Vor Biopharma Inc Aktie

Back to School Summit from Citi. My name is Geoff Meacham. I'm a senior biopharma analyst here.

We're thrilled today to have Vor Biopharma. We have Jean-Paul Kress here, CEO. So welcome. Thanks for joining. He's got the broader team as well.

So maybe give us a little bit of a -- most of the companies just give a bit of an opening remarks just for a few minutes, and then we'd get right into it.

Sure. Well, thank you, Geoff, and glad to be here and to tell you what our progress at Vor. So I'm here with my team, and they will pipe in and answer questions with me.

So Vor is a company focusing on B-cell-mediated autoimmune diseases. It has in-licensed our main asset a year ago, around June 2025. It's called telitacicept. It's a BAFF/APRIL inhibitor, which has the ability to tackle the upstream of the B-cell lineage. There's a big unmet need with that. And it basically modulates the B-cell development, production and survival and inhibits the production of pathogenic autoantibodies.

It has been approved in 6 indications in China. That's very important. There is a wealth of data out there in several autoimmune diseases. And we have chosen in the West, in the U.S. and elsewhere, to develop teli in myasthenia gravis and Sjogren's disease to start with.

Since we licensed the asset a year ago, we've made tremendous progress. You probably saw the announcement yesterday that we completed the enrollment of our Phase III trial in myasthenia gravis. It's a huge achievement for a company of our kind, especially we took over a trial which was not doing very well at the time, and it's now doing very well. Jeremy will talk about it further.

And we believe that we have a fantastic opportunity in MG. We are always hearing from the physicians that there is a big unmet critical need there. They need therapies with a deeper clinical efficacy, but even more so, a durable clinical efficacy. That's what's lacking with the current therapies. And we believe telitacicept has everything here.

And as a matter of fact, I'll draw your attention to AANEM in a couple of weeks, where we'll present very compelling and exciting data on an endpoint, which is probably the "come to Jesus" endpoint in MG, which is called minimal symptom expression, which is basically achieving less than 1 in MG-ADL for patients, basically asymptomatic. And there, we will show that we have a deep, but even more important, a durable effect on patients achieving MSE.

So that's for MG. But we also saw that we announced yesterday that we have the intention to start ocular myasthenia gravis Phase III in the first half of 2027. We believe it's a perfect adjacency. It's logical. It's not easy. There are only 2 products approved, and there is also a high unmet medical need. And we can help patients earlier in their disease journey and modify the disease because we act on the upstream and help those patients. We can achieve more than $1 billion in this indication.

So MG is our beachhead indication, multibillion-dollar potential, now complemented by oMG. Again, shows our confidence in our ability to execute in our results as well with the second myasthenia gravis indication.

And I'll finish by saying that we also have Sjogren's disease. We have a Phase III. We started de novo, I think, late last year, Jeremy? March, actually. So March. And we're enrolling very well, above expectations.

Shows the 2 things again: our ability to execute, but also the interest from the space, in a white space. There is no product approved. We have the potential of achieving multibillion dollars in this indication. We'll talk about it more. It's probably a market which at start should be more than $10 billion, but could be more because all these large indications and [ gaps, remember, AD ], there is always a potential to treat patients better and earlier.

Let me follow up on that, Jean-Paul. So that when you think about the teli and the BAFF/APRIL mechanism, there are a lot of drugs out there, there are a lot of opportunities. But talk about how you view teli's differentiation from a mechanism standpoint versus Vertexes, Veras of the world or Otsuka. Like talk about the -- maybe give us some context for the differentiation and how you see the market.

Sure. And probably a great question for Jeremy.

So first, we'll start differentiating BAFF/APRIL from APRIL. So I think IgAN has taught us that, in IgAN specifically, there's not a lot added from BAFF to APRIL. Sibeprenlimab, povetacicept, atacicept, telitacicept all have roughly similar levels of Gd-IgA reduction, proteinuria reduction across when dosed appropriately for IgAN. And so that led to the argument that we're not sure what BAFF is adding. That's the exception, not the rule.

