All right, ready? Yeah, absolutely. Awesome. All right, everyone, we'll get to the next fireside here. My name is Derek Archilla. I'm one of the senior biotech analysts. Very excited to have Annexon. From the company, we got Doug Love, President and CEO. Doug, good to see you.
Good to see you as well, Derek. Thanks for having us.
I know you-
Happy to be here.
I know you just huffed in here because some bad, bad directions, clearly, by the bankers, probably. But well, a lot of exciting things going on in Annexon. Maybe be great to kind of get the overview, and then we can kind of dig into the Q&A.
Yeah, absolutely. Great time to be at Annexon. For those of you who don't know us, Annexon Biosciences, focused on classical complement, and we love it. We're having a great deal of fun, and it's a really great time to be at the company. So what we're doing at Annexon is we're targeting the most proximal target for immune inflammation in a host of different diseases across the body, brain, and eye. And the reason I start there is all of our programs are first in kind, in which we're pioneering, and after 10 years of the journey, we're really excited about where we are today. Firstly, starting with Guillain-Barré syndrome, the first and only program in the last 50 years in this space, we really have demonstrated landmark, unprecedented data in getting patients better in this debilitating disease.
By week one, 90% of patients get better, so we're really excited about that. Following that is our geographic atrophy program. It's a beast, if you will. It is the only vision-sparing program in the world. It's received PRIME designation, among other things, and we just recently completed a large phase III program, 650 patients, enrolled ahead of schedule, and we're excited to bring that study or data forward, and last but not least, the first and only small molecule approach in the classical complement space, targeting a host of neuromuscular and other antibody-mediated diseases. Really has the potential to disrupt a market that's already well-made with antibodies by bringing forward a more convenient pill form, so, Derek, I'm sure we're going to dive into all of these-
Yeah.
and I'm looking forward to that.
Awesome. Well, maybe let's start off with tanruprubart and GBS. You know, so, you know, on the quarter, you provided some, you know, kind of updates around, you know, kind of meeting with the FDA, actually, also with the EMA, right?
Correct.
So, sort of the regulatory bodies. Maybe just kind of give us a sense of, you know, how those discussions went, and I know there's kind of this addendum component to the, you know-
Yes
- the minutes, so maybe, you know, any additional color there in terms of when we could get an update, clarity on, you know, when you can file in the U.S?
Yeah, absolutely. So tanruprubart for Guillain-Barré syndrome, as we said before, first and only program in fifty years, and what's unique about this program, this is a program we had to conduct outside of the U.S. and Europe, because we were required to run a placebo-controlled study. The standard of care here, IVIG, is an unapproved drug that has never been studied in adequate and well-controlled studies. So it was thought to be scientifically unviable as a comparator, and so we took on the kind of Herculean task of running this placebo-controlled program, in Southeast Asia, and we've run multiple studies now, so we have a placebo-controlled proof of concept study, as well as the placebo-controlled phase III study. We've done a drug-drug interaction study with IVIG and a real-world evidence study comparing our drug versus IVIG in a mass patient population.
So it's a really robust package, particularly in the context of a rare orphan disease, rare and acute orphan disease. With regard to regulatory on the EU/EMA front, we've had significant progress there. We're really pleased by that. Maybe I'll just start as a backdrop that EU and EMA, in particular, understand and have been involved in this program differentially from other jurisdictions around the world. In Europe, we were able to secure orphan drug designation based on the proof of concept study. That's quite a high bar and different than what you see here in the States. Their IVIG is approved, and so what we had to distribute, to demonstrate, to get orphan drug designation in Europe is three things.
First, we had to demonstrate that the proof of concept study was adequately and well-controlled and sufficient for which a regulatory body can make a decision on that data set. Secondly, they had to review our first real-world evidence analysis that we did based on the phase proof of concept study, and determine that that was effectively done, that we were able to match patients from Southeast Asia to patients in the U.S. and Europe, and that the outcomes were consistent. And then thirdly, they had to determine that the comparison of our drug, tanruprubart, versus IVIG, was likely to be substantially better with our drug. EMA made all of those determinations in our favor and, in fact, wrote a twenty-page, single-spaced document. So it's with that backdrop by which they are reviewing now our phase III program as it's come through.
