced as we were launching when we came out with Syfovre. Nothing else in the space, first to market, and we needed some help to be able to do that. I think where the, the thing you got to keep in mind, though, is only about 30% of the market actually sits with private equity. There's 70% that sits out there that's not attached to PE. So that focus also is super important for us, in any launch in the space as well.
Perfect. And maybe just a little start of a bit of little debate between Apellis and Annexon. You're both in the complement space. You're both going after GA, but you have slightly different targets. Doug, you're going after C1q, and David, C3. So, I'm just kind of curious to debate the merits of that. Doug, maybe we'll start with you. Why C1q versus the other complement?
Yeah, look, we love it. Our whole thesis at Annexon is that if complement is playing a key role in the disease process, we're providing the most complete protection against it by stopping it right where it starts on diseased tissue. In the case of C1q, it localizes on photoreceptor cells and synapses and starts the whole disease cascade. Why is that important? Disease of neurodegeneration caused by the loss of photoreceptor cells and synapses. So C1q's role is unique in that, as I said, it localizes there, activates, excuse me, the cascade, and results in the loss of photoreceptor synapses and photoreceptor cells, which is where vision is housed. That disease process occurs prior to the loss of RPE cells, which is what the measurement is for loss of lesion growth or protection against lesion growth.
So we're an upstream approach, which we think is providing a more complete protection against this neurodegenerative disease process by really targeting the locus of the disease. The other thing I will say is it's a very selective approach. So we're only blocking C1q in the classical pathway. We are allowing the alternative and lectin pathway to remain intact to perform this immune function. We think that's important from safety over time, and we've seen that. So we saw, for example, no conversions to Wet AMD different than sham in our study because we are allowing this immune support. So we think there's a potential benefit or advantage on the efficacy side as well as on the safety side.
David, how does Apellis look at C3?
So good, great, great answer over here, first of all. But we actually believe. We actually, you know, we actually believe that, and if you, if you look at the complement cascade, right, C3 inhibition can actually block all three activation pathways. We think that's super important. It can actually give control at a much higher level than what you can see in other, some, potentially selective pathway inhibition. And C3 deposition in the retina is what we believe is actually causing that death of that retina, or the cells there. And if you can control that, we believe we can actually slow the lesion growth at a very fast rate. So that's our, our take on it, and that's where we've, we've spent a significant amount of our time with, with the product.
If you actually look at, you know, where we are, too, we're on the upper end of the cascade, above the C5s. We're in a position that we believe we can handle the disease very efficiently.
Joe.
Perfect. Linda, we'll go back to you. Several companies are investigating how AAV gene therapies, including Adverum, but then also some implantable TKIs that are working for longer duration. Is there an ideal patient for, for some of these longer injection periods, or could this be appropriate for every Wet AMD patient? And maybe when you think about the injection burden per year, obviously, one and done would be ideal, but is there a, a lower limit to that?
The short answer is we think that our gene therapy could be appropriate for all Wet AMD patients who respond to VEGF, anti-VEGF, which is nearly all patients. So it's hard to treat patients. It's patients who respond well to the standard of care. It's patients who have Wet AMD in one eye. It's patients who have Wet AMD in two eyes, as we explore, bilateral or contralateral dosing. So we think that'll be broadly applicable. We suspect that'll likely be the case for the TKIs, but we think that we have an advantage by having the potential to be injection-free for now out to three years, where over a majority of our patients in OPTIC haven't received any supplemental injections. And based on the aflibercept levels being sustained as far as we've measured them, this could potentially be a lifelong benefit.
So you asked what the floor is, right? I mean, we think that the OPTIC data that we have is unsurpassed, both in durability as well as in treatment reduction, and we think that that would be a great profile. So far, the LUNA data seems to map onto it, and we're excited about that. You know, we can discuss, you know, why treatment burden reduction is so important, right? If you talk to patients, and we have, nobody likes to have monthly injections, right? There's the inconvenience of going with their sometimes elderly caregiver, children, to get their injections, right? There's the time and energy, there's the pain, there's the dread. It's like getting chemo every month. You know, patients, you know, start to dread that in advance.
A lot of patients don't get the injections, and whether that's because of insurance or not being close to retinal therapists or the treatment burden, and then even the patients who do get the injections have reduction in vision. So we think that gene therapy can address those treatment burden issues, and also potentially improve functional vision outcomes over time. And so we think that's applicable to all patients.
Turning back to GA, one of the more controversial aspects of the launches of the first drug, Syfovre and Izervay, has been the lack of visual acuity benefit. So two-part question. I'll direct to both of you. One, how important is it to show visual acuity benefit in order for this market to develop to its full potential? And then two, I'd be curious whether you both think that the reduction in lesion growth we've seen from Syfovre, Izervay will translate into a visual acuity benefit ultimately, or Annexon your approach of preserving synapses is that more likely to result in a visual acuity benefit? But maybe we'll start with you.
Yeah, well, we've already demonstrated by blocking C1q, we can have visual preservation, right? So our study, the ARCHER study, 270-patient phase II study, was highly dose dependent, statistically significant, and dose dependent across all measures of vision. So that's in all types of patients, foveal and non-foveal, are included in the analysis of fellow eye treatment, as well as an off-treatment analysis. So by every measure, we've demonstrated impact on visual acuity. Important to note that we use the standard of BCVA 15-letter. That is the highest standard for assessing visual acuity. In fact, it's been used more than 10 x in terms of being approved for ophthalmic disease, showing visual acuity. And in our case, we had persistence with regard to that.