In a disease where you're targeting the autoantigen, which is Gd-IgA, they're produced by mucosal plasma cells. APRIL inhibition is very effective at reducing mucosal plasma cell generation of Gd-IgA. Therefore, APRIL alone tends to be similarly effective to BAFF/APRIL in IgAN. That's not the case for any of the other autoimmune diseases we're going to talk about where you have to address the autoreactive B-cell that's making the pathogenic antibody, not the pathogenic antigen.

And even once we get there, there's differentiation within BAFF/APRIL inhibitors, some of which have a higher potency for BAFF, some of which have a higher potency for APRIL. And think of it like the bispecific antibody. If you don't get the stoichiometry correct, you'll end up either overdosing or underdosing in different disease indications with the wrong molecule.

Telitacicept specifically has a 2:1 BAFF-to-APRIL mechanism. It's the most TACI-like native TACI. That may be lucky, may be by design. But the 2:1 gives the opportunity to dose to APRIL and overdose on BAFF, which is absolutely acceptable and safe.

Benlysta taught us, belimumab, that 1 mg per kg, 10 mg per kg, relatively similar efficacy, maybe a little improvement, but no increased safety liability when you 10x the dose of BAFF. APRIL, going from even 80 mg to 240 mg in the povetacicept Phase II studies of IgAN, showed that there was clearly a dose-dependent increase in the incidence of hypogammaglobulinemia.

So at the end of the day, the goal has to be dosing to APRIL, because APRIL is the one that you need to maximize without going over. And if you do that with a drug that's APRIL-heavy, you will underdose BAFF. Whereas with a drug like telitacicept, by dosing to APRIL, we slightly -- in some situations, we may slightly over-target BAFF, but that's acceptable. And in other places and in other patients with different heterogeneous drivers, hitting that level of BAFF is critical to modulating that upstream mechanism of B-cell inhibition.

Okay. That's really, really helpful. Thank you for that. Let's talk a bit, before we get into teli development, talk about the business model with having data, having substantial body of work done in China. And maybe what are the nuances, what's predictability as you develop in U.S. and Western Europe?

Well, that's the question, right? And we are not the only ones to ask this question or try to answer this question. But we are probably the only ones that advance in autoimmune diseases. You have proxies in oncology and some other TAs, but probably we are the one on the forefront of the autoimmune space. So we're very happy with that and proud with that.

But again, we have a series or a wealth of data coming from China, from early stage to late stage, of mechanistic, which is very important, to late stage as well, many Phase IIIs, approval there. So it's not a coincidence. I think so the product works, and the product is safe. Otherwise -- more than 10,000 patients have been dosed with this product, we would have known if we have a signal. So it's a huge advantage compared to other products in the space.

Now the next question is, by how much are we going to differentiate? There are nuances here that we can talk about. We know that in China you have probably, let's say, heterogeneity that we will face with our clinical program, like any other company in the world. I mean different countries, different sites, different patients, cultures, origins and everything, involves heterogeneity. So that's one thing that companies have been struggling all over the place in immunology and beyond, especially on the placebo level. That's probably your question.

So yes, we'll probably see the placebo effect increasing, but we're very confident in our active arm. And we've done everything in our trial, when we inherited the trial, which started by RemeGen, U.S., you might say, what they had in the U.S., we optimized the study and tried to make sure that we were maximizing the active arm effect. Because we hear all the time from the KOLs that it's not only the separation from placebo. Uplizna from Amgen has a separation from placebo of 1.9 in the MG-ADL. We have, in our China study, plus 4.6, right?

So we have 4.6, but what counts -- and Uplizna has been approved and the launch is doing very well. So it's a great proxy. We don't need the separation we've seen in China, and we probably have a strong active arm. And I'll finish by that, what is very important is what I said earlier. It's the durability. And here, we separate from many products, especially the FcRns.

Yes. Okay. That's helpful. So let's get into teli development, and congrats on finishing the MG study. So maybe help us with kind of what investments you guys did to get the enrollment across the goal line. And then remind us just kind of the approximate time lines of when you think that we'll get some top line data.

Sure. Jeremy?