We did multiple country-specific meetings with regard to our phase III program, both with the phase III data as well as our phase III real-world evidence package. One of the countries that we met with was the Netherlands, really quite productive meeting with a written response from that meeting as well, and that person who led that meeting has now subsequently been named the Rapporteur for the program in Europe, and so we're really pleased that we're interacting with a really engaged regulatory body, has a deep understanding of GBS generally, as well as our program more specifically, and so we look forward to moving that forward along, and we anticipate filing for MAA approval by Q1 of 2026. In the U.S., similarly, we've had significant engagements with the regulators over the last 10 years.
I think we've had on the order of magnitude of 10 or 11 meetings over that period of time with the U.S., with really strong alignment on what's required for an approval here, which is, of course, both substantial evidence demonstrated in phase 3 program and a demonstration of generalizability. That is, again, the, the data or the patients in our phase III study are comparable to the U.S. and Europe.
We had a very productive meeting with the FDA on that, where they were highly engaged and informed and really partners with Annexon in those discussions. At the end of June, we got meeting minutes back, a month or so thereafter, and the meeting minutes read reasonably well. However, there is an additional addendum attached to the meeting minutes that relate to post-meeting comments that were made by the FDA in discussions that were had on our program without us present, so the sponsors were not there.
And there were some things raised in those meeting minutes as it relates to generalizability that we want to get a better handle on and make sure we understand before we communicate specifically where we are with regard to the FDA going forward. Some of the things I will note is that what was not raised was anything with regard to our phase III program or the real-world evidence analysis that we did ourselves. And so, exactly what they're looking for, if anything, we will get elucidated. Our timeline for doing that is in and around this fall in a Type C meeting, and then we'll update the market thereafter.
Okay, so now, so you do have a Type C meeting on the books, is that or-
We have submitted.
Submitted, okay.
We have not-
Okay.
Got a secure date yet?
Got it.
But we anticipate we will get one, because in the post-meeting minutes, they did ask for us to have a meeting with them, so.
Gotcha.
We anticipate that should go well.
Okay. I guess, so, I mean, if we get, you know, perhaps some clarity in the fall, I mean, I guess, how would you communicate that? Would that just be kind of a, the press release, or would you just-
It's a really good question.
Yeah.
Yeah, depending upon the nature of the meeting, the minutes and the alignment there, it could be anything from a management call to a press release or-
Okay
-something or another.
Gotcha. I mean, I guess you kind of told us what it isn't about, but I guess in terms of like, you know, you kind of are running this current, like, PK trial in the U.S. You know, some folks have kind of seen this as like, "Oh, are they kind of, like, hedging against something?" But I mean, I, you know, is that part of this in a respect, or is that still con... you know, more, mostly separate and more for, like, kind of informative marketing purposes-
Right
-as you guys have kind of stated in the past?
Really good question. So when we initiated the study, really important to note, we had not been requested to run the study, and we did that without kind of discussing or aligning with the FDA on. We did submit the protocol, of course, and did all the normal kind of boxing with bells and whistles and checked all the boxes with regard to that. The study really was set up to meet two principal requirements. One, for EMA, to meet the pediatric requirement there, you need to have an ongoing study in which we were able to enroll study patients who are pediatrics. So the studies that we run in our phase III, the patients, I believe, were sixteen and above. In this study, I believe they're five and above, so it really checks the box for pediatrics for Europe. So it was important from that perspective.
Two, and as important, candidly, particularly in the U.S., is that there are no consistent processes, protocols, or approaches for how to treat GBS in the U.S. Really, really important, and we've learned a lot about this just in the context of running this U.S. study we call the FORWARD study. So every hospital and every system handles GBS differently, and that's because there's been no approved drugs. There's been no sales reps, MSLs, managed care folk to go in and work with physicians or hospitals on how they are triaging and managing GBS patients. GBS patients show up everywhere. They can show up at urgent care. They can show up at the emergency room. They can show up at a larger tertiary center. How do you funnel them through the system varies hospital to hospital.
