All right, everybody, good afternoon. Welcome. We've got VOR Management with Jean-Paul and Jeremy with us.
Jean-Paul.
Jean-Paul, I'm sorry.
Yes.
And Jeremy here with us. Thank you so much for joining us this afternoon. Before we jump into the detailed questions here, maybe I'll give you a moment to introduce the new VOR and where you stand currently.
Thank you very much, and hello everyone. Glad to be here. So at VOR, we in-licensed telitacicept, a BAFF/APRIL inhibitor last June, coming from our partner RemeGen, based on the promise of a blockbuster in autoimmune diseases. The compelling reasons around this in-licensing deal for worldwide rights and all indications were mainly on the modality of APRIL inhibition, which we believe has an incredible potential to address a suite of autoimmune diseases. And we've selected MG and Sjögren's for our first opportunities here, which we believe are very sizable. Number two, RemeGen had generated a wealth of data, late-stage data, phase 3 in five indications, including MG and Sjögren's but others as well, investigating more than 2,000 or 3,000 patients. And the product has been administered to tens of thousands of patients, which gives us a great proof of concept, but also a de-risking on this asset.
Very high-quality data coming from China, which also guided us in our indication selection for this blockbuster pipeline in the product asset, and last but not least, we were able to assemble the capital and the human resources around this opportunity very quickly, in less than six months. We have a full team now executing on the program that we have fully transferred to the company, and we believe that in the midterm, we'll be able to generate tremendous value with this asset.
Exciting to get into the details here. As you say, MG and Sjögren's are the leaders here. So maybe let's start with RemeGen's recent data in MG, which looked very strong but had some interesting facts, interesting signals in the data there. So maybe you can just remind us what the headline was from RemeGen's outcome and how we should interpret some of the difference between BAFF/APRIL data and other depleters in this space.
Great question. Jeremy.
Sure, sure. So obviously, the data from China was really impressive. There was an MG-ADL delta change versus placebo of roughly four. This is roughly twice what's been seen with many of the other mechanisms in the MG space. There was a notably very low placebo rate. We attribute that partially to the nature of the Chinese population. The QMG data, which is the objective physician-measured motor data, was more similar to the global population, but similarly impressive with an effect size substantially larger than has been seen in other mechanisms. So we're fairly confident that we have a drug that has good efficacy. We think the China population provides, at the very least, proof of concept, and we're looking forward to duplicating that data, replicating that data in a global population. Now, you mentioned a notably low placebo response rate.
Certainly, that's part of the contribution to your very strong placebo-adjusted response rate. So what are the specific drivers of placebo response? Why is it so different in China? And what do you expect when we think about Western trials? Yeah.
So again, it's hard to put a finger on one thing. I think one of the things in China is the fact that patients don't try to tell their physician what they think they want to hear with regard to their improvement. There's a little bit less, appears to be a little bit less in the way of patients saying they feel better in an effort to stay on the study. And we find that when you go to a more global population in other diseases, not specifically MG, patients feel like they might want to give the answer that makes their physician happy and keeps, "I want to study drug in the absence of other available therapies." So we think that when we go to a global population, we will likely see some degree of creep in the placebo rate.
We think that hopefully that creep will proportionately move up in both the placebo and active arms, maintaining our delta. Should the delta narrow slightly, we're comfortable that we still have the potential for best-in-disease efficacy, even if we see a significant narrowing.
Right. We have plenty of room with the current delta right now, which allows us for some adjustment with a global trial, which we can expect the placebo to really be up. And what I'd like to add is that if you talk about MG, MG is actually a larger opportunity than some people might think because the market is growing. It's forecasted to be a $10 billion market in 2030 with a lot of unmet medical needs. We're at a phase now that the products on the market have shown some limitation that the KOLs and the treaters want to see being addressed. And mostly on the upstream, we can talk about the modality as being very compelling to address that because the ask now is for medicines to be more durable, and this is modifying.
So we think we can provide that based on the data generated by RemeGen, and we'll aim at replicating this quality and magnitude of data. And that will allow us to be very competitive in a market which is growing where there is an unmet need. And we think we can achieve blockbuster status in this indication only.
So since you bring up the difference in the mechanism, let's dive in a little bit there. Drop in IgG isn't as fast as it is for FcRns, perhaps expectedly, but.
But it's still fast.
But it's still fast. But you say it's not a problem, obviously, here, and you're focused on the disease-modifying nature of the drug. So can you talk to us a little bit about how we should interpret the slope, both in MG and in Sjögren's, but how we should interpret the mechanism when we think about comparisons to competitive agents with different mechanisms?
Yeah. So obviously, BAFF/APRIL inhibits BAFF and APRIL. The APRIL side of things is inhibiting antibody-producing cells, plasma blasts, and early plasma cells. So we do see a reduction in immunoglobulin. But the BAFF side of things is also modulating that upstream B-cell activation process. And what we know is that autoreactive B cells are very sensitive to BAFF. They need it for survival. So as you starve the system of BAFF, you get a relative selective depletion of autoreactive B cells. So we're seeing two different steps here. One is the modulation of antibody-producing cells through APRIL and the inability to replenish those autoreactive antibody-producing cells through inhibition of BAFF. And it's by covering that spectrum of the B-cell maturation pathway that we think we see this broader efficacy. You bring up the reduction.