Yes. So I mean, I think the key thing is -- enrollment is always a hockey stick, and it's when you can create that inflection in enrollment. The things we did were really several-fold. One is Dallan and his field team really engaged with the KOLs. RemeGen was a China company. They weren't aware of some of the KOL networks that were critical to access. Some of them enrolled patients. But really, they created an enthusiasm and excitement around the mechanism throughout the MG community, which really got sites and investigators excited about enrolling in our study.

Many of these sites are enrolling multiple studies simultaneously, and they ultimately have to choose which drug they will then prosecute; they will then offer to patients. So we saw a great uptick in the use of telitacicept from those sites.

The other thing that we did was really making ourselves the sponsor of choice. We got into the sites. We made it easy for them. Sometimes when you have a CRO, it's not so easy to access the CRO. They have my phone number, the CMO. They have the phone number of the study director. They have the study director of my head of clin ops and the clinical lead -- and the clin ops lead for the study.

And so by making it easy for sites, you make it easy [Technical Difficulty] fail, is there anything we need to correct systematically in our study? And is there anything we can do to rescreen this patient? Because the screen failure was a temporary setback that's going to be transient. And at the end of the day, it brought us in not just on time, but ahead of time. And I think it really shows the ability to take a company from 0 operational presence to a high-performing operational presence in less than a year.

And that gave us the confidence for the next chapter. I mean when we saw that a couple of -- I mean, we didn't know at the beginning. And then with the weeks and months, we got our confidence boosted, and we decided to go on ocular MG.

Great. Yes, absolutely.

Sorry, you asked a second question, which was the timing of data. So obviously, the 24-week clock starts with the last patient dosed. We anticipate we'll have data locked and then we'll be able to have top line data. We're still guiding towards the first half of '27. Obviously, this brings it more proximal in the first half of '27 than we had anticipated.

Let's maybe frame that data update that we could expect in first half '27. Maybe given the trial design, what should we look for?

The key messages are going to be the way we benchmark, which is still the delta for the MG-ADL. All other studies have asked that question. And when you look at comparators, everybody says, what's the delta on the MG-ADL?

So again, we highly anticipate that our placebo will be higher than observed in China, consistent with all the other global placebos that we've seen. That's the population they enrolled. That's the population we enrolled. We've done some things to mitigate the placebo, but it will be higher. We anticipate that placebo will go up. We anticipate the active arm will similarly go up, leaving us a relatively preserved delta that approaches, if not duplicates, the delta we saw in China. So that's the MG-ADL delta.

But the other 2 pieces, which we're really excited to be able to communicate, are the breadth of response and the durability. Now at 24 weeks, durability may not be easily reported and may have to come through a subsequent report, but the breadth of response, we'll be able to show.

So for instance, early on, the approvals for MG were based on a 2-point improvement in MG-ADL, and efgartigimod, when approved, had a roughly 67% rate of 2 points improvement, which is considered maybe the minimal clinically important difference. We've raised that to 3 points. We'll report that. And we'll also be able to report higher levels such as a change of 5 or 6, which starts to become a very meaningful number. And that's the breadth of response.

So when we show that and you compare it to what's been seen with other mechanisms, we hope to be able to additionally show not just a greater depth of response, but a wider breadth of response in terms of the probability that if you give a patient telitacicept, they will have a clinically meaningful response.

Great. And then I guess, looking at safety and tolerability, what should we expect there on myasthenia gravis?

So obviously, there's a significant amount of preexisting data across the China. So we don't expect any real surprises. We've obviously seen the data point, and again, it looks consistent with what we've seen for telitacicept.

Rates across the historic telitacicept program showed a small increased rate of minor infections, urinary tract infections, upper respiratory tract infections. But notably no increased imbalance in serious infections, infections leading to hospitalization, infections leading to death, or opportunistic infections. And we think that's probably the message we'll hopefully be able to continue to tell 6 months from now.

Just on the MG market, what would you say, by the time you guys have the data and are launched, how do you guys view the -- maybe the bigger pockets of unmet need?

