Good morning and welcome once again to TD Cowen's 45th Annual Healthcare Conference. I'm Phil Nado, one of the biotech analysts here at Cowen, and it's my pleasure to moderate a fireside chat with Doug Love, the President and CEO of Annexon. First, I'll kick it to you. Can you give us a state-of-the-company overview, the strengths, the challenges, and what does Annexon need to do over the next year to two to create shareholder value?
Yeah, thanks, Phil. Thanks for all of you joining us. Happy to be here today. Really a good time for Annexon, notwithstanding kind of the broader macro market in that we've really been able to execute this classical complement platform in a multitude of ways. For those who are less familiar with us, we're targeting C1q, the initiator of the pathway. What we like about that is it is the component of the complement that binds disease tissue, anchors complement, and drives this inflammatory process. By blocking C1q, we're able to block all downstream complement activity in the body, the brain, and the eye. We're led by three lead programs. Guillain-Barré syndrome is our most advanced program, which we are looking to submit a BLA shortly on the basis of a landmark phase 3 data win.
Following that is geographic atrophy, a 630-patient phase 3 study on the backs of a really positive proof of concept study that really is the first program to show vision sparing as well as protection of photoreceptor neurons in the eye that are associated with visual acuity. Last but not least is our small molecule oral program, ANX1502, the first such oral program in the classical pathway. We're in a proof of concept study and we'll have data in the middle of the year on that. All of our programs are advancing as hoped. I think, you know, the challenges, notwithstanding kind of the macro market perspective, is continuing to execute on these programs in the way in which we have set out to do so. We've passed the technical hurdle as it relates to GBS. We're now engaging with the regulators.
We will have our pre-BLA meeting with the FDA shortly, and then we'll follow that with a meeting with the Europeans in the same or ilk. That is just a regulatory topic that we just need to work through there and make sure all systems go. We will come back to the marketplace and update on the commercial opportunity in GBS. I think that's really important over the next year. This is an acute monophasic disease and it impacts 7,000 patients a year in the U.S., another 15,000 in Europe. It is a disease where no one has seen the real commercial opportunity. The thing we like about it is that 90% of these patients have to get treated. This is a devastating neuromuscular disease. Virtually everyone is treated right away. There is a real opportunity to capture this market.
IVIG is what's used as standard of care, but it's unapproved. It really has a paucity of data. We have shown in a real-world evidence head-to-head comparison that we are far superior to IVIG in that effect from that perspective. I really want to get GBS approved and make sure we commercialize this the right way and take it off from there. With regard to GA, over the next year, we have to continue to execute. As I said, we're in a large phase 3 program. We will complete enrollment in the second half of this year. We'll have data next year. This really looks to be the potential market winner. I am really pleased with the regulatory alignment that we have been able to generate both in the U.S. and Europe.
This program has the potential to be the first approved drug globally for geographic atrophy for vision sparing, which is very different from lesion growth. I am sure we will talk more about that. Annex 1502, we have to complete the proof of concept study, show that we can effectively inhibit complement up and downstream as well as impact key markers of hemolysis. From there, get going in a host of different diseases that we like, predominantly antibody-mediated neuromuscular diseases and more. Execution, execution, execution is where we are at today, Phil.
Great. Let's dive into those programs in a bit more detail. GBS, the pivotal data were out last year as you referenced in the real-world extension data towards the end of the year. Can you talk about the highlights of those data and in particular, what do you think will appeal to physicians?
Yeah, absolutely. It's a really differentiated program. I mean, this is the first targeted therapy for GBS in 40 years, the first placebo-controlled studies run in 40 years. I will say, folks, we are not dabbling in this space. Over the last nine years, we've run two proof of concept studies. We've run a drug-drug interaction study versus IVIG, and we ran a real-world evidence study to compare the effects of ANX005 with standard of care IVIG. In the phase 3 landmark study, what we showed was patients get better sooner and more completely. By week one, we're seeing almost a tenfold improvement versus placebo in that patient group where we're getting patients back on their feet and giving them hope to live their best lives.
