All right, good afternoon, everybody, and thank you once again for joining us for our First Annual INI Summit. I'm Jørn from the TD Cowen Biotech team, and it's a great pleasure to have with us today the management from Vor Therapeutics. We have Jean-Paul Kress, who is the CEO. We have Dallan Murray, who's Chief Commercial Officer, and we have Jeremy Sokolove, who's Chief Medical Officer. Somewhere in the background, weaving all his magic is Sandy, the CFO as well. Thank you, everybody, for joining. We appreciate it. These are action-packed 20-minute fireside chats. We're going to cover a mechanism to Sjogren's, to gMG, and we're going to touch on commercial ops as well. The first question is, we've seen this pathway is really getting a lot of attention.
There's other BAFF compounds, but you guys are a bispecific hitting both BAFF and APRIL, and that really gives you a more profound and sort of broader ability to target B cells, plasma cells, and long-lived plasma cells as well. Can you maybe talk about the mechanism and why that's relevant and this broader activity is very important for, let's say, let's start with Sjogren's and gMG?
Mechanistically, BAFF and APRIL are both survival factors for the B cell lineage. BAFF tends to be a survival factor for early B cell populations, and APRIL is a survival factor for the plasmablast and early plasma cell lineage. Blocking one or the other abrogates one particular cellular population, while blocking both really tends to target the wider population of B cell lineage. This becomes relevant, especially in a disease like Sjogren's, where autoantibodies are clearly important, and thus abrogating antibody-producing cells is important. Really, the antibody-independent function of B cells is often these more immature B cells, which are acting through T cell activation, cytokine production, and inhibiting their development, especially using a BAFF blocker, which inhibits preferentially the development of autoreactive B cells. We end up seeing a modulation both upstream and downstream.
We get not just a reduction in autoantibody production, but we also get a reset of the pathogenic population. That remodeling of the B cell repertoire towards a less autoreactive population is really part of the key mechanism that drives the BAFF-APRIL dual combination.
When we look at the activity, it's not immunosuppressive, but it's got a reduction on IgG, IgA, and IgM as well, and no real infection signal. The efficacy has continued to look really good. It's approved in three different indications in China, and they filed for two more. Can you talk about what is it? Is it really just an effect on plasma cells? I mean, or is it via an antibody reduction, or is it also B2 T cell signaling that's being addressed here?
Yeah, there's definitely a component of antibody-independent B cell function that's being inhibited. That's, again, the BAFF mechanism in addition to the APRIL mechanism. The combination of the two is what really covers that broad stream of B cell function. The autoantibody reduction levels are enough to get you what you need, but they're not so severe that they bring you to a state of immunodeficiency. There's nothing, no free lunch with immunomodulation. There are some small increased rates of things like URIs. After 60,000 patients treated in China with this drug, thousands in clinical trials, very little, if any, signal for increased infections and no serious infections or serious adverse events.
We think this is really a very balanced approach to B cell modulation, which is enough to get you what you need across the spectrum of the B cell population, but not so much that it puts you in an immunosuppressed state.
Okay. For the audience, if you want to ask questions, you can email me or put that on the chat that I have here in front of me, and I can see it and ask the questions on your behalf as well. Okay, let's talk about perhaps the next, I want to maybe just spend a second on the actual structure of Tele itself. You're binding to CRD1 and CRD2. You're binding essentially to the common binding site, right, on BAFF and APRIL. Other companies in some of the earlier drugs, let's say, there's a difference in sort of how you're binding, and some of them are only doing CRD2 in terms of what they're targeting. Can you talk about why that's important?
Yeah, I think that at the end of the day, anything that neutralizes BAFF and APRIL will have similar effects. The advantage of telitacicept is it's the most natural design. It's more like the TACI receptor than either atacicept or blisibimod. In doing so, it really allows that balanced binding of BAFF and APRIL in the way that it was designed as a binder. Some of the modifications, the protein engineering, has increased in vitro affinity of one versus the other. At the end of the day, the dose and the efficacy really give you that PK/PD relationship, which gives an optimal response for this more natural version of TACI attached to an Ig.