So we had to distribute visual protection on two consecutive visits, to meet the standard. So we've demonstrated it. We know that vision preservation is the most important factor for the marketplace, right? If you're an elderly patient and you go to the DMV, they're not asking what your lesion score is, for example. They want to know, can you see? And, you know, we want to get people back their lives, right? So giving folks back their independence so that they can interact with their grandkids, they can cook their own meals, they can drive their cars, is really, really important. And so that's, that's our primary focus.
The only thing I would add to that, and, and so I think one of the things that we've... as we've launched, right? So BCVA and other measurements aren't necessarily always something that's going to be specific to give them the right story with what you see in lesion reduction, right? So we go back to the lesion reduction data to currently, right, physicians are having to make that leap with their patients in that discussion around what will happen over time, which is hopefully that functional, that functional improvement. And that's where we spend our time focusing currently, because, you know, in other measurements, it's just not as specific, for us to be able to give direction on, you know, and physicians have, have, have dealt with that, a lot.
You can see that our performance has been very strong since last year.
It may be another two-part question on commercial. Tell us, last week this week announced a new prevalence estimate, the [data blur]. I guess it was last week. One million people in the U.S. is the new estimate for how many who have GA. So the question is, one, is this market large enough to support multiple players successfully? And then, two, what do you think will be the major determinants of share over time, safety, efficacy, convenience? How are all those going to factor in?
Yeah.
Maybe we'll start with you.
Yep. So when we launched, we used all the epidemiology work, and all the market research told us we had about one million patients in the U.S., right? If you look at the data now, we've done some additional market research. You also look at how fast the launch took off and where we saw a patient influx. We believe it's probably about 1.5 million patients in the U.S. So it's definitely bigger. To answer your first question, is the market big enough to handle multiple players in the space? Absolutely. And I actually don't know that we even know that the market's 1.5. It could be bigger than that, right? So we really don't know.
Frankly, one of the things that we've learned is that 50%+ of the patients that we believe actually have either a diagnosis or could be diagnosed with GA don't even sit in the retina offices. So we aren't even fully identified on the number of patients that sit out and have not been diagnosed yet. So we're in a full referral process work right now from OD offices and general ophthalmology to get those patients diagnosed. The market is definitely big enough, and I think the market's hungry for additional opportunities out there to treat patients. So over time, I think you're going to see it's probably even bigger than 1.5 million.
With your initial work, you're out there competing in the market now against, against one competitor. What do you think will determine share over the long run?
Yeah, look, first of all, and I think it's going to come down to efficacy. So you can have lots of conversation and obviously, discussions around all different parameters. Efficacy is going to drive it, followed by safety. And I think safety is going to be important across the board, right? That's the risk-benefit with the patients, and that discussion with the physicians. And our efficacy is outstanding. We've got up to 42% on non-subfoveal patients, and that is the biggest number you're going to see in the space based off of the efficacy today. So...
As you build the clinical database, around ANX007, how do you think you can differentiate it? What, what will be the determinants of share?
Yeah, first off, I agree with everything David said. So I think, Apellis has done a fantastic job in launching this drug and really making a market that was further, you know, prior to this, just less understood. And very, very much like other indications, as you get into and offer a therapy, you find more patients, and that's what they're doing. So I think they're doing a tremendous job with regard to that. And to David's point also, I think the impact on lesion growth is quite significant by Apellis. I think it was approved in the teens, and now it's 40%+. So you just can't argue with the numbers with regard to that. I think the hanging question is whether or not that translates to an impact on vision function in a reasonable period of time.
When you look at our clinical study, for example, the average age of the patients coming into our study was 80 years old. Coming out of the study, they're 82 years old. And so showing an impact on lesion growth over 2 years, 3 years period of time, and not necessarily having that correlate with any impact on function is a topic, and I think an opportunity over time for new interests in the marketplace should be demonstrating impact on vision. So that to me is where the differentiation opportunity is. Can we help give patients their lives back by protecting against the loss of vision, or maybe even over time, you know, increasing their vision? But that's probably out in outer years, but that's the differentiation from our, our perspective.
... Great. Maybe we'll start with some company-specific questions and kind of go in and give it a little round robin here. But, Linda, we'll start with you alphabetically. The phase II data for LUNA started coming out in February of this year. Maybe if you could just hit a few of the high points there, and, obviously, some of the other gene therapy programs also had data around that same time. So if helpful, maybe compare and contrast the competitive dynamic as well.
Sure. So at the highest level, our goals with the LUNA data were to recapitulate the OPTIC efficacy and safety data or potentially do better, and to do that with the lower dose that we tested in OPTIC 2E11 and a new lower 6E10 dose. The short answer is that we continue to have the best-in-class efficacy in terms of treatment burden reduction, both the percent injection free at six months and 14 months, where we... Sorry, six months and as well as injection free and treatment burden and injection reduction. We also have long durability, right? So the data that we see from LUNA maps onto the OPTIC data, where we expect that it will continue to trend. So we expect to see that long-term efficacy from OPTIC.
Then importantly, we also had a very strong benefit risk, where we had a cleaner safety profile than OPTIC. We identified a potential go-forward regimen for prophylaxis and are very pleased with how that de-risks our potential phase III. How does this compare to others? On the efficacy side, as I mentioned, we have the best treatment burden reduction that's out there when you look at in-office delivery of gene therapy, so excluding subretinal. Nobody's presented data past six months, right? We have out to three years for the LUNA. We've started to show how that continues, and we're best in class. So highest efficacy, strongest durability. In terms of inflammation, all gene therapies have dose-dependent inflammation. You've seen that with the REGENXBIO suprachoroidal. You've seen that with 40D MT.
