I'm Tazeen Ahmad. I'm one of the senior SMID biotech analysts here at the firm. Our next presenting company is Annexon. Presenting for Annexon is, of course, President and CEO Doug Love. Good morning, Doug. Thanks for making the trip to Vegas.
Thanks for having us. We're delighted to be here.
Maybe we could do just a quick introduction about Annexon, the company, how you feel you're differentiated in what you're doing, and some of the catalysts. We'll go into specifics right after that.
Yeah, happy to do so. So Annexon is a complement company focused on the classical complement pathway. And importantly, the lead target is C1q, the initiator of the classical complement pathway. And that really differentiates us from other complement companies in that we are stopping this inflammatory activity right where it starts on diseased tissue. As a result, that's allowed us to build a really multi-pronged portfolio studying indications across autoimmune, ophthalmology, and neurodegeneration. Over the last 10 years of research and development, we've built a robust portfolio where we now have really strong proof-of-concept data in multiple diseases, including Guillain-Barré syndrome, which I'm sure we'll talk more about today, geographic atrophy, Huntington's disease, and others. So we're really primed, as we sit here today, to unlock meaningful value for patients and shareholders with our next set of data sets that'll be reading out over 2024 and 2025.
Within complement, what are your targets, and how is that differentiated?
Yeah. So as I said, we're targeting upstream complement activity. That is C1q. What's unique about C1q and our target there is it's a recognizing molecule that localizes right on diseased tissue, anchoring and driving the inflammatory cascade right from the start. So by blocking C1q, we're blocking upstream inflammation activity that results in tissue damage and inflammation in a host of differing diseases. That's very different from downstream targets like C3 or C5, which are blocking this pathway once it's already started. It's akin to trying to stop a moving train after it's got going. Upstream has macrophage or microglia activity, depending upon the disease, that really does result in meaningful sequelae in a host of different diseases. So by blocking C1q, we can provide the most complete protection against aberrant classical complement activity. And we've seen that consistently result in functional benefit in multiple diseases.
So with that in mind, you picked GBS as your lead indication, your beachhead if you were. Can you talk to us about why that's an attractive market for Annexon? And then you, of course, do have a pivotal study that's set to read out very soon. We can talk about that after.
Yeah, absolutely. So GBS, really important disease. It's an antibody-mediated autoimmune disease. We chose it as a beachhead because C1q in the classical complement pathway is the key effector for autoantibody attacks. The role of C1q in the classical complement pathway in this particular disease has been known for 50 years or so. We really leveraged the learnings in the industry over the last 50 years with regard to the science here. By targeting C1q in Guillain-Barré syndrome, what we're looking to do is really to block against severe nerve damage that happens acutely in this disease. Guillain-Barré syndrome is the number one cause of acute neuromuscular paralysis in the world. It really is an unfortunate disease that happens to any type of person, all walks of life, who one day was normal, completely healthy. They got food poisoning or some other type of infection.
Their complement system turned on to clear that food poisoning and then shut off. And for whatever reason, two weeks later, it aberrantly kicks back on, attacking peripheral nerves and striking patients of all backgrounds. One in four patients result on a ventilator. After one year, almost 20% of patients are unable to walk without assistance. And 5% of patients still die from this disease every year. So we think it's a really significant disease that we're trying to halt right at the start and make patients better. From a market perspective, there are 7,000 incidents of GBS every year in the U.S., another 15,000 in Europe. So this is a really meaningful market as it relates to that. Importantly, virtually every one of these patients gets some type of treatment. Right now in the U.S., it's IVIG, used off-label. It's not approved for that.
It has a bit of a limited effect. But all of these patients need to be treated. And so that's a really important market for us that we think we can step right into by, as you alluded to with our Phase 3 data, showing that we're getting patients better sooner really gives us an opportunity to make hay in this market.
So your guidance is for the data to be in this half of the year, the first half of the year. Can you just remind us what the study design is, what the primary endpoint is?