Okay, got it. All right, so let's talk about Sjogren's next. This was a late breaker recently at ACR. The data from the Chinese studies, the Chinese study, the phase III in 380 patients, you tested 80 and 160, and it was fairly impressive. This is patients with systemic disease. So you showed a 4.4 reduction at 24 weeks on ESSDAI at the 160 and three points at the 80. And also, you actually hit on the ESSPRI again on the order of about one and a half to just over two points. It is fairly unusual to really hit them both. Not many drugs have been able to hit both of them, I believe, so far. Only Amgen's Dexdalimab, the CD40 ligand inhibitor in phase II, was able to hit it. That is in phase III.
Currently, you also showed a star responders, about 75% on 160 versus 21% in placebo. This is really good data. One of the things is the placebo, if you look at the active arm, you would argue it does in line with what you would have expected in a global population when you can compare across. The placebo did very poorly, very poorly relative to a global population, I should say, ex-China. Maybe can you address that? What should we expect as you take this globally now in terms of the placebo effect?
Yeah. For the first point, the placebo, the whole study was such that there was no background therapy. Patients had to wash out of their background therapy. That reduces both the background effects of therapy, but also what we call the syndrome of sudden compliance, where in a lot of global studies, patients who are on "stable" background therapy begin taking that therapy. You see that increased placebo creep with patients who on paper were stable, but really they were non-compliant and became much more compliant at the start of the study. This study eliminated that. You are seeing the pure effect of the drug on disease burden in a really clean background population. To your second question, what is going to happen when we go to a more global population?
As with any study, when you go to a more heterogeneous population, you get increased variability and generally an increased placebo rate. We do anticipate that we will not completely phenocopy the results that were shown in that phase III study. We anticipate some degree of placebo creep. We are also optimistic that whatever effects that placebo creep brings will also bring some degree of a change from baseline in the active group. So our 4.4 reduction becomes, assuming we creep by a point, becomes a 5.5 reduction with a 1.6 reduction in placebo. We hope to maintain our effect size. I think important to note with our dose response, we are pretty confident in this 160 milligram dose. And even if we do see a minor decrement in the total overall effect size, it will not be extremely unpredictable to see what is still best in disease efficacy.
Can you talk a little bit about why the placebo in terms of what background meds they were on and how that compares hydroxychloroquine versus kind of a more holistic methotrexate and steroids as well in a global population?
In the China study, they were washed out of all background meds. That really flattened placebo. In our global phase III, we're evaluating the exact inclusion and the exact way we're going to handle the background meds. I think we've learned a lot from the INLMAP studies from Novartis, and we're very grateful for that learning. We're going to be incorporating that into our study. One of the big opportunities this brings us is Novartis did us a large favor by training many, many Sjogren's investigators on a fairly complex metric, the ESSDAI tool. We anticipate that with increased precision on the ESSDAI tool, we'll see more precision on the grading of placebo and that reduction in that placebo response.
Okay, got it. As you think about, there's a lot of discussion about ESSDAI of two is considered clinically meaningful. And we're talking about anything ESSDAI of kind of six and above is considered moderate to severe, right? Just to kind of orient everybody, a lot of times you see these patients coming in, sometimes I think nine and above or ten and above is considered severe, right? So two-point benefit would be important. But it's not that easy to find. Novartis obviously was rating between a half a point to a point. Just to put it into perspective, if you look at the FCRNs, they did around 2.2 in phase II. And that's actually more or less the same with what Dexdalimab did. But that's sort of the state of the data right now, and these are sort of the best therapies along with yours.
What do you think you really need to show to really get traction commercially?