Being able to gain experience on how the patient journey actually happens in real life, really, really important for us, and working with these key centers on how to streamline that and do that in the most efficient, effective way. So that's the purpose for the FORWARD study, and it continues to be the purpose for the FORWARD study. The FDA has not required us to do that as of yet. Whether they do so or not is to be determined.
Gotcha. Like, is that trial, how has it been enrolling? And I guess, any, what's the status update, like, when?
Yeah.
You know, is that something that you'll produce data at, like, a medical meeting? Like, what's, what's-
Yeah, really good question. Yeah, so we've got sites up and running here in the U.S. We will soon have sites up and going in Europe as well. And what we will do is, it's an open-label study, as currently constructed, is we will compile cohorts of data where we feel like we can answer questions. Some of the key questions for me in the study is, one, just really demonstrating that the PK/PD that we see in our phase III study is replicated here in the U.S. We think that's a very low bar. This is an antibody, tanruprubart, that's been dosed in the U.S. for multiple other diseases, and in any event, antibodies translate very well region to region. There's a high 90%+ translatability effect.
The other, which I think is really important from a commercialization perspective, is to demonstrate really rapid benefit on GBS patients treated with tanruprubart in the U.S., similar to what we saw in our Bangladesh and Philippines study. And the reason why I say that is 90% of patients treated with our drug in our phase III study got better by week one. That is a strikingly significant number. We know that with IVIG, patients are still declining at week one, and why week one is so important is healthcare professionals are making decisions about what patients are going to go to ICU, be on ventilation, stay on ventilation, or be, perhaps, transferred to skilled nursing facility, et cetera, so real-life treatment decisions are made at that point in time.
Secondly, week one is the most prognostic factor for outcomes for GBS patients when you look out to six months. So how you do early in this disease in terms of protecting peripheral nerve damage is everything to how you fully recover. So being able to replicate that here in the United States and being able to educate on that in concert with really developing robust, consistent protocols and systems for managing GBS here is really important. When you think about stroke, for example, everyone knows how to handle stroke now. It's an acute disease, it's debilitating. All hospitals handle it very similarly. We need to get that in place for GBS, so we can make sure we can bring our best to these patients here.
I mean, are you surprised by, like, how, you know, the different regulatory bodies have looked at this? I mean, obviously, you know, it's surprising to me, I guess, like, that the EU, they have IVIG. I would think they'd be like: "Uh, you know what? Like, you know..." But I'm not saying that that's what the FDA is doing, but are you a little surprised on how this all kind of played out a little bit?
It's a fair question. Yeah, I mean, we certainly thought it would be smoother sailing, but on the one hand, on the other hand, from day one, we knew that this was a case of first impression for everyone, not just regulators, but certainly for investors and everyone else we've been interacting with for ten years. Because GBS is a disease that's never been studied. No one had done any research on it. In fact, there are no institutions in the U.S. currently studying GBS, whereas in Europe, there are several institutions studying GBS. So there's just a different knowledge base, and so we've always kind of thought about that a little bit. So that's one. Two, we just always knew that. We've not, and nor has anyone, run a ton of studies in Southeast Asia.
So there's a bit of the unknown there that you just know you have to navigate through, but that's who we are. Like, our core value is built in and around warrior spirit. We knew we were pioneering when we ran that proof of concept study, and we learned that patients were getting out of bed by day two or three for a disease that otherwise robs people of their lives. We're just fully committed to bringing it forward. Like, it's something that serves our mission, and then we think, you know, it happens to be that it's a really significant commercial opportunity, which I'm sure we'll touch on as well.
Yeah, I was gonna say, like, I guess, you know, as we think about the opportunities here, you know, EU seems like it's come up first. I mean, I know you've talked about monetizing potentially the ex U.S. rights to, to GBS-
Yeah
or potentially even the whole program. So where do you kind of stand on that? And obviously, you know, with the caveat that you need to clarify some stuff with the U.S. regulatory agencies.
Right.
But again, you know, where are you kind of landing on what you want to do with this program?