Yeah. So we'll have data this quarter. This is a large study, one of the largest studies ever run in Guillain-Barré syndrome, 241 patients. There are two doses. One is a 30 mg dose. The other is a 75 mg dose. The differences in the doses is how long are you suppressing complement. For 30 mg per kg, you're suppressing for one week. For 75 mg, you're suppressing for three weeks. Those doses were chosen based on data from our proof-of-concept study. So by blocking the disease for these differing time periods, we're looking to show a meaningful impact on multiple measures in this study. So the study is designed to show at eight weeks a statistical improvement on the GBS Disability Scale. This is a seven-point scale with zero being normal, six being dead. We're only studying patients with disabilities.
So patients who have an inability to walk, patients who are bedbound, or patients who are on a ventilator. We're looking to show a shift to better in these patients, getting them better pretty rapidly over the course of our treatment. And as a result, we also are looking at other secondary endpoints that we think are important for the study as well as for the marketplace. We're looking at secondary endpoints like impact on ventilation days, days in the ICU, et cetera.
Yeah. So those are important things to be looking at. As you look at the treatment paradigm, you talked about the U.S. using IVIG off-label. What is it like in Europe?
Similarly, IVIG is used in Europe. It actually is approved there. So it's on a compendia. They didn't run studies there. It's on a compendia of multiple uses for IVIG. But the treatment effect or impact on the patients is similar in Europe and in the U.S. And we know that because there's a 2,000-patient natural history study, the IGOS Natural History Registry, a prospective registry studying GBS around the globe. It's in most all developed countries as well as many developing countries. And so we have a really good handle on the effect of IVIG in this patient population. And what you see at kind of the 10,000-foot level is the more severe the patient is, the less effect we're seeing with regard to IVIG. And that's why the IGOS and others in this space are attracting new therapies to study this disease.
OK. So when the data does come out, the press release does come out, what would you consider to be a successful study?
Yeah. Well, we want to win on the primary. So that's the GBS Disability Scale at week eight. Really important for us to do that. But in addition to that, we want to show benefit on multiple other measures. Just as it relates to the study design, I may not have said this before. The study is blinded through six months. The primary is at week eight. But we are following patients out to six months, which will allow us to assess things like days on ventilation, days in the ICU over that six month period of time. Given the severity of this disease, many patients are not out of the ICU at week eight. So we need to do this for a longer period of time. So a win for us is absolutely winning on the GBS Disability Scale. We'll be super, super thrilled by that.
It has not been done before in a placebo-controlled study, full stop, in the history of the world, but also showing impact on other aspects of the disease that are important to health care professionals and patients.
Is there a minimum point improvement that you're looking for in the primary?
Yes. We are looking to show that patients on drug ANX005 improve twofold over patients who are on placebo. So a shift to better over the scale. Think about patients who are starting at a four or five . We want to see a twofold shift to better on the scale. And as a result, less patients in that most severe category vs placebo.
OK. Now, you've talked about needing to do additional work before being able to apply in the US. Maybe let's talk about that. I think your view is you'd have to do some bridging analysis before an NDA or a BLA would be able to be filed.
Yeah, really good question. So we've been working with the FDA on this program now for nine years. The thing about GBS, as I said before, given the devastating nature of the disease, IVIG is administered to all patients in the U.S. and in Europe. You just have to do something for these patients who are rapidly advancing to a state of severe disability. However, because IVIG has not been approved and has never run a study against a placebo, they have not gotten the label. And so for us to get a label, we need to do a placebo-controlled study. To do so, for ethical reasons, we had to go to jurisdictions where IVIG is not readily available. We have done that and running this study in Bangladesh and the Philippines. These are two jurisdictions that have a significant amount of GBS.
They also are really strong contributors to this IGOS Natural History data set that I referred to. These folks are experts in the state of GBS. In discussing this with the FDA, the requirements for us to get a label are twofold. One, we have to win on the study and demonstrate substantial evidence. Two, we have to demonstrate that the patients who are treated in our study outside of the U.S., in Bangladesh and the Philippines, are comparable or matched with patients in the U.S. There, the FDA really wants to know two things. One, is GBS the same all over the globe? And two, if you're a patient getting treatment in Bangladesh or a patient getting treatment in Philadelphia, does your disease progress similarly?