Yes. Sjogren's is such an unmet need, especially for the highly active disease population, that any improvement is going to be beneficial. I think the Novartis data did show a five-plus, almost six-point improvement. On the active arm, now the fact that placebo had that as well obviously limits the phase validity of the drug effect, but it does not negate the fact that patients did feel better and appear better. I think that anything that gives a significant meaningful differentiation from placebo, which gives phase validity, but at the same time makes patients feel better, will have a place in the market space. I think as we also further narrow the population most amenable to B cell modulation in Sjogren's, we will start to see even a better effect across the global population. Again, it is a very heterogeneous disease.
In your study, I mean, you showed a very quick separation overall, and it continues to kind of the curves continue to get deeper and deeper and deeper. Do you expect a plateau at some point, or kind of what linearity would you expect?
Yeah, I think that there'll definitely be a plateau at some point at a population level. Again, some patients will reach a level of low disease activity, less than two, less than one. That'll be a plateau that just can't be overcome for good reason. I think the real difference is that some patients will respond very well and very rapidly. The criteria that move quickly are things like joint pain and the biologic criteria. We see rapid movement in some of the markers of systemic B cell activation, cryoglobulins, or not in this case, but IgG, complement, rheumatoid factor. The signs of biologic effect will happen very rapidly. We think it's a secondary effect that people start to feel better and the organ manifestations resolve secondarily to those biologic improvements.
Okay. Let's move to also gMG next. Here too, based on the phase III from China that again looked very good. I think that data has been sort of the best data we've ever seen. It actually even looked better than Vyvgart in that sense. Same questions apply. The efficacy looked very good and Vyvgart-like. The placebo, obviously on the active arm, the active arm did as well as Vyvgart. The placebo obviously did very low. Whereas Vyvgart showed about three-point benefit, you showed even more than that. I believe you showed around four or so. When you look at the MG-ADL, you look at the QMGs at baseline, they really do look very comparable to a Western population. Again, MG-ADL is around 10. Vyvgart was around 9. QMG, you were at around 17-18.
Give you a sense, most of the other drugs are sitting at 15-17, 15-19, right? So right in the ballpark, pretty much. Again, any sense, why did the placebo not do better in that study specifically?
I think, again, it has to do with the homogeneity of the population and the healthcare system. Patients tend to be very compliant with their medications as prescribed. We're not seeing a lot of patients who are starting medicines that they shouldn't be, prohibited medicines that they shouldn't be starting. We see consistently patients taking their medications and having access to those background medications. I think the background is one thing. The other is the consistency of reporting across a population. As you get a more homogeneous population dealing with a healthcare system in a consistent way, you just see a more consistent result. The fact that it's such a clean study really lets you see the magnitude of effect of the drug in what we call a clean population.
To anticipate your next question, do we think the placebo response may change in the global population? We do. Again, as you can see from the effect size, minus one to minus 5.7, that delta, even if it narrows by half, is still by far best in disease.
Okay. Your global phase III is now underway, right? You're recruiting patients. Fifty-two-week study. I think that you're hoping to have data in the first half of 2027. Hoping to complete enrollment first half of next year. Can you give us a sense kind of where are you enrolling and what can you do to control some of the placebo effect? Most recently, some of the FCRN, some of the studies, encouragingly, we've not seen issues with the C5 or the recent C1S. I think the Immunovent study had a higher than expected placebo effect. How can you control that?
Yeah. I think it's partially about really well-trained investigators, patients who are aware that they have to keep their background medicines as steady as possible, making sure that we select patients who have active disease with clear demonstration of the components at baseline so that there isn't a regression to the mean from overexaggeration of severity to get people into the study. It is about training investigators, about training and treating the patients well and letting them know the importance of how they behave will affect the outcomes of the study. Really trying to make sure that we are on top of every change that's seen and justify that.
Great. I mean, Dallan, maybe over to you. Sjogren's is much more open, right? I mean, technically, we have the Novartis data. I guess we'll have to see. I guess technically they have two positive studies. Whether it's clinically meaningful is another question. Amgen will have data late next year. FCRN's first half of 2027. So you'll be probably coming right after that in Sjogren's. In gMG, the market's obviously more competitive. You obviously have a different mechanism of action relative to the rest of the drugs. Kind of commercially, how do you view each segment?