Yes. Well, again, currently, it's around $3 billion in the U.S. It's supposed to top $10 billion in the U.S. by the end of the decade. So it's growing fast with the arrival of new products.

The space was owned by the FcRns until now. And before that, it was just complement inhibitors. So there has been phases of innovation. There is no doubt that the FcRn completely transformed the space, but it's a very downstream mechanism. We hear all the time from the physicians that it's like mopping the floor with the faucet still open. We close the faucet, or at least we modulate the faucet. So that's very important. And there is an unmet need because the durability that Jeremy alluded to is probably the result of this mode of action.

Commercially, I mean, it will follow. We believe that the market is hungry for this unmet medical need addressing. And we believe that products will be rewarded if they provide the right clinical profile. The proxy is probably Uplizna. It's a CD19. It's usually reserved -- it was reserved to heme malignancies, as you know, and it's more carpet bombing on the B-cells. It doesn't really address the modulation that we speak about. And it doesn't address actually the antibodies production itself, really only address killing the B-cells upstairs, if I might say. So despite that, doing well. For us, it's great because it shows the appetite. And we've done market research that I could talk about that, but we hear constantly that from the KOLs and the physicians.

Now it will take commercial muscles, obviously, and we have a team for that. They're preparing. We have a great medical affairs team, many people coming from great competitors. So these guys know usually, they know the KOLs, so they know when a product is good. And we have already a team engaging, which for a biotech is usually not the most easy thing, but we have been able to assemble that very early.

Maybe just frame the development into ocular MG, just give us some context for that. What is -- is that a different segment of an unmet population? Like maybe what are the decisions that went into that?

Yes, I'll just start at a high level and Jeremy will explain further. I think the decision was made, as I said, when we felt confident enough in our ability to execute and the appetite from the space for our product. It's a very logical choice. And there was also some derisking from other products, some data and filing and approval, which clears the space here. It's an adjacency.

Jeremy, do you want to say something?

Yes. So there's obviously the operational opportunity. We have now engaged with a wide range of sites, wide range of key opinion leaders and investigators. So operationally, it's a logical time to move into this adjacent indication of ocular MG. A lot of the same sites, a lot of the same KOLs, a lot of the same investigators and a lot of the same pathways. So we've already had that optimized, so we can continue leveraging that momentum.

But also, as Jean-Paul mentioned, it's an open space, right? There may be one entrant soon, which would be argenx, potentially UCB behind them. That's still the FcRns, which don't really modulate the disease pathogenesis upstream. And what we know about ocular MG is that 80% of ocular MG progresses to generalized MG. This gives us at least potentially the opportunity to intervene with a disease and immunobiology-modifying drug which could then potentially prevent that progression.

So back to the sink analogy: before the water seeps through the floor and starts destroying your insulation. So I think that's kind of the goal with getting into ocular MG.

And then the other point is, in addition to whatever Dallan tells me, $1 billion market, and I go, "That's a great market," but it also increases that halo around MG because now providers don't have to make that decision or justify their decision to give telitacicept based on a preponderance of ocular symptoms. The payers have put a limitation, right or wrong, they've put a limitation saying, "Oh, this is ocular, not generalized. Therefore, we're not paying for it." Unless you show a study where you demonstrate that your drug specifically affects ocular.

So by giving that to the community and giving it to the payers, we open up the aperture for all MG patients who may be -- who someone might want to prescribe telitacicept. And I think argenx has done us a huge favor of developing the outcome measures, which are reliable. And also, I think there's an increased teaching that it's not just mild MG, there's a lot of morbidity. If you think about a disease like TED, thyroid eye disease, it's double vision, blurry vision, but a very serious condition.

Ocular MG is the difference between driving and not driving, using a computer and going to work and not using a computer and going to work, being able to do the activities of daily living that you count on. And we want to be able to get those patients back to that status.

Maybe one more for me on MG, but could you talk a little bit about, looking at broader MG, just discussions with regulators, how that's going as you're approaching later-stage development or in later-stage development?