Fortunately, we're able to do a really comprehensive matching exercise of the patients in our study with Western world patients out of this 2,000 patient natural history IGOS data set. So it's a protocol we've aligned with the regulators on that. And so we will turn over cards with our study later this quarter on the substantial evidence topic. We will then complete the matching exercise aspect of the study over the balance of the year. And then we'll submit all of that data in the first half of the year to the FDA.
OK. And is there a possibility that FDA would ask you for more than the data that you've agreed to thus far?
That has not come up thus far. We've had no discussions with regard to that. They've been actively involved. I mean, the thing to note about this program is this is our third study in GBS. We really are not dabbling in this space. We ran a really robust proof-of-concept study, which, again, in Bangladesh, which showed really strong outcomes across disability, neurodegeneration, muscle strength, et cetera, all of the key elements of that. We took that data and did a matching exercise actually for submission to EMA last year to get orphan drug designation there. We've been through a bit of a test exercise with that. It has not come up that we would need additional data. But I guess the outcomes of the data will inform that.
OK. So then thinking ahead to commercialization, is this the size of the opportunity one that Annexon can handle on its own? Or would it be attractive to have a partner?
Yeah, very much so. Yeah, with regard to the former, yeah, we really like this indication for commercialization in the U.S. So as I said, it's 7,000 patients annually. They are predominantly treated at centers of excellence around the U.S. GBS is a population-based disease just because it's incidence-based. So it's in larger jurisdictions, California, Texas, Florida, New York, and the like. We can really develop a targeted commercial footprint in going after this disease, calling on hospitals to ensure that it's on formulary. We've got a really robust commercial plan to do so. And then we'll turn to Europe, where we will be looking to do something similar. We also will be open to other approaches in Europe. So we'll be opportunistic about what we do outside of the U.S. The U.S. will look to commercialize.
OK. What kinds of investment and infrastructure would that need?
Yeah, not significant, which is one of the reasons we like it. So you'll need a handful of sales reps. Really, where you're focused on is field-based managed care folks to ensure you're on formulary and MSLs to ensure that physicians and health care professionals understand what actually GBS is. GBS is a unique disease in terms of kind of how it is treated. Because it is treated in the emergency room and the ICU, those patients are seen by one set of doctors. And then they are referred over to the neurologist after they leave the emergency room. So no one set of doctors actually is following the patient journey from soup to nuts. We're going to bring all that together so that they really understand how patients are faring with regard to this disease and our therapy.
So a set of MSLs will be involved with that as well. But all in, a very efficient commercial footprint to do so.
OK. Do you have a sense of what the cost of using IVIG off-label is in the U.S.?
Yeah, it's about $25,000-$30,000 a year for a course of therapy.
Not including hospital stay or anything like that?
Not including even hospital stays at all. What's really important about GBS with regard to that is we know the cost to the health care system to treat these 7,000 patients or so a year is greater than $2 billion. Again, these are costs associated with days on ventilation, days in the ICU, skilled nursing facility, et cetera. So it's not just the drug cost. The drug cost is the small part of the burden with regard to dealing with GBS. So we think that allows us some pricing flexibility, frankly, as it relates to that. And we've designed our study to capture those types of endpoints, as I've said before, by blinding the study out to six months so that we can have that data and make health value-based discussions with hospitals and payers.
OK. So we'll look forward to that top-line data coming out in the next few weeks, it seems. So let's move on to GA, to Geographic Atrophy. I think some folks mistakenly believe you're a GA company. You're a complement company. But GA could be, in the near term, potentially your biggest indication. So I think it gets a lot of attention. So as you mentioned in the beginning, you're focusing on C1q, which is higher up on the complement cascade. The most recent new drugs approved in the space are C3 and C5. As you compare in the GA space, what do you think inherently some advantages of C1q could provide that we are not seeing for the approved drugs?