Absolutely the right question. Yeah, so we're fully intentional about not commercializing ex-U.S. And in fact, maybe I said that in a negative way. The more productive or positive way to say that is, we're fully intentional about putting this in the hands of people who already have a hospital-based neuro business and the wherewithal and understanding on how to do this in multiple countries across Europe and beyond that. And we're really excited about that. We've been involved in multiple ongoing discussions. There are quite a few players around the hoop who have a real track record at hospital-based businesses in Europe, which is a different commercialization animal than what we deal with here in the U.S.
It would take Annexon's eye off the ball a little bit if we decided we were gonna go out and try and commercialize this in Europe on our own, and so we are looking to monetize that. We feel like we've got really good traction on that, and we look forward to what's ahead with regard to that. In the U.S., it's a different beast. In the U.S., it's a highly concentrated market. 175 hospitals control 60% of GBS patients year- over- year because it's an incidence-based disease. In fact, 26 hospitals account for 20% of the patients year- over- year. With a very concentrated commercial footprint, you can go in and get after this.
And what's really key is that you do some level of education and really making sure you iron out the processes and the patient flow with hospitals here in the U.S. is one aspect of that. And we're underway with regard to that, predominantly in the media, print media, print media-type activities. We're sending information out electronically to folks who've opted in for that, and it's thousands of physicians already. Really pleased with the way that's jumped off. Secondly, is it's just making sure your drug is available, and that's a formulary thing. And what's really most important about this, we get a lot of questions on commercialization in the U.S. in the context of a hospital-based business.
Yeah.
It's not how we think about it. We think about this much more akin to a CAR T-type business, where the predominant payer for GBS is currently commercial payers. About two-thirds of GBS patients have commercial insurance, and so that's what allows you to really be able to get the pricing and reimbursement that you would like, and it makes sense for the payers. We bring a value proposition. We're getting you out of the hospital sooner, out of ICU, out of the ventilator, less skilled nursing facility. Commercial payers pay for all of that, as well as lost time and wages from work, whereas the hospital is only really just kind of paying for the drug costs and in and around kind of the hospital-related costs.
And so, being able to work predominantly with the payers really makes us attract commercial payers and attract commercial footprint. So, we're really active on that as well. So, as we sit here today, we're thinking we're gonna commercialize this in the U.S. We've got a good team up and running, doing a very nice job with regard to that. We'll see how that plays out.
I guess, how do you think about the overall market opportunity, both in the U.S. and EU? I guess if we're trying to like, you know, shoehorn, like, what type of deal economics you could get in the EU-
Yeah.
What's that opportunity look like for that as well?
Yeah. No, it's a great question. So 15,000 patients a year in the EU, year- over- year, very, very consistent. Mid- to high 90% of those patients currently get treated with IVIG. So again, working with a partner, it's making sure that the drug is available and used, usable for patients there at all of these hospitals. The drug has a four-year shelf life, so you can put the drug on the shelf, and patient and physician or hospitals can pull it off. When they use it, they could do that through buy-and- bill, or they can do it on consignment, or we can do drop shipment through some of the large carriers, like a McKesson or Cardinal Health. And so we think with that opportunity, plus with the value-based proposition, we will be releasing our health economics analysis later this year. Dynamite.
More patients than what people think, and the cost to the healthcare system is more than what people think. The last time this was done was twenty years ago, and it was academic work. We are doing this in a commercial way, where we're going deep, and we're really excited to show that there is a real commercial opportunity. And I guess the last thing I would say is that as we're having discussions with potential partners on the EU side, they're valuing it similarly to where we are. Still some negotiations to be done there, but we feel like that's gonna be an accretive deal for us.
Interesting. Is that something that's, like, very near term, or, like, how are you-
I don't want to put a timeline on it-
Yeah
- because these things can be tricky.
Okay.
But we're working on it.
Okay.
It certainly has our attention.
Gotcha. So it's definitely, front and center. Got it. Anything else on GBS that we didn't touch on before we-
I think we've covered it. Look, we're excited about the program. We think from our perspective, from a regulatory perspective.