That then translated to a durable outcome that month six, two and a half times more patients got back to a position of normal, which is really, really huge in a disease like this. For those who aren't familiar with GBS, you're normal one day, you get an infection, the next day you're on a ventilator. Like it is really debilitating. The recovery is weeks, months, years if you ever fully recover. Getting patients back to normal by month six is really, really huge in the data set. We also got patients off a ventilator 30 days sooner than on placebo. We got patients able to walk 30 days sooner. That means they're able to get out of the hospital than on placebo. We went on every measure that we could hope.
Importantly, we should point out that this is a really vulnerable time in patients' lives. We're stricken with this disease. The safety profile for ANX005 really mirrored placebo when you look at it. It was a really clean package from a safety efficacy perspective. We then followed that up with a real-world evidence study whereby we matched patients in our study with patients in a 2,000 patient registry, one for one, and then showed, and these were patients who were treated with IVIG. We showed a treatment effect of ANX005 versus IVIG. The numbers that I just quoted with regard to ANX005's treatment versus placebo looked very similar versus IVIG. Really much more pronounced efficacy effect in week one, which was durable out to month six. We got patients out of the hospital sooner.
We got them off a ventilator sooner, et cetera. It is a really positive outcome across the board. It really allows us to differentiate in the commercial market with a drug that is infused with a single infusion versus five days of IVIG, really good safety profile and profound efficacy effects early in the disease and durably over the course of the disease.
Can you talk about the rationale for doing that real-world extension study and a real-world evidence study and what role that data package fit in the overall filing?
Yeah, really important topic. For those who are not familiar with GBS, again, IVIG is the standard of care here. However, IVIG has never been approved for GBS, notwithstanding they've run multiple phase 3 studies. The challenge with IVIG is they never have run a well-controlled study. They have not run a study that was blinded with a control. While it is the standard of care, it could not serve as a control in a program in which we wanted to go head-to-head against IVIG. That forced us to go into jurisdictions where IVIG was not available to run placebo-controlled studies. We did this in Southeast Asia, in Bangladesh, and the Philippines to be specific.
To import that data back into the West, into Europe and into the U.S., we need to demonstrate that the outcomes in the patients in Southeast Asia are similar to what we should anticipate here in the U.S. The real-world evidence study we did allows us to match patients from our study with patients in the West using this IGAS registry and showing, one, that the patients are similar, that we can generalize treatment effects all over the world. GBS is GBS, one. And two, what's the treatment effect of ANX005 in those matched patients versus IVIG? For purposes of a label, we will submit both our phase 3 data set, which demonstrated in our view substantial evidence, as well as the real-world evidence data set. Both of those will go in to the FDA to support the BLA.
Perhaps the most controversial aspect of the pivotal data was the fact that the low dose had better data than the high dose. Why do you think that was? What's the theory to why low dose is better than high dose?
Yeah, we were pleased to see it candidly. That very much mirrored what we saw in the proof of concept study where the low dose outperformed the high dose. The way to think about these two doses is that both fully inhibit complement, but it all relates to duration of complement inhibition. The low dose, 30 mg per kg, inhibits complement for about a week. The high dose, 75 mg per kg, inhibits complement for about three weeks. What's important for GBS is it's a monophasic disease, an acute monophasic disease. The disease process is about a week. What we've learned both from our proof of concept study and now the phase 3 study is you want to inhibit complement's deleterious activity during the acute disease phase or about a week period of time.
After that, you want complement actually to come back and be part of the repair process. What we learned is there's a defined treatment window for treating GBS. You want to treat it during the active disease phase and then allow complement to come back thereafter. That is what we saw with the two doses. By the way, this is very similar with IVIG. IVIG has run studies where they give two doses of IVIG. It works not nearly as well as a single dose of or a single course of infusion for IVIG. It is contraindicated. This treatment window is pretty well defined now for GBS.
Now you've gotten to meeting with the FDA prior to the filing in the first half of this year. I believe that there's actually two meetings. There's an end of phase 3 meeting and a pre-BLA meeting. Have either of those happened yet or they both? One has?