I think that the speed that you see is logical because unlike an FcRn where you immediately take out the end product of IgG, in our case, you have to starve out the B-cell that's producing the autoreactive antibody to get that reduction in immunoglobulin. I think, as you point out, FcRns only decrease IgG. The recent data showing a prevalence, one-fifth to one-third of patients with MG have anti-IgM or IgA anti-acetylcholine receptor antibodies fits well into the mechanistic hypothesis that part of the nonresponse to FcRn might be those people who have those autoantibodies. And we see 60%-70% reduction in total IgM and IgA. And we think that that's only a subset. We think that we are even deeper in depleting the autoreactive IgA and IgM.
Now, I'm familiar with the data that shows residual IgM and IgA autoreactive antibodies, but I'm less familiar with data that links that directly with lack of response to FcRns. Is there preclinical data that points that arrow pretty directly, or is it just a reasonable supposition?
So the only preclinical data that's been generated so far is data showing that these IgA and IgM anti-acetylcholine receptor antibodies in a cellular system fix complement very efficiently. There hasn't yet been a study looking at using the presence of those autoantibodies to predict nonresponse to FcRn. I think as more and more patients are treated with FcRns, registries evolve, and we have the ability to test those, we'll be able to test that question more directly.
Yeah. Very reasonable supposition. I look forward to seeing those sorts of tests done. Let's keep going about MG and the competitive landscape here because we moved away from kinetics a little bit. It makes sense the way you talk about the slope. But I'm also curious about the long-term durability of BAFF/APRIL-driven disease control relative to the other mechanisms. How do you think about beyond the primary analysis period and what control looks like in the longer term?
Yeah, I think that's one of the most impressive things we saw recently, the 48-week data. So most studies are 24 weeks and declare victory register. The 48-week data was really shocking in that there was a continued improvement in MG-ADL lowering and QMG lowering during the duration from 24 to 48 weeks. There was a relatively small reduction in total IgG and total B-cell populations, but there was a continued improvement in efficacy. And we think that represents some degree of remodulation of the autoimmune repertoire such that people continue to improve their underlying autoreactive autoreactivity over time between 24 and 48 weeks. And we think that's what's really driving that continued improvement. If you look at the final 48.
Even in the absence of further changes in IgG.
Total IgG, we think there's still probably changes in that small fraction of autoreactive IgG.
Makes sense.
We look forward to being able to measure that in our phase 3 study. Mechanistically, that's our hypothesis as to why we see that continued improvement and that durability that really not only lasts but continues to improve from 24 to 48 weeks.
And this is what the market is asking now, these durable medicines, longer, potentially disease-modifying. So we've seen this iteration finally happening here, and we're very pleased to be part of that.
Let's move to Sjögren's maybe. There's a competitive landscape here as well, although it's maybe less intense than arguably than MG but other IgG-driven diseases. What's your bar for success in phase 3? What are you thinking about translatability from the Chinese data here as well?
So let's talk about Sjögren's and step back a little bit on the opportunity. I mean, MG established disease, I would say, pretty well explored, pretty standard way of investigating it with what we just discussed. I mean, it's well known, and it's addressed, although highly competitive, but with unmet need. Sjögren's underserved, untapped. We just recently published our partner's data, RemeGen's data on their phase 3 on 380 patients showing unparalleled results on most endpoints, actually, which actually is a fantastic proof of concept for us. It's almost the ideal version of a phase 3 with very pure patients with few background medicines. So we know it works, which is fantastic because it gives us the possibility to carve our own phase 3 studies.
We also saw recently another pharmaceutical company readout of their global phase 3 trial on a B-cell depleter and showing that, yeah, they opened the door for activity, but there is much more to do. So we think there is a real path on B-cell targets here, which we are addressing, as Jeremy explained, in, we think, a very compelling way and more subtle way. And this is a very large market. This is probably the most important next opportunity in autoimmune diseases. It's like lupus in its times, but with also some probably epidemiology, which is underestimated. So this is larger, bigger. We need to be a bit more patient because we will be starting our phase 3 next year, which takes a couple of years, but should completely transform the profile of the company.
We do have to talk about the recent competitor data that you just alluded to. It comes back around again to the question of placebo response.
Isn't it haunting everyone in immunology, right?
The hounding is right. Here is another data set out of China where you seem to have a very low placebo response. This is exactly what tripped up your competitor in their trial where they had a very substantial placebo response. So what happened in their trial in your eyes? But also then how do you mitigate against this phase 3?