Interestingly, it's not just that, you know, you have the dose-dependent inflammation. We've seen that in all programs, but now we're seeing based on where the drug is administered, that you see inflammation. So for example, REGENXBIO made a big point of saying that one of their suprachoroidal cohorts didn't have any intraocular inflammation, but they delivered their drug periocularly, and they saw episcleritis, so periocular inflammation. So not to diss them, it's just a fact that inflammation is seen with gene therapy, and it needs to be well understood, manageable, and acceptable. So we are very pleased with the LUNA results and look forward to presenting additional data with our interim analysis this mid-2024.
And maybe to drill down on the inflammation point, because you did mention if it's well understood and manageable, what does that profile look like? I guess, what sort of inflammation is problematic inflammation? What is inflammation that the treating physician might be comfortable with, I guess, in terms of severity and then timeline you would see it?
So we've been seeing physicians get increasingly comfortable, right? When gene therapy started, people said no inflammation was acceptable. Our investigators, who've now treated patients across multiple studies, are now understanding that, the kind of inflammation that we see, which is mild to moderate inflammation, it's at the front of the eye, so it's typically AC cells that are measured. It's responsive to local corticosteroids. It's finite. So what we've seen is that it's well understood, it's manageable, and it goes away. So the investigators are comfortable having some level of inflammation. What's acceptable? You know, we've got prophylaxis, where we've looked at an injectable, dexamethasone that, elutes over time. We've looked at that, with, drops, and that's a very strong profile. We've also looked at drops alone.
The drops that we've given are up to 22 weeks, including a taper. And frankly, having that kind of prophylaxis out to six months, potentially even longer, is something our investigators have said they would do hands down for this potential lifelong benefit. So as long as they see that mild to moderate inflammation, front of the eye, well controlled, it's okay. What they don't want to see is the back of the eye inflammation, the vasculitis, the choroiditis, all of those things that were associated with bad outcomes with Beovu and Abicipar pegol and other, other agents, and we haven't seen those with Ixo-vec and Wet AMD.
Maybe just one last one before we move on, but you mentioned a little bit the go-forward regimen for the-
Mm-hmm.
The steroid protocol does include the injection. Maybe can you... Why did you decide to go forward with this? And maybe talk a little bit about compliance in these patients with their steroid regimen. And then on the flip side, are you concerned about any potential AEs? Obviously, in the literature, there is some, you know, pressure changes with the injection if you want to address that.
Yeah, great questions. So, we've led the field in terms of looking at gene therapy for Wet AMD. So in our first trial in OPTIC, we, with the benefit of hindsight, grossly under prophylaxed patients. And so in LUNA, the idea was to try multiple prophylactic regimens to understand the benefit from more extended prophylaxis, to look at the injectable, to understand whether compliance is an issue, and we could get a benefit. And we even did this with and without oral to see if there was a benefit to looking at systemic steroids. So number one, just to put the data out there, we found that oral didn't provide incremental benefit, which is great. Nobody wants to provide oral steroids to elderly patients.
When we used Ozurdex initially, we were doing that both alone or with oral, we found that the PK didn't last long enough, and so we added drops into those, and we found that we had very great benefit with those, as well as nice benefit with just drops, better than OPTIC. We like both going forward, number one, because we had a very, very clean safety profile, with over 90% of patients having no clinically significant inflammation, either zero or 0.5 cells. But the other is it does remove the compliance issue. We've had patients who've lost their bottles of drops and didn't report, and then all of a sudden have inflammation, patients who've been hospitalized, and they can't continue on their drops. So not getting the prophylaxis that they need is a challenge.
So having Ozurdex on board removes that compliance for the initial period, and then adding drops, you know, is something that I think patients have tolerated well and been very accepting of.
Doug, we'll go next to you. You referenced some of the ARCHER data in your answers to the prior questions, but maybe to take a step back for those less familiar, can you discuss the design of ANX007 trial in a bit more detail and the data that you released last year?
Yeah, happy to do so. So it was a reasonably reasonable size phase II study, 270 patients, as I alluded to. Every month, every other month, treated with 5 mg with ANX007 intravitreal administration. And we were frankly quite pleased by the outcome. So this was the first demonstration in the clinic of our mechanism of action, which has led to the founding of the company. And what we saw in the clinic was really supported by what we saw pre-clinically in a light-induced damage models. What we showed there was protection. By blocking C1q, we were able to protect photoreceptor cells and photoreceptor function. So we demonstrated that pre-clinically. We then went into the clinic, and what we showed was using BCVA 15-letter as the primary endpoint.
And maybe just to point on that, because BCVA 15—BCVA as an endpoint, best-corrected visual acuity, which is the standard for visual acuity in all ophthalmic studies, can be variable at lower levels. So if you look at five-letter loss, for example, there's a meaningful level of variability among patients with regard to their vision. 10, it gets a bit better. 15-letter is the gold standard that represents three lines of letter loss over whatever period of time in which you're measuring that. So we use that standard. Excuse me. And again, as I said before, we assess this on two consecutive visits so that we can ensure that there was durability with regard to what we saw there.
What we saw was, at month 12, highly statistically significant, dose-dependent impact on preserving against the loss of 15-letter loss on BCVA 15. We also showed a reduction of risk of about 73%. By dosing with ANX007, reduce your risk of losing vision by 73% over the course of the study. We showed it both in the foveal population and in the non-foveal population. We showed in patients who had healthier eyes that had even more benefit, so really suggesting that treating early with this, this drug was hugely important. Then we looked at various other assessments, like fellow eye assessments. So patients who had bilateral GA in both eyes, we treated one eye, and the other eye, we did not treat. And there we also showed a 70%+ protection against loss of vision.