No, yeah, one has had. You're absolutely right, two meetings. We've had an end of phase 3 meeting with the FDA. In that meeting, we discussed with the FDA GBS, the disease itself. Again, this is a disease that has not been in front of the FDA in over 40 years. We spent a lot of time talking about the neurotype, how the disease operates, the role of complement with regard to the disease, as well as our phase 3 package. What did we actually achieve in the phase 3 study and why does it matter to have an impact, for example, excuse me, on the disease early and in the middle and late and the differing endpoints? We've done that.
The next meeting we will have is a pre-BLA meeting where we will go back and meet with the FDA and we'll talk about two things principally. One will be our real-world evidence data. We've briefed that and submitted that to the FDA. We have not had a discussion on that package with them yet. We will discuss the mechanics of the BLA submission itself. That meeting is upcoming and we'll complete that and then hopefully be moving forward to our BLA submission.
Are there any major issues that you need to resolve in the pre-BLA meeting? The two elements that you just outlined seem pretty straightforward. Are there any questions that you have, any potential sticking points in the filing?
Not in our mind, but of course we got to hear from the FDA. I mean, the thing I will say is a couple of things. One, this is a really robust rare disease package, right? You rarely see a program where you have two placebo phase proof of concept and phase 3 studies as well as a drug-drug interaction study and a real-world evidence. A really robust rare disease package. That being said, we need to understand, is the FDA aligned with this that we've demonstrated generalizability? That is, the patients in our study are comparable to patients we would expect from an outcomes perspective in the Western world. We will have that discussion with them. Outside of that, I think it's the normal BLA topics that you would expect to talk about.
The design of the RWE trial, that was done in conjunction with the agency?
Yeah, absolutely. This was a formal protocol on doing a real-world evidence with a statistical analysis plan. All of that was submitted to the FDA. They commented on that. They will not be surprised by that at all. Yeah.
Perfect. Can you discuss where O5 could fit into the treatment paradigm in GBS?
Yeah, front line. I think this is a monotherapy. Yeah, we're considering this a monotherapy. Single infusion, completely shut down complement, patients get better in a matter of five to ten days. That's what the data says, both in our phase 3 study, our proof of concept study, our phase 3 study, and now the real-world evidence study. As a single infusion, we don't anticipate that the patients would then be cycled on to IVIG, which is a five days of course of therapy infusion. We're looking to really provide a complete response to patients in this disease or answer.
How big is the GBS market? How many patients have it? How many patients are hospitalized? How do you think about pricing for a physician?
Yeah, really good question. This is a really meaningful market for a rare disease. $7,000 patients a year in the U.S. are hospitalized with GBS. There's a bit more who actually get it who do not get treatment. But $7,000 a year, year- over- year, we did a claims pool to confirm that number. Another 15,000 in Europe. Importantly, 90% of these patients, 90+% of these patients get therapy. We know where these patients are. This is an incidence-based disease. It really tracks or mirrors the population in the U.S. Based on the work we and others have done, there are roughly 400 hospitals that treat 80% of GBS year- over- year. That allows us to have a very efficient commercial footprint and Medicare's footprint. We are really excited about the ability to do so.
We are already engaging with these folks from a Medicare's perspective and making sure that they're educated on the disease itself as well as our therapy and what's the standard of care out there. From a pricing perspective, some of the more exciting aspects of the data that we produce really lends itself to, in our view, pricing flexibility. What we've shown is, for example, in our phase 3 study is that we're getting patients off a ventilator 30 days sooner than they are versus placebo, 15 days sooner versus IVIG. Every day on a ventilation is not only lost brain cells, but a really significant cost to the hospital system. We're getting patients on their feet 30 days sooner versus placebo, which is hospital days. We have a single day of infusion, overnight infusion versus five days of infusion with IVIG.
All of these are costs associated with the healthcare system in treating this disease. We have multiple measures from a health economic perspective to make clear that by treating with ANX005, we're both getting patients better, sooner, and more completely, but we're saving the healthcare systems hundreds of thousands of dollars. We think that gives us tremendous pricing flexibility, which we are quite encouraged by.
What is the approximate price of IVIG for?