Yeah
In the U.S. and Europe, but U.S. more specifically, it's a question of when and not if. So the data is robust. We've got the most robust package you could hope to have for a rare disease, as I said before, two placebo-controlled studies, drug-drug interaction study, real-world evidence, and now we have some additional data coming in from the U.S. on that. And the drug is super safe. I mean, when you look at our safety profile, it looks very much similar to placebo. So a benefit-risk analysis checks all the boxes on that. We want to make sure, of course, that our partners, the FDA, are comfortable with the generalizability analysis, and then get this drug out to patients to benefit as soon as possible.
Got it. Maybe, you know, we can shift to GA.
Okay, sure.
You know, a couple of years ago, it's like, okay, yeah, we got this data coming along in, like, 2026. So, like, here we are. We're on the cusp now, probably within a year, hopefully. So maybe just refresh us on, you know, the excitement around this program. Obviously, you're the phase II, you know, some folks think mixed, but you also were the only drug to ever show a, an improvement on BCVA, so that, that's highly relevant and important. So, how should we kind of start teeing up-
Yeah.
You know, how we should think about the phase III?
Absolutely. Listen, we love the GA program. Like, it's the thing I would say about GA, maybe just taking a step back. GA is the thesis of Annexon. Annexon was founded on the neurodegenerative mechanism of action of C1q and targeting upstream classical complement in the eye by the late Dr. Ben Barres, chair of neurobiology at Stanford. That is who we are, what the company... So this is our flagship program in the neurodegenerative space, and for anyone who thinks the phase 2 data are mixed, they just should dive a little deeper back into the data and GA itself. I recognize that people have said that because they're focused on lesion growth. I'm here to tell you that lesion growth is irrelevant to visual outcomes. Not me saying that, it's the data.
You have two approved drugs out there, two, three, four years' worth of data, no association with vision. You're not gonna see it preclinically or anywhere else. You have regulatory bodies like Europe, who've looked at it and said, "No scientific relevance for vision." And in our phase III study, the FDA has not required us to study lesion growth as a measurement in the study. So it's important that people understand our data in that context. What have we shown? In our phase II proof of concept ARCHER study, two hundred and seventy patients, sham controlled, we showed two really important pieces of data. On vision, using BCVA fifteen letter loss, which represents 50% of your vision loss in a one-year period of time, you have to turn in your driver's license. You lose your independence. You cannot see.
We showed statistically significant preservation against the loss of vision at 12 months and over time, which is really important, on what is the gold standard endpoint for visual acuity. It's used for wet AMD, diabetic retinopathy, retinitis pigmentosa, et cetera. This is the gold standard for vision. We also showed it on its sister indication, which is low light visual acuity, which is assessing visual acuity in low light conditions. Rarely do we have perfect light, statistically significant. Statistically significant, whether we looked in foveal patients, non-foveal patients. When we look at patients earlier in the disease process, 0 out of 56 patients lost vision, versus 17% with sham. Why is that really important? If you are looking at a neuroprotective, neurodegenerative disease, you should always do better in an earlier treatment patient population.
The more damage you have to your neurons or depth to your neurons, the worse off you are in neurodegeneration. So by treating earlier, you should have a better effect. We see that in a pronounced way. It's been recognized by the regulatory bodies on both sides of the pond, if you will. We're really excited about the comprehensive nature of what we see on the functional side. Turning to the structural side, the key assessment for structure as it relates to vision in geographic atrophy, and frankly, all neurodegenerative eye disease, is damage to your neurons in the eye. In geographic atrophy, those are photoreceptors. We are the only company to show significant preservation of photoreceptors in the central retina of the eye.
I focus on the central retina versus the pan macula, where some companies have produced data showing impact on photoreceptors in the pan macula. It's only the central retina where vision is housed, and you have an impact on visual acuity. Our protection there is in the neighborhood of 50%-60%. Imagine that. We are preserving the function of neurons in the neighborhood of 50%-60% versus the drugs that have been approved for RPE lesion preservation at, what, 14%-17% on something that doesn't relate to vision. So when I hear people say the phase II data are mixed, we're saying, "Go back and study geographic atrophy and see where the field has progressed over the last eighteen months." 'Cause everyone's focused now on RPE and photoreceptor preservation.