Once we stopped the drug, what we saw was the preservation of vision loss went away. So patients began to lose vision again once we stopped the drug. So every way we looked at it, we saw lines of evidence showing that we were having a meaningful impact on preserving against the loss of vision. The last thing I'll say is, we also showed this on other assessments that were pre-specified, like low light visual deficit. That's in effect, BCVA, under low light conditions, low light visual acuity. So we're really encouraged by the totality and the consistency of the data in this study. We're now moving forward with the top-up phase III.
I think probably the most common question we get from investors on the phase II data is on the mechanism of benefit. So skeptics wonder how you can preserve vision without preserving or without slowing lesion growth. I think you have a very compelling theory. Maybe you could describe that.
Yeah, really good point. So again, this is well-published literature. Losing photoreceptor cells occurs prior to losing RPEs. Assessing impact on lesion growth is an assessment on RPEs after you've lost photoreceptor cells and synapses. So our mechanism is, of course, targeting upstream photoreceptor cells and synapses, and over time, we believe that impacts the overall retina health, the whole photoreceptor unit. We should have an impact on RPE and slowing that growth. That's, in fact, what we saw in our study. So when you look at our data in the first 6 months of the study versus the second 6 months of the study, we had a meaningful impact on slowing lesion growth in the second six months of the study.
Additionally, what we are now seeing with regard to OCT and an assessment on EZ analysis is, we're also showing an impact on preservation on OCT and EZ analysis. When we saw the vision data, what we did as a company is we just went super deep over the last six months in assessing that in every way possible, because there had been no prior demonstrations on impact on vision. What we are now doing is doing a deep dive analysis on our impact on anatomical measures. And so we're releasing data on this at Macula Society. We'll have new data coming out at ARVO, but we are showing an impact not only on RPEs in the second six months, but also on OCT, which is an assessment of photoreceptor impact, which directly aligns with our mechanism of action.
So we're super encouraged that we're seeing it both on function and now on longer treatment, you're gonna see a greater impact on lesion growth. So for example, we saw that in the DERBY study, right? You needed 18 months to see a statistical impact on RPEs. We see at month 12, we're having a meaningful impact, suggest that with longer treatment, we're gonna get there as well. So more to come with regard to that. We think it's the totality of the mechanism.
On the alignment with the FDA and the phase III program, which you alluded to, could you describe the design of the phase III trials and the rationale behind both?
Yeah. So we've got a global phase III program, really with the aim of winning both in the U.S. as well as in Europe. There are no approved therapies at this time in Europe, and so we are running a sham-controlled study globally. It's just a replication of what we did in our phase II study. We just have powered it up. It's, it's, you know, 40% larger, and it's in, you know, both U.S. and Europe, and we're super excited about that, changing very little from what we did in our phase II study. In addition to that, the FDA has asked that we do an injection control study. So there, in our second study, we're calling that ARROW. We'll be doing a head-to-head comparison with Syfovre as an injection control.
The primary endpoint will be BCVA 15-letter loss, which we think is hugely important. You know, in our alignment with the regulators, neither body has required us to study loss of lesion growth, impact on lesions as an endpoint. I mean, it is an important biomarker, but it's a surrogate biomarker for vision. Both jurisdictions have requested that we are aligned with this on studying BCVA 15 as the primary endpoint. So those are the two studies that we'll run. We'll start the first in the middle of the year, the ARCHER II, and then we'll start the ARROW study towards the end of the year.
Perfect. David, we'll move to you and Apellis. There's an old saying about the year 2020, anyone who made a prediction about what was going to happen that year was wrong. I feel like you say the same thing about the Syfovre launch. Anyone who made a prediction of how that was going to go was not correct. Very, very tumultuous year. Can you give us an update on where the launch stands today, and in particular, how are the rate of new patient starts comparing Q1 versus Q4, Q3, Q2?
Sure. So if you've ever been on a roller coaster ride, Phil, you could have, you could have been on a seat next to me. So look, we've been super happy with the launch. It's exceeded expectations, even despite the issues that we had and with vasculitis and the things that we've learned. The good thing about that is we know it's a very rare occasion, and it's 0.01% of everything that we've done since then, as far as the vials that have been placed in the marketplace. So we're confident in that, and we continue to have, you know, success as a result of coming through that with the efficacy story that we've got.
We ended last year, when you heard our Q4 update, with about 160,000 vials have been shipped out, which is fantastic. We actually added another 40,000 to that, when we come through February, which is a very nice move. January and February are the two biggest months in vial sales that we've had since launch. The growth continues, and we continue to see patients uptake with the product have conversations with their physicians. We also continue to see double-digit new accounts come on board every week, and that's happened since we launched. That means that there's someone buying product in a location and putting product in a patient in that location that wasn't happening the week before, which is a really good success story for us.
So, we feel great about those numbers, and I think we're gonna have, you know, a really good continued launch as we go into the rest of this year.
And, we did a fireside chat yesterday with Cedric and Adam. And I think the number one question we got after the fireside-
Mm-hmm.
What did Apellis say about Q1? There was some confusion coming out of the Q1 call. Seasonality was referenced, but people seemed to miss the part that Apellis said January and February were the biggest months. So, can you reiterate what the trends are in Q1 versus Q4?
We miss a lot sometimes in these conversations, right?
We do.