Yeah, I'll let Jeremy dive in that. But I think in a nutshell, we're very fortunate with the timing because not only we know what they have read in their trial, so we know what they've been facing. But they have been working on this thing for more than three years, educating sites, preparing the field in untapped disease, I would say, which means a lot of progress made since then. We're going to benefit from that. We're going to continue to educate, but we're going to benefit from all the progress made. So that's a great time for us to start a phase three. Jeremy, do you want to explain how we want to minimize the placebo response?
Yeah. I think that to be, as Jean-Paul said, we're going to leverage some of the learnings. I think without putting your finger on any one specific thing, the high placebo response is in part due to high variability in a global population. Investigators who, in order to conduct a study that size, they needed a wide range of sites. Many of those investigators weren't familiar with the SDI score, and we think that might have led to some inflation in the baseline SDI score. So we're going to work very carefully to make sure our investigators are trained. We're also going to leverage some of the same sites which are now well-trained in using the SDI score. It's a complicated tool which requires a special understanding and experience. By minimizing that baseline score, it minimizes your placebo change over time.
We're also using central adjudication to really make sure that patients who are entering the study enter with exactly the number of points they should have, and anytime there's a change in points, it's justified by the source data. We're training sites. We're training investigators, and we're training patients. Again, background medications were not part of the China study that minimized the placebo response to some extent. In a global population, there will be some background medications. Patients who are, on paper, taking background medications but perhaps not reliably enter a clinical trial and begin taking their medications more reliably, so it's about patient education and really getting to those patients and saying, "Please let us know exactly what you're taking.
Please don't suddenly become compliant with the medication as you become observed in a clinical trial because that inflates the placebo response," so working with patients, working with sites, working with the CROs, and working with the training agencies, the Sjögren's Foundation does an amazing job here getting people to run the best study possible. Do we think we're going to have a placebo the same as China? We do not. We will see placebo creep. But as we talked about with MG, we're going to get placebo. If we see a similar increase in the active arm, we maintain our delta. And even if we see a relative narrowing of the delta, we have plenty of room to go to maintain a best-in-disease profile.
What sort of scenarios have you envisioned for the phase three in both indications, frankly? If you see narrowing of that delta for whatever reason, the powering of the studies that you've picked on, not just for what a commercial win would be, but what are the scenarios you've envisioned in designing the trials?
Yeah, we don't communicate on the powering or the biostatistics, but we are well organized for addressing the meaningfulness of the response here, and we'll make sure that in our final protocol, which is under design right now, we will learn from also the statistics from the other product. Commercially, I want to come back to that because even if we would just incrementally improve from the other product we'll be ahead of it, we have an amazing opportunity because the market is so large. When you talk about these kind of large indications, you don't assume there will be only one product. Our assumption will come with a better profile, but even in the event we would be similar, I think we have an edge.
Enough market to go around.
Yeah.
Are you capping the number of patients on background therapy or at least stratifying?
Not currently. We are capping the number of background therapies they can be on as is usually done. We're also going to be looking at our geographies to make sure we assure representation across the key geographies and not get overrepresentation of geographies which are known to have higher placebo rates.
Okay. Makes sense. Can we talk then about the rest of the BAFF/APRIL field briefly? Obviously, some of your competitors with assets that don't have the wealth of data that RemeGen has in China but have similar mechanisms of action are starting their programs in other indications and have prioritized a different development path. Can you talk a little bit about how you view your molecules different A and B, the choices you've made on the development side?
Yeah, I think let's talk about the choices, which I think is more important than the difference in between the molecules. I mean, the biochemistry tells us so much. We think we have a very good biochemistry structure, which is actually very quickly mimicking the natural binding site of TACI and BAFF/APRIL. So this is actually a very natural and effective way of binding. Not going to comment on the two others, but we have very proven, which has also been demonstrated by our dose response. We have very characterized dose in several indications, which is not the case for all the other BAFF/APRIL inhibitors in different indications. We are very pleased with the two indications we have selected because we are the first in MG. We are definitely the first in Sjögren's in this modality. The others have chosen IgA nephritis.
We have data from China in IgA nephritis that we are actually using as a validation point vis-à-vis global data. We compare very favorably and what we should show, so there is no bias from China data, or not, on that, and we think that we have the right indications to generate the value and compete in a more effective way in the space.
Excellent. I think we are out of time, but just in the last seconds while we go into the passing period, can you talk about the path to commercialization timeline and the current cash runway?
Yes. So we have around $300 million of cash, which is enough to cover us until the next catalyst, which is our MG global trial readout. It gives us around half of the Sjögren's study, which is fine. We'll see where we are at that time. But the most important is to be funded for the MG trial and its readout. The path forward for commercialization, we assume we will commercialize ourselves to generate the most value possible. We have the team for that. We have a medical affairs team, very experienced in MG, bringing a lot of KOL engagement capabilities and relationships, which we think is paramount. So we've been starting very much on that. And we will do the same for Sjögren's. We have a bit more time for that, but we have the whole organization capability to seize the opportunity here.
And then, if you think partnership or not, we'll see later. We still have time for that.
Excellent. All right. Well, we are now well out of time, but thank you so much for joining us.
Thank you very much.
Thank you.