Yeah, listen, we really like targeting C1q. We think it's really important in a disease like GA and all neurodegenerative diseases. This really gets back to C1q as the target itself, as you alluded to. C1q localizes on diseased tissue. In Geographic Atrophy, that's photoreceptor synapses and photoreceptors themselves where vision is housed. The other downstream approaches are targeting kind of a surrogate for vision, if you will, the loss of RPE cells and slowing of lesion growth, which is an anatomical biomarker that does not associate with vision with multiple years of dosing. By blocking C1q, we're able to preserve neuronal function in the eye and allow patients to actually protect against the loss of their vision. It's a paradigm shift in the way that GA would be treated. We're really encouraged by the data we've seen out of our Phase 2 study.
What we showed in our Phase 2 study was significant dose-dependent impact on visual acuity, preserving vision in patients. That data was supported by multiple types of assessments. We saw this both in the foveal and non-foveal population. We saw this in a fellow eye analysis where you treat patients in one eye but not the other eye. We saw protection against vision in the treated eye vs the non-treated eye. We also saw that once we withdrew drug, the vision protection that we provided over the course of the study, we set a new baseline for the patients. The treatment effect began to wane once we took drug away. A lot of biological and clinical rationale for why our drug is providing visual protection. We've more recently started to release data on the anatomical aspect of our drug on the eye.
There, just a couple of weeks ago, we were at ARVO. We presented multiple new data sets from our Phase 2 study. One relates to vision function as well, low luminance visual acuity or LLVA. A second measurement of visual acuity, it's really BCVA under low light conditions. There, we showed we were statistically significant on that endpoint as well, a really sensitive measurement for visual acuity. What's important about that particular endpoint is because you are looking at vision loss in low light conditions, you're really affecting the cones in the center of the eye, again, right where you lose vision. First and only company to demonstrate significance on that endpoint. We love that. Then on some of the anatomical measures, we show preservation of photoreceptors using the EZ-OCT analysis, almost 30% preservation of photoreceptors, statistically significant there.
And now we are looking at lesion growth. I think the story around lesion growth bears much more attention than what's been seen thus far. What we're showing is impact in preserving against the loss of RPEs in the fovea or the center of the eye, again, where you're losing vision. No other company, to our knowledge, has shown data in preserving against slowing or lesion growth in the center of the eye. So the story really all comes together when you look at our functional vision data, both with BCVA-15 and LLVA. And now you're looking at anatomical data showing preservation of photoreceptors and slowing against the loss of RPEs right in the central macula of the eye. So we're really encouraged by this program. We're looking forward to moving into a Phase 3 study shortly.
Yeah, so on the point of lesion size, I think that was an area of focus. Because at the time of your top-line readout, it didn't appear that there was an effect, a meaningful effect, on slowing down the rate of those lesion growths. Whereas the C3 and the C5s, they did not show an impact on VA. But they did on lesion size. So is there a reason, theoretically, mechanistically, why that impact on lesion size would be delayed with C1q?
Yeah, absolutely. So targeting RPEs are downstream from photoreceptors. It's, in effect, a lagging indicator for what is going on in the eye. And so what the downstream approaches are doing, primarily through the alternative cascade, is they are protecting against the loss of RPEs. That happens after you've lost photoreceptors and photoreceptor synapses, or i.e., your vision. So it really is a lagging indicator. Whereas by targeting C1q, as I said before, we're targeting really the hot spot for the disease. We're targeting photoreceptor loss and photoreceptor synapse loss, which results in vision loss. By protecting the photoreceptors, what we're seeing is, over time, we're protecting the entire unit of the eye. And what we're seeing is a greater impact on RPEs over time.
When you look at our data set, the second six months of the study, we have a much more, more than twofold better improvement in slowing lesion growth in the second half of the study. It takes longer because our mechanism is starting with photoreceptors and working downward to RPEs. So we're starting with vision. Whereas the other approaches are starting downstream, focused on RPEs, but unfortunately have not shown the ability to move upstream. Because when you look at where RPEs are lost in the eye, you've already lost your photoreceptors and the synapses. And so that's a bit of a challenge for these other approaches.
OK. So you gave a clear reason on why you feel confident about your mechanism vs what's already out there. You're going to start your phase three. Can you just talk to us? You've gotten, I think, the most robust trial design that we've seen to date. You're looking at VA benefit as your primary endpoint. And you're doing an active control vs Syfovre. How much of this is based on confidence that you, as a company, have of your product vs some of the changes that, I guess, the ophthalmology division within FDA has decided to take in the GA space, just given that they now have these two approved drugs?