So, let's just remember, January and February are the two biggest months since launch. That's what everyone needs to know. Seasonality in this space is always important, right? When you come into the new year, you've got Medicare plans that need to go back and reverify patients. You've got launch dynamics that happen in the front end of a year that takes a little bit of time for, you know, patients coming in. They got appointments that are getting rescheduled, that kind of stuff. And what I think Adam's point was is, we saw a really nice move for one of our best months in January. Could it have been better without seasonality potentially, right? And that's, that's what I think he was talking about. But hands down, it was the best two months in the launch.
So, the seasonality is natural, I think, in this space. Anyone who's getting an IVT or anyone who's on Medicare, Medicare plan is gonna have some things they have to work through in the front of the year. I will tell you, our team on our hub actually did a re-verification, incredibly successful for the first time through. That's when you're nervous in December about re-verification, but it comes through the way it did, I feel like we had a really successful start to the year.
Cedric, yesterday reiterated that Apellis looked on the last six months as building trust with the community, so that people understood the rates of vasculitis and the risk. The next six months will be about growing confidence, so that the uptake can resume to its fullest extent. So maybe, maybe two-part question. One, where does vasculitis stand today? How much trust is built among the physicians? And then two, where do you go from here? How do you drive increased uptake over the next six months?
Yeah, good question. So if you take a look back over the last six months, one of the things that we did, especially in the summertime, when we had the vasculitis cases that came through, commercially, we actually went to all the accounts and said, "Look, let's just make sure we do what's right for you and your patients. Let's get comfortable." Right? So there was accounts that we were talking to, and of course, doing what we can to service them, but it was not a full-on press to make sure that we got more patients on product. We really took a step back. I think that, along with being transparent, we communicated almost weekly, or at the most, that community on a regular basis. And you guys saw a lot of that when we did it.
And then we, of course, had the teams out also talking both medical and commercial around everything that we were learning. So I think that helped, right? So you kinda get through that, and then you start talking about, you know, what that means moving forward. I think where we are moving ahead now, it's all about the efficacy story. We've got three-year GALE data, completely impressive, with 42% lesion reduction, in, excuse me, reduction in lesion growth, which is on the high end, and no one else can say that number. And right now, it's all about making sure we continue to do education. We bring patients in, like I talked about earlier, from the referral process, so we can get them identified and diagnosed. And we help the offices with actual disease state education, which is continued, right?
We actually have that even through on the television. So, I think there's that, that'll still happen out there as well, and then, of course, continue to answer questions. I also believe that continuing to get more confidence is continuing to help solve additional questions around vasculitis, which we are still working on, right? So, we don't have all the answers yet, but we believe we can continue to help improve that discussion as well.
Maybe last follow-up with [Henry] before handing it back to Joe. In terms of the vasculitis, it sounds like most physicians are comfortable. Is that a fair assessment, that physicians have gained comfort with the 1 in 10,000 risk? Or, and where is the market in the process of accepting the risk, understanding it, and gaining comfort?
Yep. I think you can go back to the third conversation that you had with Adam yesterday, right? So when we had the vasculitis cases come up, we had a third of the physicians that said, "Look, I'm comfortable. I know how to manage this. I think my patients have done well so far in tolerance, and treatment, and safety, and efficacy." So they continued to move forward. We have a third that kind of stopped. They said, "I'm not going to take patients off the product. We'll continue to treat them. We're not going to start new patients." And then we were early enough at the launch build that, you know, there's a subset of physicians that hadn't done anything yet. I think what we're seeing now is a lot of confidence that we have answered the right question.
We're trying to give the offices, the physicians, and the patients tools to have the right conversation on risk-benefit, which is super important, and make sure they take the time to talk about that across, across the disease state, and then make sure that we allow them to make that decision moving forward. And look, I think in general, the 0.01% is pretty well accepted. If you would have gone back to ASRS and all the other meetings last year, the number one thing was talking about is that the right number? Now, what we're talking about is efficacy again.
We're getting into rooms and discussions where, certainly, vasculitis is a part of the comfort level in the discussion, but at the end of the day, we don't spend the majority of our time on it, and the physicians don't when we're in the offices either.
On the back to you, we are going to see some more phase II data mid-year this year, with all patients followed out to 24 weeks. So can you just let us know what should we be expecting in that data set versus what we saw in February? And maybe what is the company looking for from an efficacy and safety profile at that time point? Kind of set the stage a little bit for the interactions.
Sure. So the 26-week interim analysis data will come out mid-year, and we haven't guided to anything more than 26 weeks. We expect to show similar safety and efficacy endpoints that we looked at with the preliminary data, where we'll look at treatment burden reduction. We've talked about vision maintenance, fluid reduction, and fluid maintenance, and fluctuations in fluid levels, which are important for long-term efficacy, and also differentiating for Ixo-vec versus other agents, looking at, you know, safety as well. Importantly, at 26 weeks, more of the patients will be further along, so we can assess treatment burden reduction and all of these other endpoints. Also, more of the patients will be off prophylaxis, so having a more meaningful safety update. And what would we like to see?
You know, we think OPTIC set the bar, and we'd like to continue to show things in that range as we've done with the preliminary data so far.
After the 26-week data, is this when you would take the data then to regulators, or what do you want to see in the existing package? Obviously, you do have longer-term follow-up from the phase I study. Maybe how are regulators using that, maybe in your conversations as well?