Yes. Obviously, we cannot say too much, but we've been doing all the steps necessary with the FDA, and the EMA, by the way. We have -- everything starts and ends with the data. So we're focusing on a very strong outcome with our data. So we finished recruitment, but now the phase of data quality, data collection is starting, is very important. We don't base on the level of enrollment only. So that will be paramount.

But we have all the activities and the work streams in place, and the expertise internally and externally, to compile the BLA, which is now our number one priority for MG. And it includes, obviously, manufacturing, quality, et cetera, et cetera. So we are in a good shape, but it's going to be a lot of work, as always.

Let's switch gears to Sjogren's. So maybe just give us a quick -- a couple of liners on the pathophysiology of the disease. Obviously, a huge unmet need. And then you guys obviously dosed your first patient earlier this year. Talk a little bit about how you tend to kind of really leverage the BAFF/APRIL kind of mechanism in this disease.

Yes. It's a beautiful modality for Sjogren's.

Yes. So Sjogren's is really a prototypic B-cell-driven autoimmune disease. And it has -- I like to think of it as 2 components. There's an antibody-dependent component, whereby antibodies drive pathology, they target antigens, they make immune complexes, they cause inflammation.

There's also an antibody-independent component to Sjogren's, which is the hyperactive B-cell. These hyperactive B-cells, some of them make antibodies, but others don't make any antibodies. They're literally having an antibody-independent pathology whereby they make cytokines and drive tissue inflammation. They activate T-cells through co-stimulation to make cytokines to cause tissue damage.

So the damage in Sjogren's is really a B-cell-centric disease, but involves multiple B-cell mechanisms. And the nice thing about telitacicept is it sits squarely in the middle of that pathology. It affects the upstream B-cells which are making cytokines and causing co-stimulation. It also affects the downstream plasma blasts and plasma cells that are making pathologic antibodies.

So if you think about the mechanisms currently being evaluated in Sjogren's, there's things like FcRns, which drop antibodies, but don't affect upstream B-cells. There's things like BAFF receptor targeting like ianalumab, which affect upstream B-cells but don't particularly affect the downstream antibody production. By covering both sides of that pathologic spectrum with hyperactive B-cells, we think that really is a key to being able to demonstrate a step-wise increase in the level of efficacy.

And that level of efficacy is critical, because I'm going to be honest, the outcome measures in Sjogren's are still pretty crappy. And because of that, they have a lot of heterogeneity and variability in how they are interpreted. And that creates a challenge in getting positive studies.

The way to get around that is twofold. One is well-designed studies, well-trained investigators and very clear protocols. We do that. Beyond that, it's about having a drug with a large enough effect size to overcome the heterogeneity in the background population to show an effect size that beats out that variability and that heterogeneity that has limited the effect size of some of the recent studies.

We are fortunate to have -- to start out our first half of our trial now in this era, while others have started a few years ago -- actually many years ago, several years ago, and they experienced the hard core of what Jeremy described in the difficulty and the heterogeneity and the kind of challenges with the evaluation scales, which are not used in clinical. Now we have a much better-trained bench of investigators that we can select, that we have selected and are better equipped to deliver on results. So the timing is very good.

So there's regulatory clarity on the ESSDAI scale. Talk about the challenges of that even given multiple organs that are in Phase III...

Yes. That's the heterogeneity. So there's multiple domains. But most of it's driven by a relatively smaller subsegment of the domain. So if you look across the Phase III China study and you look across the Phase III ianalumab study and the Phase II nipocalimab studies that have reported out domain-specific improvement, it tends to go across the musculoskeletal, skin, glandular lymphadenopathy and biologic domains. And we drive all of those because of our mechanism.

So because our mechanism is so strong at each of those domains, we feel confident that we'll be able to show, in a typical population with those manifestations, the ability to change and improve those symptoms. So I think that's really the opportunity.

The other thing is the ESSPRI, which is the symptomatic scale, which no one has been able to win on because, again, it has a very narrow dynamic range. So the only way to win on the ESSPRI is to have such an effective drug that overcomes that background heterogeneity and that background variability. And we think that a drug like ours that affects so many parts of the potential pathology driving fatigue, dryness and pain has the ability to overcome that heterogeneity. And if you look at the Phase III China study, the only Phase III study ever to be positive for ESSPRI was telitacicept.