Yeah, really good question. It's both. So we're running two Phase 3 programs. One is a sham-controlled study. So you mimic an injection into the eye. This is a large global study. It'll be in the U.S. and Europe. And we're really excited about that. That, in effect, is the most close replication of what we did with our proof of concept study. So really, pretty much on all fours, what we did, we're just going to do it again in our Phase 3 program. And we'll be looking to get approval in Europe and potentially in the U.S. as well. In the U.S., they have also asked us to do an injection-controlled study. So there, we did an assessment of all the differing ways in which you could do an injection-controlled study. And this will get to kind of your question with regard to confidence.
We looked at potentially doing an injection with saline. We looked at potentially doing an injection with low-dose ANX007, our drug. Ultimately, we decided to do an injection-controlled study against Syfovre. The rationale is, one, it does check the box for the FDA to do an injection-controlled with another type of drug or saline. We chose Syfovre. It checks that box. Two, it is the market leader. We have a really good understanding of what the visual acuity has been demonstrated with regard to those studies. They've studied 1,200 or more patients, foveal and non-foveal. We know a lot about that drug and how it operates. If we're going to go into that space with visual acuity, we thought it would be good to go after what is currently the market leader.
Yeah, so on that point, it's a big debate between the differences between IZERVAY and SYFOVRE. So you've picked SYFOVRE. Do you think there's a difference between the two? If you had picked IZERVAY, do you think that the chances of success for your study would be different?
No, I think we probably wouldn't there too. But we know less about Izervay. So Izervay only studied non-foveal patients. In our study, we're looking to treat as many GA patients as possible. So we're studying foveal and non-foveal patients. And so we knew more about the Syfovre population because they studied foveal and non-foveal patients. Izervay is a little bit of an unknown with regard to that. I do think well, I won't get into my thoughts on with regard to the drugs.
OK. Now, in terms of your adjustable patient population eligible for this study, what's the entry criteria?
Yeah, very much similar to what we did with our Phase 2 proof of concept study. So we are taking patients who have a demonstrated impact of loss of vision, visual acuity. I won't give the specific numbers. We've put a lot of time into enriching our Phase 3 study in terms of kind of the cutoff for patients we'll take with BCVA vision loss upon entry into the study, among other characteristics. But I think the short answer is very much mimics our proof of concept study with some enhancements to ensure we're getting patients who we know can have a sufficient number of BCVA letter loss events over the course of the study.
Have you talked about the powering of the study and what level of VA benefit's going to be needed to be stat-sig?
Yeah, well, we haven't said what level of VA benefit's to be stat-sig. But we do need to be stat-sig. And so that is not a trivial thing. There's been roughly 30 GA Phase 2 and Phase 3 studies in this space looking at everything from the anatomical endpoints. All of them include BCVA-15, the endpoint we're going for. And no one has moved that. So our ability to demonstrate that in our proof of concept study is not trivial. It's just you can't really luck your way into this endpoint. It results in three lines of vision loss, this BCVA-15 letter, which is losing 50% of your vision in a year-year period of time. You have to legally turn in your driver's license. So it's a really high bar. Statistical significance on that endpoint is clinically meaningful.
That's really what our aim is for the Phase 3 study.
OK. So based on where you think you'll start to enroll, how long do you expect that enrollment to take?
Yeah, 12 months. We expect 12 months between the U.S. and Europe.
It's a big population. So I think some folks were wondering whether having the competition from these other drugs would deter patients from wanting to enter a clinical trial.
Well, you know patients ultimately care about vision and function. These are elderly folks who don't have the ability to drive themselves anymore, who don't have the ability to read in the way they used to, or even recognize loved ones. And so when you talk about the requirement of having to come in to get a poke in the eye every month or every other month, you are looking to preserve function and vision so that you can maintain your activities of daily living. The work we've done with the patient groups and individual patients, as well as the health care community, really makes clear there is strong demand for a drug that can preserve vision, allow patients to live their best lives still, at a more vulnerable state in their life. So we don't anticipate much of any concerns with regard to recruiting the study.