Yeah. We haven't guided to anything formally about the interactions, but we have said when asked that we expect that the 26-week data will be adequate to interact with regulators for a formal end of phase II meeting. We have been and will continue to have both formal and informal interactions with regulators. As I mentioned, we were prepared to go into phase III three years ago. The fact that we now have much longer follow-up, right? We'll have four years of clinical data at some point this year from OPTIC. We think will all be just beneficial for what it is that regulators are looking for.
Then now, I guess, just if you could opine a little bit on what a phase III program might look like. Is this one or two studies? Maybe what is the right comparator set and endpoints? As you mentioned, you were ready before with the phase III designs, before the DME experience and now the new phase II. What are your thoughts on what a phase III could look like here?
There's been a lot of movement in the space with the FDA draft guidance that came out and some of the trial designs that the, you know, the TKI companies are considering. But net-net, you know, while we haven't guided formally, we like the non-inferiority design better. We think it's going to be very hard to enroll patients with the superiority design. And what does your label say if you're better than one dose of Eylea? I think that's challenging. So we like the non-inferiority design. We expect that with all gene therapy, you're going to need a year of follow-up. We expect the comparator is likely to be Eylea every eight weeks, which is what's been standard for the other trials.
Vision has been the endpoint for all of the trials to date, and, you know, for this kind of a product, it's going to be two trials for FDA.
Perfect. Maybe last question before we go to the line again, but can you talk a little bit maybe just about the reception of the kind of the patients that you've dosed so far, and maybe just the physician community in general about receiving and using a gene therapy approach to Wet AMD? Is this going to be a large push that the company needs to do, or are people pretty amenable to using a gene therapy approach?
I think for any new modality, there's going to need to be a push, but I think there is a great deal of receptivity. There's a lot of interest, you know, in providing something that could be a functional cure for over half of the patients, where they don't need any injections out to three, four , potentially, you know, potentially lifelong. We also see patients and physicians getting comfortable with the prophylactic profile, et cetera. You know, there's, we talk a lot about CST reduction and vision, but when you look anecdotally, right, there, there are other visual endpoints, right? As people have talked about here, right? Our patients report that they can see better at night, they can drive, they can distinguish black and blue.
You know, there are other things beyond visual acuity that make a difference in terms of what it is that they can do functionally day to day, and we see that benefit, and those are things that we'll be tracking in phase III, you know, in addition to BCVA. So, we think there'll be a lot of benefits. One of the key things about the retina space, though, is it's a very concentrated space, right? So you can cover it with a small footprint, and we've seen tremendous uptake, right? So you can see with new agents, there's receptivity with the launch of Syfovre. You can also see that for Vabysmo and high-dose Eylea, they've turned over the market dramatically, even though, you know, those incremental benefits would be much more marginal than what we're proposing with gene therapy.
We're very optimistic about the uptake, but, you know, you have to work hard to be able to realize those benefits.
Sure. Doug, we'll turn to you, maybe one or two follow-up questions on GA before turning to some of the other important pipeline events that are coming up in the not-too-distant future. So first, on GA, you mentioned the design or described the design of the pivotal program. On timelines, when could data be available, and when is it possible, so for the EOP2?
Yeah. For the first study, the ARCHER 2 study, the global study that's being run in the U.S. and Europe, as I said, we'll launch that the middle of this year. We anticipate we will have full data in 2026. And so this could be in the market as early as late 2026 into 2027.
Perfect. And then turning to the other pipeline programs, you had an analyst meeting on Friday discussing the GBS trial. I think we'd be remiss if we didn't discuss that since the pivotal data is right around the corner. So could you review the design of the pivotal trial on GBS for zero zero five and talk about the phase I, two data that give you confidence it's likely to succeed?
Yeah, super excited about that program. So for those who are not familiar, this is the other side of the house. Again, as I said before, we're targeting C1q in the classical cascade because it initiates this inflammatory process. In the GBS side, this is an antibody-mediated autoimmune disease. We have multiple indications here. We've run three studies now on Guillain-Barré syndrome. This is an acute disease where you're healthy one day, you get food poisoning or some other infection, your immune system comes on, clears that infection, and then, for whatever reason, two to four weeks later, turns back on, attacks your peripheral nerves, and causes acute paralysis. It's the number one cause of acute neuromuscular paralysis in the world. One in four patients are on a ventilator, 5% of the patients are dying still here in the U.S. on top of IVIG.
There are no approved therapies. Super excited about our phase III program. It really mimics, again, what we did in our phase II program, where we had robust proof of concept. This is a 240-patient study looking at the GBS Disability Scale, the primary endpoint, as our outcome. We moved that meaningfully in our proof of concept data set. We're also looking at other key measurements like muscle strength. So the patient's ability to walk and function is essential for this type of disease. We showed an impact on that in our proof of concept study. That translates to less days on a ventilator, less days in the ICU, less days in the hospital, et cetera. So we'll have that full phase III data set in Q2. Really, really excited about that. We've had robust alignment with the FDA with regard to that program.
So we'll get that data out into the marketplace and hopefully bring the first new therapy for this disease in over 40 years to this patient population. And it's a meaningful size patient population. So we see this as a blockbuster type of disease. We put out data last week, as you alluded to, Phil, showing that the size of the market is roughly 30% larger than what people have thought historically. And again, you know, there's, there's been no therapies, and so that, that's what's occurred there. So we're really encouraged that just in the U.S. alone, there's a blockbuster potential, and certainly when you pick up Europe, it's a meaningful, meaningful opportunity to benefit patients and shareholders.
In terms of the FDA alignment, you've been very clear exactly what the FDA expects to see in order to support a filing and approval. Could you describe what that agreement is?