It's those two data sets combined, that when we went out with our phase III study, which is very closely designed to replicate what in the phase II did, 659 patients enrolled. We enrolled that study, the fastest enrolling phase III study we're aware of in geographic atrophy. We enrolled it two months ahead of schedule, and more than 30 patients over enrolled. And so the physician population, who understand the disease in a very sharp way, have really globbed on to this program, and we're excited about it. It's been really fantastic in the U.S. and Europe. Of course, we're watching it very, very closely. And the last thing I guess I'll say, and I said it before, is that we ran this study to really closely mirror or replicate what we did in the ARCHER study. We made very few changes.
One change that we did make, I'll just call out quickly, is we did enrich the patient population based on your baseline vision or BCVA levels. What we observed in our study, and then looking at Lampalizumab, which is the world's largest phase III program, run by Roche, as well as the Syfovre and other datasets, is that patients who are too far gone in the neurodegenerative disease process, you really can't save their vision or preserve their vision. It's just they've lost too much, and you can think about this in Alzheimer's or other neurodegenerative diseases. Patients who have progressed too far, you can't help. So we've really honed in the sweet spot on patients who will lose vision over the course of the study, but in a manner in which we can stop that and show a delta.
So it's really, really important for us to be able to do that, and so that's how we've constructed the phase III study.
What's that entail in terms of the enrollment criteria? What specifically is-
Just really a cutoff on your BCVA-
BCVA.
Yes, baseline, baseline levels, which we have not shared publicly. We think it's proprietary.
You know, we're one of the only companies who could do this type of work because we were able to demonstrate vision in our proof of concept study. If you don't have a database to be able to do that, that's difficult to do. So we were able to do that, so we've kind of held that a little closer to the vest.
So I don't know how much this is really gonna matter, but, I mean, obviously, we get questions like, "Oh, well, how did they show, you know, a slowing, you know, of, or, you know, basically a benefit on BCVA preservation, but they still showed, they didn't show any, like, signal on lesions?
Yeah.
Right? Although you already just said, like, you know, the regulators aren't even that-
Lesions-
... It's not even. It doesn't matter in your trial, but, like, I guess, like, I can explain. So let me ask about that.
Yeah, yeah, yeah, I can absolutely say. So the way lesion growth or RPEs, which is when you lose your RPE cells. RPE cells provide trophic support underneath your photoreceptors. Photoreceptors are where light comes in, and that's where you have vision. When you lose RPEs, the thought was, the hypothesis was, if you lose your RPE cells, you're gonna have damage or loss to your photoreceptors, and that's gonna impact your vision. What the key step that was left out of it is, is that you actually lose photoreceptors before you lose RPE cells. So RPE loss is a lagging indicator. It doesn't. Once you've lost, once you've lost RPE cells, you've already lost your photoreceptor synapses and your photoreceptors. So it doesn't matter really what. I shouldn't say it doesn't matter.
I mean, of course, you want to keep all of the structure in your eyes, so I don't want to kind of bemoan that, but it doesn't translate to vision, and so that's the answer, is that. So that's one. Two, by protecting photoreceptor integrity, you will protect RPE integrity over time. So when you look at our data, if you break it up into six-month intervals, in the first six months, very limited impact on RPEs and slowing of lesion growth. In the second six months, we double that.
So we double the rate of RPE preservation and slowing the lesion growth, which, what does that tell you? Go out to eighteen months, go out to twenty-four months, you're gonna be probably be stat sig in showing preservation of RPE. And by the way, that's not too dissimilar to what we saw in the phase III Syfovre study. You remember the DERBY study. At twelve months, they weren't stat sig at twelve months in RPE preservation. They had to go out to eighteen months to get there.
Right.
Right? So it takes a little bit longer. We're coming top down, preserving photoreceptors and then RPE. The downstream complement approaches are going bottom up. They're preserving RPEs, but unfortunately, by the time you do that, you've already lost your photoreceptors. So that's the distinction between the two approaches.
Understood. I guess, and going back to some of your comments about the agencies, I mean, it sounds like, again, at least, you know, with PRIME designation in Europe, which is, you know, you know, you're alone in that. No one else has gotten that. But I guess, you know, how is the FDA looking at, you know, basically your endpoint versus the others? And obviously, this would, you know, probably result in a different differentiated label, right?