OK, very good. In the minutes that we have left, I did want to touch upon an area that's become exciting, both for you and other companies, focus on C1s as a target. Can you just talk about the nuancing of C1s vs C1q?
Yeah, absolutely. So C1s is just part of the C1 family. When you look at the classical pathway, C1q is the initiator of it. But part of that family is C1s and C1r. These are serine proteases, which allow us to target for a small molecule approach. So we like C1q. And all of our antibodies are targeting C1q. But you can't drug it from a small molecule approach. So we went to C1s, which is just right downstream of C1q.
So does that open up so you're formulating an oral. Does that open up indications that were not under consideration before?
Yeah, absolutely. I think so. So our oral is targeting antibody-mediated autoimmune diseases, so a host of autoimmune diseases. We're already in that space with, for example, Guillain-Barré syndrome is one of those diseases. But it's hospital-based. It's an IV. You can treat that with an infusion. The oral allows us to go much broader. So it allows us to target a host of autoimmune conditions that are chronic and devastating, where patients have severe sequelae and how they go about living their lives. Providing them a pill, really from the comfort of their home, is a game changer. The other thing we like about it is that it's still upstream complement. So it's still upstream of C3 and C5. So it's still providing more complete protection against this inflammatory cascade than some of the downstream approaches.
It's kind of got two aspects of it that we really quite like.
Yeah, so large pharma, I think, put C1s on the map recently in terms of attention. As far as your program goes, when should we expect to see the next round of data come?
Yeah, we are initiating a proof of concept study shortly. We'll have proof of concept study with our oral drug in the second half of this year. We're doing that in cold agglutinin disease. With good data there, we will move into, hopefully, multiple autoimmune conditions where we can bring the small molecule oral to patients.
In terms of where you think the company gets most of its value now, so back when we took you public, it probably would have been a different answer than it is today. We've talked about a few programs. If you were asked, where do you think the valuation is mostly focused, what would those items be?
Yeah, I mean, candidly, I don't think we're getting value for anything. I mean, that's my honest answer. But I tell you where the value is. GA is the floor from a valuation perspective. It's a really large market. There are 8 million patients worldwide, 1.5 million or more in the U.S. And we've got what is undoubtedly the most comprehensive, powerful set of data in that space that completely aligns with our mechanism of action. So we love that. But we also really love GBS. GBS is a unique disease. We are absolutely looking to change the lives of these patients who are one day healthy. And the next day, they and their families' lives will never be the same. It's really, really devastating. And there's a lot of patients. And it's costing our health care system a lot of dollars.
And so we feel like we can very efficiently transition into a commercial stage company without a large footprint, really help a lot of people, and create a lot of value for those patients and for shareholders with GBS. And it's a gateway to other types of autoimmune conditions. Like what is kind of a cousin to GBS chronically is CIDP. We've been doing a ton of work on CIDP over the last nine years. That's something we would potentially like to take forward with our oral drug candidate, et cetera. So we think that GA is the floor. GBS is kind of the next opportunity. Or it's a really meaningful opportunity that's near term. And then the oral just has really kind of unlimited potential as it continues to advance as it has been.
OK. And maybe last question just on macro. The interest rate environment went from not clear to maybe we're going to have some rate cuts to not sure again. As a biotech company that's keenly aware of needing to make advances but needing to also manage expenses, is that in any way affecting the decisions you're making at the company?
Yeah, we certainly pay attention to it. Obviously, as money gets tighter, then we have to manage our company with that in mind. And that's one of the things we like about biotech. It's discovery, it's drug development, it's commercialization. But it's the macro market as well. And you have to factor all of those into. So it's certainly a consideration for us. And we have a multi-pronged strategy to always continue to capitalize our organization. Historically, we've used equity markets to do so. But as our programs have advanced and really have gotten to kind of valued inflection points, we are increasingly having discussions about potential for non-dilutive funding, partnerships, and the like to really leverage how we can bring this portfolio forward to as many patients as possible.
OK. With that, we're out of time. So thank you so much for joining us from San Francisco today. And thanks, everybody, for coming into the room and listening to the presentation.
Thank you.