Yeah, absolutely. So this is a study that is run 100% ex-U.S. The reason for that is IVIG is the standard of care here in the U.S., notwithstanding that it's not been approved and have run multiple phase III studies. So we had to go to jurisdictions where IVIG was not readily available. That's in Southeast Asia, where we've aligned with the FDA is on two parts. One, we need to demonstrate statistical significance on the primary endpoint, GBS Disability Scale. We're also looking at a host of other measurements, the secondary endpoints. And then two, we need to demonstrate comparability of patients who are ex-U.S. with patients in the U.S. And there we're quite fortunate in that we're able to lean on a 2,000 patient prospective natural history study called IGOS, which has data covering patients across the globe with Guillain-Barré syndrome.
The key prognostic factor for patients with GBS, irrespective of where they are in the world, is their baseline muscle strength, as measured by MRC. So really very objective measure. We've got a really nice workup with regard to a real-world evidence to assess these patients, ex-U.S. with patients in the U.S. We submitted initial data from our proof of concept study doing this analysis in Europe, in the EMA, and there we got orphan drug designation in the fall, which we were completely thrilled with. That's never been done before in this disease, and it's rarely done in any other disease. And so we'll take that same analysis. We'll apply that to the phase III for hopefully, you know, a robust label.
... I think the most common question we get on the GBS pivotal, that you did a great job answering last week, is how is Alexion going to succeed when Alexion and Soliris failed in GBS? Can you talk about the differences in trial design and, specifically the trial design that give you confidence that you're going to succeed where they failed?
Yeah, there are two components of it. So one is the mechanism of action. I continue to go back to it because we think it matters that if complement is playing a key role in the disease process, stopping it where it starts is the most complete protection against this inflammatory disease process and tissue damage. That's what we've seen now in GBS, that's what we've seen in ALS, that's what we saw in Geographic Atrophy. So turning back to GBS and why we think we'll be different than what we saw with Soliris, one is the mechanism. So targeting C1q has been demonstrated in multiple indications now to be different than targeting C5, which is, in effect, trying to stop a train once it's already roaring down the track. We're stopping it before it gets started. The second piece, Phil, as you alluded to, is the trial design.
So when you look at the Alexion studies, those studies were somewhere in the neighborhood of 30-40 patients. This is a disease of high heterogeneity, so patients come in at various forms of GBS, which is really, really meaningful. In our instance, we have 240 patients. This is one of the largest GBS studies that's ever been conducted. And importantly, we also stratified the patients in our study based on their baseline muscle strength. As I said before, that's the key prognostic factor for how patients are going to do. What's your baseline muscle strength, and what is it at week one? So we've stratified and balanced the group. So the size and the balancing of the treatment arms, we think is really important to the overall outcomes. It'll differentiate it from what we saw with Soliris.
The last question before moving to Apellis on the small molecule, so C1s inhibitor. Can you give us an update on the status of that program and when we can see the proof of concept there?
Yeah, super excited by that as well. Our third flagship program, again, stopping complement right at the start. All of the programs heretofore in the autoimmune space have used an antibody, so these patients are being infused every other week or a subQ, and they're being dosed multiple times a week, etc. We've come forward with an oral small molecule targeting antibody-mediated autoimmune diseases, again, stopping the complement cascade right where it starts. That allows us to go into a host of different autoimmune conditions that have been difficult to treat. All of these are severe, devastating conditions, where patients really are robbed of their ability to live normal lives in a multitude of different ways. Small molecule, we completed a healthy volunteer study late in the year, last year. Really pleasing what we saw in the PK, the early data on the PD.
However, in a healthy volunteer construct, patients' complement levels are relatively normal, so we need to go into a patient population to really finally validate this molecule. We have done that, and so we anticipate we will have proof-of-concept data in the second half of the year for that program. That's [audio distortion] .
Perfect. David, back to you and, and Apellis. I think we are all on Wall Street among investors surprised at the share that Syfovre has today. It was quantified last week, this week, as 90% share of the overall patient population in GA, 70%-80% of new patient starts. To what do you, do you attribute such a high, high share with Syfovre launching?
I think there's a comfort level with the efficacy, for sure, right, in the data that we have. And we'll talk, I'm sure, in a little bit about, you know, our GALE study and the GATHER2 study. But efficacy certainly drives that, and that discussion is what we've... Is our, is our lead discussion on everything that we talk through. And I think there's a comfort level with just the sheer number of vials that are out there with the safety side of it. So we've got 200,000 vials that are out there, 215,000 injections, including the phase III studies. So I think there's a comfort level that has, has developed, around both the efficacy and the safety discussion that we've had. And not to mention, I think, you know, we were the first ones out.
We had a chance to really kind of set the stage with the, with the physicians and the patients. And this is also a conversation of risk-benefit that they're having with the patients, and the patients almost always opt in because they know the alternative is to go blind. So, we were able to help generate the conversation there early with them. So that's really where we spend most of our time.
How do you think that long-term data from GALE and the second year of GATHER2 has played into share? Is that the fact that your effect size is growing with time, whereas it seems like Izervay is likely declining, is that impacting physicians' opinions?
Absolutely. I think the fact that we can step into an office after a third year of an extension study and say that we have 42% reduction in lesion growth is a very big number, right? And even though it's taken, you know, two or three years to get to that number, it's increased consistently over time. We haven't had a single report that we've come out to the street or to the physicians that we've anything that dip below that, and we report it every six months. On the Gather side, the same patient is at 14%, and they actually did have a decline that you alluded to, Phil.