Yeah, absolutely.
So like, I guess, yeah, put that all together for us.
Yeah, so the label on it would be, in the U.S. and Europe, would be the preservation of vision for the treatment of dry AMD that causes GA, and FDA's been fantastic. Ophtho division, really strongly intact, really super collaborative. We just had a face-to-face meeting with them recently. Really completely signed off on the phase III program, the design of the program, the analyses in the program, and BCVA fifteen letter loss is the gold standard for the FDA. So had we come in with another vision endpoint, we would have had an issue.
Yeah.
There was no discussion at all. It was just, "We agree with your endpoint." So it's all completely reconciled on both, in both jurisdictions, which we really like, and so, you know, replicating this data gives us an opportunity for the first global approval for GA, for the preservation of vision, which we think is just a complete game changer for these eight million patients affected around the world.
Gotcha, and so you've highlighted data in the second half of 2026 . Any, like, you know, early, late? Like, what do you figure?
Still too early for us to say, and-
Will you give updated guidance, like, the beginning of the year?
We may, and I'll tell you why. What we're looking at is events of BCVA 15-letter loss in a blinded fashion, so we're not obviously unblinding the study. But you know you want to have a certain level, number of BCVA vision loss events, 15-letter loss of vision events over the course of the study. For us, it needs to be on two consecutive visits. We know all that. But once we hit that threshold number, we'll have a good sense of where we are with regard to things from a timing perspective. So it's still too early for us to say that. That's something that's naturally monitored as part of your safety monitoring board, which, by the way, is going really well for us at this stage.
Wow.
Good. So, yeah.
Got it. Okay. Maybe last up, you know, 1502 .
What did I get?
Oral C1s. So, you know, you guys have been developing this for quite a bit. It's gone, it seems like, an iterative process. Maybe just kind of-
Absolutely.
Walk us through where you are today with that program. I know you've highlighted data by the end of the year. You know, what should we be expecting?
Yeah, really good question. So I'll just say at the outset, I know folks have probably been a little frustrated with this program. This is not a program for the faint of heart. As I said at the outset, we are only focused on first-in-kind innovation, game-changing programs. GBS is game-changing. GA is game-changing. Fifteen oh two is gonna be game-changing. So this is an early-stage translational program, and I think it's important for people to understand that we didn't really go out and tout this disease. People picked it up in various forms and started asking us about it, so we've been responsive to it, but we're learning how to bring forward the first-ever small molecule in the classical complement space.
And it's important that people think that through because you would think when you look at industries or diseases like MS or RA, et cetera, they start antibody, and they move to small molecule, you know, in the market. We thought that eight, nine years ago when we started the small molecule approach, and it's a little bit curious because you would think some of those who have big, large antibody, multi-billion-dollar franchises, they went from IV to subQ. They didn't go to small molecule. So we have an opportunity to really jump in a really strong position in this with data. So what have we learned? We've learned something every step of the way.
We started with crystallography, preclinical approach, did CH 50 and everything there to really elucidate what are the target drug levels we need to show that our small molecule are comparable to the antibody that are already in the clinic or have been approved targeting C1s, so we had a really good barometer on how to do that, and we had our own C1s antibody, so we were able to compare all of these head-to-head. That set our target levels for the clinic. We started with the liquid suspension. We were able to achieve those target levels with the liquid suspension, then quickly moved to a film-coated tablet. Worked very, very well from a PK perspective. Also saw some nice hints on PD, which was unusual, and patients who had any elevation in complement, we were able to knock it down, but I'm sorry, these are not patients.
These are healthy volunteers, so they have generally low levels of complement or normal complement, but if they had any elevation of complement, we knocked it right down, so it gave us some hints of PD. We were really encouraged by the film coating. We did see some tolerability in that, saw some nausea, a little bit of emesis in that program, and so our thought was, we needed to get the drug past the gut and to release into the intestine, into the intestine, so that we could see its effect without having nausea, so we developed an enteric coating. Now, each one of these steps are learnings, first in kind. Every time we learned something new, people said, "You guys are delaying the program." We're like: We're doing drug development. We're not cutting corners. Sorry.