It's about $25,000-$30,000 for a course of therapy. Notably, half of the patients who get IVIG get two courses of IVIG treatment, even though, again, it's contraindicated on the practice guidelines because patients actually don't do as well with the second course of therapy. That gets back to hitting them in the treatment window for IVIG. The reason it's happening is that after a single course of treatment with IVIG over five infusions, patients still need help. Physicians don't know exactly how to deal with that when their family members are really banging on them. They are giving them a second course of treatment. The price for IVIG should be thinking somewhere between $40,000-$50,000.
Got it. You mentioned that you are working with some of the centers now through your Medicare folks. Can you talk a bit more about what the Medicare team is doing at the centers that treat GBS today?
Yeah, we've got a full field force out educating again on GBS, the disease, as well as our data. Sorry about that. What's important about GBS is to really understand the patient journey. This has not been well elucidated because there's not been a lot of studies or companies going after GBS. They're spending a lot of time really understanding how hospitals manage GBS. Some of the learnings are really, really quite stark for us and for the hospital systems. There is just a lot of man hours. You can imagine that if a patient is bedbound, even getting that person to the restroom, et cetera, additional man hours. Importantly, some of these patients go into really small facilities and then are transferred to other facilities with larger neurology type units. The question is, when are they getting IVIG?
Are they starting IVIG treatment in the small center before the transfer? Is it along the way or is it once they get there? There is a mix. There is an education opportunity there. They are spending a lot of time understanding that and beginning to develop strategies from an education perspective. The other is just diagnosing GBS. Some hospitals and centers do a tremendous job at diagnosing GBS when a patient comes in. Bear in mind, it is not necessarily a standard diagnosis when you think about it because this is a person who is otherwise healthy and overnight they have become paralyzed. What is it? It could be any number of things. However, there are a few things to look for to make the diagnosis really straightforward.
Our Medicare groups are out working with folks to understand how they're doing it today so we can develop the right tools to make sure we can optimize that and diagnose people as quickly as possible. Time is nerves in this disease.
Maybe switching to 1502, you mentioned that there will be an update mid-year from that program. Can you talk about what we'll see, how many patients, and what you're looking for?
Yeah, again, this is a program we really quite like. This is again an oral-administered drug targeting C1s, activated form of C1s. And it's a target that's been clinically validated and commercialized in other instances. So we really like it quite a bit. With ANX1502, as the first oral, we really are just elucidating its dosing profile. This is a translational early-stage program. We're looking to really demonstrate PK/PD tolerability and impact on some of the efficacy measures. In this study, we will be looking at first, are we fully engaging complement and fully shutting down the entire cascade? If you can't do that, you can't go Pascal. You have to make sure you can fully shut down the complement system and bad inflammation, if you will. We also will be looking at its effect on hemolysis.
Impact on bilirubin, a really objective measure in cold agglutinin disease, is something that we would expect to see move fairly rapidly within a week or so in virtually all patients. We will be looking to see that getting back towards normalization with regard to that. We will be looking at a host of exploratory things. We will look at, for example, hemoglobin. We get that question from time to time. Bear in mind, this is a short study, two to four weeks. We expect that we will see some trends in activity on hemoglobin, unlikely to be statistically significant. It is important to note that hemoglobin bounces around in patients. In fact, there is a drug that is approved for cold agglutinin disease. You can see that in those approved data sets, 60%-75% of the patients are impacted by hemoglobin.
It is not even all patients with regard to that. We will look at that. And then, of course, safety and tolerability, obviously very important as an oral.
When we assess the magnitude of bilirubin decline, should we be looking at NGMO as the proof of concept? Is that kind of the relevant bar? Whatever NGMO is over two to four weeks is what you should be expecting.
Absolutely. Which is getting patients back to the normal range, right? Close to the normal range of hemolysis levels.
What would be the next steps for the program after the completion of the CAD trial? Will you be able to outline the indications and trials at the same time that you give us the data?
Yeah, absolutely. With success. We've worked up quite a few studies. Listen, we've been in complement now for 10 years. We love the antibody-mediated diseases. We love the neuromuscular diseases. When you think about GBS as an acute neuromuscular disease, really the tip of the spear in terms of the most aggressive neuromuscular disease, success there in learning how to drug indication like that really bodes well for some of the more chronic indications like myasthenia gravis, CIDP, et cetera. There are other indications that are maybe less obvious to folks where we've done a great deal of work, but really look to be quite interesting from a small molecule perspective with a classical complement inhibitor. We will outline the next set of indications in our go forward plans there from a development perspective.