So I think it's just really important that among all of the data and all of the clutter and all of the things that happened in this space, because it was a bit of a fury of activity last year around a number of things, to really focus in on the fact that the efficacy is significantly better with Syfovre, and the fact that we're now able to manage very effectively and confidently a 0.01%, very rare on the vasculitis side, so the safety profile is holding as well. So I think that's super important.
With all the turbulence in Syfovre, I think investors have lost a bit of focus on Empaveli, but in fact, the Empaveli pivotal data is probably the next big data readout for Apellis. How do you size the C3G, IC-MPGN market-
Yeah.
Where could Empaveli fit into it?
So remember, we launched Empaveli in PNH, right? There's around roughly 1,500 patients or so that are treated in the U.S., maybe a couple thousand that are diagnosed. We've been very successful there, and the product is incredibly safe. No infections over 1,400 patient years that have come through with that product, through the studies and through our launch. We're now at year 3, right? This summer, we'll be at year 3, and feel like we've had a really successful launch in PNH. The real beauty of C3G IC-MPGN is that market is high unmet need, so we have an answer for patients that really don't have an answer today.
50% of those patients will end up in most likely transplant, so there's a situation that if untreated, 5-10 years later, they're gonna have a much bigger issue that they need to deal with. And we're in a situation with those patients in the U.S. alone, it's about triple the size of PNH, so it's about 5,000 patients, 8,000 ex-U.S. So it's a much bigger market, still rare, right? Still very rare, but incredibly high unmet need, and, as you know, with our phase II data, we work there. We've yet to get through our finalization of phase III. In the summertime, we'll have a readout, and I fully anticipate we'll see similar results.
Do you have a sense of what physicians think clinically would be clinically meaningful? What type of data do you need to show the drug update?
So I look, I think as if you go back to the phase III data, I think it was 39.2%, right? That was, that was in that, in the phase II data that we reported last year. They are very impressed with our phase II data. Very impressed. Matter of fact, we have, as the readout, what happened last year in, the only one of the biggest meetings that they have in the fall, and we actually have patients coming to us now, a number of physicians are calling us now to say, "What can I do to get patients access to product today?" So I think where we're currently sitting on our phase II data, is someplace in that marker is going to be impressive to these physicians.
Great. I think we are just about at an hour, but to conclude the panel, maybe with one final question, and, and Linda, we'll start with you. We ask all our physician panels what they think is going to be the biggest surprise in their field over the next ten years. What do you think will be the biggest surprise in ophthalmology, gene therapy, biotech, whatever you want to opine on over the next ten years?
Oh, my goodness. That's something I wouldn't have thought of.
I probably should have warned you that was coming.
That wasn't on the list.
Yeah. Yeah. I guess I would just say that, you know, Adverum is my first ophthalmology company, my first gene therapy company, but to combine the two, I think this gene therapy approach can be incredibly compelling for many indications. We've seen it for the inherited retinal diseases, where it's transformational, but we're seeing it now with these, you know, very large indications and, you know, if you're going to be trying to address geographic atrophy and dry AMD, these are diseases that, yes, they progress, yes, patients go blind, but they do it over a long period of time. They're younger, it's burdensome to get the injections. Wouldn't you like to have a gene therapy approach that could be benefit? You can potentially see the same thing with glaucoma and other indications.
I'm really bullish about, you know, the opportunity for gene therapy in the ophthalmology space. That's not going to be the biggest surprise in biotech.
That's fair. That's great. What, what do you think?
Well, that's, that's a hard question for me. I mean, I think there are going to be a lot of things over the next 10 years in biotech because I think drug development is getting so much better, right? We're just so much more informed with the tools that we have to do robust drug development. If I could be selfish a bit, where I think we're really going to surprise people is the role of the immune system in the brain. We see it in the eye, right? And the eye is an extension to the brain. It's the founding thesis for our company, Annexon. And so I think really specifically targeting aspects of the immune system in neurodegenerative diseases like Geographic Atrophy, like glaucoma, like Huntington's disease, like ALS, is the next frontier, and we love that, right?
Because, you know, we're a population that's aging, that population is getting larger, and we're showing breadcrumbs that we're getting closer towards that. So I think we'll see a lot more, you know, even over the next five years with regards to that.
That's a great answer.
I actually agree with a lot of that. I hate to say that, but I do. Actually, I look, I think if you go to ophthalmology, and this is the first true retina product and space that I've been in, but I think that the science of the space and what we're going to be able to do for patients is gonna, by leaps and bounds, move very quickly. I think everyone here knows that already. But it's amazing what we didn't have three or four years ago and what we're developing now, that within the next four, five, six years, you have multiple products for Geographic Atrophy, potentially in the next five to seven, right? You're gonna have lots of other options for patients.
The space is definitely big enough for all of us to survive and do well, and patients are gonna have the ability to do things for a much longer period of time than the same lifestyle that they had for forever, right? That they didn't have choices. I mean, doctors were telling patients, "I can't help you. Go back to your optometrist." I mean, just think about that, that those days will be gone in certain diseases, which is fantastic. I actually have a special place in my heart for other areas like Alzheimer's, ALS. We're working on all those things at Apellis as well. The science that we can carry from what we're learning here into those other disease states is super important and quite honestly, just as devastating as what has happened in, you know, in years of not being able to control blindness.
So I think, there's a runway here with what we're learning that, part of it, and hopefully, I'm still around when it all comes to fruition, so.
Those are great answers. The last physician panel, one of the physicians said she hoped that we could get a quarterly injection for a drug, which so I think yours is more creative than that. Thanks so much for your time. That was, that was very interesting.
Thank you.
Thank you, guys.