Like, we can't be a slave to a timeline on something that's never been done before. I just think people should understand that. We're not gonna listen to that. So in any event, we did the enteric-coated. It worked beautifully. We did it first in healthy volunteers, matched what we saw on the film-coated from a PK perspective. Tolerability immediately improved, so we were like, hip, hip, hooray, we're rolling. We're now in a phase II proof of concept study in patients, first ever, with elevated complement, and they're taking food. And what we've seen is a few things. One is, very pleased with the PK. In fact, the target exposures in these patients who are fasted, that is, without food, are well exceeding what we were hoping to see. So we're really excited by that. This is BID, twice a day dosing.
However, in that same patient, if they eat food, the food, the drug gets washed out in the gut. So the gut needs an acidic environment for the enteric-coated to go through. If they eat food, the acid goes with food and washes out the drug, so you have no tolerability. So when, and each patient pretty much serves as their control with BID dosing, we see consistently in all of the patients, without food, exposure levels well above target, with food, not. So what are we now doing? And it took us a few patients to understand what was going on, because notwithstanding that, we were still seeing very nice trends on bilirubin reduction.
Mm-hmm.
We were still seeing an effect. We thought it could be bigger, and so we really dove into this, and we saw the different exposures depending upon whether you ate or didn't eat. And so what we're doing in this next set of patients, just a handful of patients, to confirm what we've seen is they'll be fasted at both doses. And the fasting that we're talking about is, you need to be without food an hour or so before you eat, an hour or so after you eat. So it's not an all-day fast or anything. So in the morning, what we're saying to people is, "Take your medicine when you get up, when you wake up. Eat your breakfast an hour later.
In the evening, have your meal, take your pill before you go to bed, an hour or so after you've eaten or later." Right? And so it's that type of, kind of fasting scenario. And once we have that data, we feel like we'll have an answer, yes, no, or, and, and go from there. I will tell you, it's a high bar for us to move this forward into the next time. We've got a lot of programs, and we're seeing a real consistency in this mechanism. And so to move it forward, it's got to pay for itself.
It's got to meet that bar that both doses are clean, it meets our tolerability levels, obviously, and it meets our drug exposure levels, to really demonstrate that the potency is equivalent, if not better, to the antibodies, and we'll move that forward from there. That's where we are. It's been a journey. We're having some fun with it. I mean, you know, if you're not whistling while you work, what are you doing?
Gotcha. I mean, how, like, intently are you watching, like, again, the Dianthus data and some of these other C1s, you know, molecules?
Yeah.
You know, and ultimately, like, where would you want to even take 1502 , you know, presuming that the data look-
Yeah, we're watching it really closely, and we think... You know, we're pulling for those guys. We pull for everyone, candidly. I think that it should work, but I would expect that C1s should work in MG for these guys and their other diseases. I think the question for Dianthus and some of these others is not the science or clinical, it's the commercial.
Mm-hmm.
How do you differentiate commercially against the big boys who are well-entrenched with billion-dollar franchises and are not gonna roll over very easily?
Yeah.
You know, versus if you think about MG, for example, patients come in with MG, they all get cholinesterase inhibitors. These are orals. They're trained on orals.
Yeah.
It's once they break through, they then move to these IVs or sub- Qs. We want to bring you right back to an oral. We think it's a real differentiator. And because it's an oral molecule, we can titrate dosing, we can do differing things. We think the penetration in the tissue will be greater, et cetera. There's a potential for it to even have better efficacy, but at a minimum, we know it's gonna be meaningfully different from a convenience perspective. And these are diseases of severe neuromuscular impact. I mean, these patients are not in great shape and have to kind of schedule their life around going to get an IV or doing, you know, this needle phobia circumstance and overcoming that is not trivial, particularly given that these patients were trained on orals.
Yeah.
So we really like the opportunity for this drug, but we got to prove it out.
Yep.
And so we're just gonna walk it down, and hopefully, Macula will be able to, you know, present data by the end of the year and move on from there.
Sounds good. Well, Doug, we'll leave it there. Thank you so much.
Thank you, Derek.
All right. Appreciate it.