Great. In the last 10 minutes, we'll turn to GA. Archer trial data were released a couple of years ago. For those less familiar, can you provide the highlights of the data in GA?
Yeah, really important study, 270 patient study in geographic atrophy. There, what we showed was the first and only program to show a significant preservation against the loss of vision. We did that in multiple measures. We did that in normal light conditions, low light conditions, and importantly, in healthier eyes. What do I mean by that? In normal conditions, that's your standard BCVA 15-letter endpoint. That is the approvable endpoint for visual acuity in most all ophthalmic diseases, for example, wet AMD. We really were quite significant with regard to that. In low light conditions, it's the cousin, if you will, to BCVA. It's LLVA or low light visual acuity, another 15-letter. Very few companies have ever been able to move that. Why that's important is it activates different aspects of the central retina and the cones in your eye.
There were statistically significant in preserving vision in low light conditions. A room like this would be considered at low light conditions where you don't have perfect light. Looking at patients who had earlier onset geographic atrophy, we were able to preserve vision in all 56 patients who fit that criteria. That's huge. When you're looking at a neuroprotective approach, your drug should be better in earlier disease. Indeed, we are. 0 out of 56 lost vision, whereas 17% did in the sham arm. We're really encouraged by that. Over the last year, what really has us super excited about this program is our protection against key structures of the eye that are associated with visual acuity. These are neurons in the eye called photoreceptors in which light comes in, and that is actually how you see.
Where we show is we're showing that we're able to protect photoreceptor neurons in the central retina in the eye that's responsible for vision, 50%-60% preservation against the loss of these photoreceptors. This is the only structure in the eye that we're aware of that's ever been published to show a correlation between structure and vision. We're really excited about the ability to show protection in our Archer phase 1 study on not only vision, but the structure in the eye that's responsible for driving vision, your neurons in the eye. It's a really powerful package. Last thing I'll say is just with regard to the drug candidate, ANX007, it's intravitreal administered into the eye, non-pegylated. It's built on the backbones of Lucentis. We know a lot about it.
When you look at CMV rates, for example, in our phase 2 study, CMV rates mirrored sham. We are not converting patients to wet AMD in the phase 2 study. We have seen no vitreitis or any of the other things. It thus far looks like a very clean program from an efficacy and safety perspective, and it makes rational sense. I am sure you have a follow-up question. I will stop there.
Yeah, I think investors are very familiar with the C3 mechanism, the C5 mechanism, and how they preserve lesion growth, but do not seem to impact visual acuity. Here, C1, you are preserving visual acuity, although not impacting lesion growth. Can you talk about the mechanism behind C1 preserving vision and why it would be different than a C3 or C5?
Yeah, it relates to exactly what I said. We are protecting the structure in the eye, photoreceptor neurons that associate with the vision. RPE loss has no bearing on vision. It is not our data that tells you that. It is the approved drugs that tell you that. With three, four years' worth of data, you now see that you can protect RPEs to whopping numbers. I mean, some of these guys are out 30%-40% preservation of RPE growth, but still no vision. The reason for that is RPEs provide trophic support underneath the photoreceptor neurons. They do not directly drive vision. The thought or hypothesis is that if you slow the loss of RPEs under photoreceptors, they will ultimately make photoreceptors more healthy. The challenge with it is that by the time you have lost your RPE cells, you have already lost your photoreceptors.
RPE cells is a lagging indicator of vision in geographic atrophy. It just took years of studying it for folks to really understand that. There is no data that will tell you otherwise clinically or preclinically. It is our mechanism, C1q, again, as I said at the outset, localizes on disease tissue. In the case of geographic atrophy, that is the photoreceptors and their synapses and their degradation. We are preventing that degradation from occurring before you even lose your RPE cells. We are targeting the locus of the disease, and it is why we are seeing vision by protecting the neurons that are responsible for vision versus RPE support.