Yeah, Jørn, it's a great question. There are two very different opportunities. The first one, as you say, with MG, it's a large and growing market. If all we did, if all we could do is get the non-responders to the FCRNs, that's about one in five patients. It's a $4 billion market today. It's growing to $10 billion by 2030. We believe with the data that Jeremy just talked about that we can be best in class and we can fight for number one place in that market. We are going in with an intention of winning in the market, and we're going to fight hard for the number one position. In a market like MG, where today only 30% or so are on biologics, there's an opportunity, a real opportunity.
As we fight our way to the number one position in that market, we're going to be having, we're very hyper-focused on myasthenia gravis and winning in that market. Sjogren's, as you say, it's very different. We're building a market. I think we couldn't be in a better position there, but it's a different position, right? Novartis is viable. I think the B cell strategy coming out of ACR seems to be the strategy that is going to be the winning strategy. We're following Novartis with best-in-class data. We know that Novartis will invest in disease awareness and health economic data, real-world data. They'll really pave the way in terms of awareness.
The question that you were asking, Jeremy, earlier about what's the meaningfulness of this data and generating a value proposition that payers don't necessarily love when there's not a cost offset, when you're not replacing an existing therapy. That is a lot of heavy lifting that Novartis has to do. I think we're in the perfect position to come right after them and to share in building the market. Two entirely different opportunities. We're excited about both.
Yeah. I mean, Sjogren's recalculated, even patients who are SSO positive, moderate to severe, it's about a third of the market. And at the current cost of biologics, we're talking about $8 billion-$10 billion, if not $8 billion-$12 billion.
Yeah. Yeah. And those EPI estimates range from a third to up to a half. You can see some EPI that says it's up to a half. Yeah, absolutely. That's the way we're looking at it too. I came for the opportunity of MG. I was in neuromuscular disease, super excited about that. As talking to Jeremy and Jean-Paul about this Sjogren's opportunity, it's even larger. It's a more long-term opportunity, but it's an even larger one.
Yeah. And then maybe in the last, I know we're just getting to time, but you've also shown with your partner RemeGen at ASN positive IgA nephropathy data. That's not something you're prioritizing right now. That market obviously is competitive. Again, it's approved in China for RA, for SLE. And as we mentioned, there's three other, obviously, I believe it's approved also for gMG, if I remember correctly.
Yes, it is.
Yeah. Right. And they filed for Sjogren's and IgA nephropathy. At what point would you consider adding a third indication?
We have a luxury of choices here, as you just mentioned. Eigen is actually very compelling because it's also a proxy with the two other BAFF APRIL inhibitors. With comparing our data, it's the only indication we can really compare with the same modalities in the West. They are very similar. It is a great validation point I would like to draw their attention on. In terms of other indications, it is too early. We are very focused on MG and Sjogren. These are two large indications. In theory, we could go to any B cell indication, and it is the pipeline of a product. We have to be cognizant of the capital allocation.
Yeah. Yeah. You just raised capital. Maybe final question. With the latest raise, can you give us a sense how much capital you have and how long does that take you through?
Go ahead, Sandy.
Sure. Jørn, we raised capital, obviously, that brings our cash balance to approximately $315 million and gives us a cash runway to approximately the middle of 2027, which lets us complete the phase III trial for myasthenia gravis. Also pays for all the commercial launch and the medical affairs expenses, as well as the manufacturing ramp that's needed, and also gets us about halfway through the Sjogren's trial as well.
Okay. The manufacturing launch. Then halfway through Sjogren's as well.
Sure. Right. Yeah.
Terrific. Team, thanks so much for joining. We very much appreciate it. I know I'm going to see you again later on tonight for dinner as well. Thanks so much for joining. Thanks, everybody, for joining. If you have any questions, let us know. Good to see you.
Thank you. Thank you.