That is very helpful. The phase 3 trial you mentioned in your opening remarks, can you dive into the design a bit more?
Yeah, I really like this study. Look, we're looking to mirror the Archer study. We're calling it Archer 2 as much as possible, but enhancing it with learnings from the Archer study as well as other programs in the space. It's a 630-patient study that's being run in the U.S. and Europe globally. We really quite like it. The primary endpoint is BCVA 15-letter loss. Vision, key secondary is protection against photoreceptor cells. Really nicely conducted. There are some other things that we've done to enrich the study, which I won't share because we think it's proprietary. Suffice to say, it's the only program that has gotten prime designation, i.e., breakthrough in Europe, which we're really encouraged by. It is the only program that has aligned from a regulatory perspective, regulators in Europe and in the U.S. as a single path forward for approval globally in this 8 million patient population disease.
There was a time when Annexon was contemplating a second pivotal trial head-to-head against Syfovre. Given that Syfovre doesn't seem to have a path to the European market, does it make sense to conduct that trial?
Yeah. In fact, we announced earlier this week we are no longer going to do so.
Oh, yeah.
Yeah, yeah. No worries.
I missed that.
It's okay. Yeah. I mean, there's no vision with Syfovre. So there's no real reason to kind of prove that they don't have vision because they don't have vision. One, and two, the regulators haven't required us to do so. We just got a very clean package to go forward. We went on Archer 2 will allow us to have a label in Europe and allow us to have a label here in the U.S., and we are moving forward with that approach.
Can you quantify the GA market opportunity?
Yeah. It is quite a large market. It is a million and a half to a million to a million and a half patients here in the U.S., another 3 million in Europe, and then folks around the globe, a total of 8 million patients. You guys know this market. This is an elderly population. The average age of the patients who came into our phase 2 study was 80 years old. In the phase 3 study, it is right about that, between 80, 81 years old. These folks are losing independence. What does that mean? They are having to move out of their homes into nursing facilities or to live with loved ones, et cetera. This is a really motivated market when you have an appropriate drug.
In fact, if you look at the early launch, first three to six months of Syfovre, for example, which was going exceedingly well before they ran into some challenges around safety, et cetera, it really speaks to the demand. Coming forward with a drug that has vision-sparing properties is really, really huge. Europe is super, super energized. We're really pleased with the enrollment of this study. It's going as hoped, if not a bit better. We fully expect that we'll get the study enrolled in the second half of the year and then turn over cards next year.
You have a long-acting formulation of 007 in development. Can you provide an update on the status?
Yeah. Early days. This is a life cycle play. Right now in our phase 3 study, we're dosing every month. We think that's quite doable from a commercial perspective given the motivation of the patients. We see what's going on. The patients are dosed roughly four to six weeks with the currently approved therapies with no vision sparing. We think that works. However, playing for the long game, we are looking to dose this drug less frequently, whether that's once a quarter or twice a year. We have been active on that. I do not want to share too much from a proprietary perspective, but we are working with an external partner who specializes in long-acting formulations with antibodies administered into the eye.
Any update on business development? One, you have some programs that you're looking to partner or license. Any update there? Two, anything that you think you could add to your portfolio that would be beneficial?
Yeah, we've got a lot already. We're not looking at anything into the portfolio. I will say that. Look, we built this by design to be wholly owned to get to a place of strength where we've de-risked our assets and hopefully could partner or do some other type of thing from a position of strength. We think we have done that. As it relates to GBS, we are not experts in commercializing in the hospital business in Europe. We're probably going to do something in and around that. We'll be opportunistic with the other assets. Like they're just getting to a place where value can really be derived from them. We want to make sure we derive absolute maximum value for our shareholders and for the patients, et cetera. We'll be opportunistic with regard to other assets in the portfolio.
I guess last question, you reported earnings yesterday. What's the cash balance and cash runway guidance?
Yeah, about $310 million on the books as of our report yesterday, which gives us runway into the second half of 2026, which gets us through many of the milestones we just talked about, including the proof of concept in ANX1502, as well as the data with geographic atrophy, the phase 3 data there. We're kind of rolling.
With that, we're out of time. Thanks so much.
Thank you, Phil. I appreciate it.