Great. Yes. I guess as your Phase III is ongoing, could we -- you talked a little bit about efficacy here, but maybe could you comment on some safety and tolerability expectations and, I guess, how that would work in Sjogren's?

Yes. So safety, obviously, is going to be consistent with the safety we've seen previously. We are not anticipating any new signals from Sjogren's versus what they've seen in Sjogren's elsewhere.

Tolerability, there's always the issue of a weekly injection. Some people will not like weekly injections. Most people will tolerate it just fine. We've put in place a lot of really good trainings so the patients, who can self -- who choose to self-administer at home, learn how to self-administer at home well.

The China studies had incredibly low rates of discontinuation. They require patients to come to the clinic every week. We're giving patients the optionality to be trained and go home. And we're going to optimize that to make sure our patients, who take that drug home with them, know how to give themselves the injections and are comfortable coming back for retraining if they're finding it uncomfortable.

Right. And you talked about KOL commentary around myasthenia gravis. So maybe given the unmet need in Sjogren's as well, could you comment on what you're hearing from KOLs?

So maybe Dallan can answer this question.

Yes. We've been very excited about the KOL reception. And Jeremy, as he said, has designed a great study, in consultation with the KOLs. And the early enrollment is far exceeding our initial expectations.

And I think there is a really good understanding of the mechanism from the KOLs. And particularly some of those KOLs looking at the risk factors for developing lymphoma, they've done -- there's been a lot of work around APRIL and BAFF, and APRIL being the highest predictor of developing lymphoma. We've -- it's early. It's early days in terms of our KOL engagement in Sjogren's versus MG, but the reception is really, really positive, both in the U.S., in Europe, especially in France where there's a lot of good research.

It's a complete coincidence. But the other thing I would say is that we have the opportunity to mold the space here much more than in MG, although we think we'll transform the field in MG. But in Sjogren's, there is an appetite from emerging KOLs because it's a new disease. So that's always great. Remember, RA, AbbVie days or Abbott days at the time, or Amgen and these kind of things. So you can really partner with them at an earlier stage in their career or in their journey. And that's why we see so much accolade from the space, and that's very encouraging.

I mean we have to enroll 250 patients for our Phase III. I will not say numbers yet, but we are well advanced in our early phase, and especially on U.S. patients, which was the opposite for the MG trial. We had to work a lot to correct things from the beginning. Here, it's really going well.

What are the lessons learned from a risk context from Sjogren's in China or any other geography based on where you guys, and also how you perceive the landscape?

Yes. You mean clinical development point?

Yes.

I mean, obviously, what we've seen is twofold. One is the placebo effect. And the placebo in the one Phase III study that's been positive was incredibly high, and that limited the effect size. It's hard to know what drove -- exactly what drove that placebo effect, but a lot of it is investigator training, having investigators who early on in that study at baseline, didn't have the same experience they had 52 weeks later at the end of the study, probably resulted in some regression from a high baseline to a lower final score. And we adjust for that by, again, as Jean-Paul mentioned, leveraging those already very experienced investigators.

So we're very grateful to Novartis for having trained several hundred investigative sites in the ESSDAI, and we were able to leverage them to overcome some of those -- that precision liability that is inherent to the scoring system. I think that's really the key risk there.

The other, obviously, is the heterogeneity of the disease. And that just again is overcome simply by really having a mechanism that addresses the breadth of heterogeneous mechanisms driving the pathology, but also the heterogeneous mechanisms driving the different components of the pathology: the arthritis, the skin rash, the lymph node enlargement, the glandular enlargement.

So I would just add that the bar, the regulatory bar, we don't know yet, but we'll know soon with Novartis, obviously. With the unmet medical need in this disease, I would assume that the bar would be quite lower than it would be in the future. So that also helps for the potential of having some room in our results.

We think we'll do better than Novartis with our asset in our trial, but you don't need a separation of 5 points on the ESSDAI to be approved. And by the way, Novartis was negative on the ESSPRI. I mean failed this endpoint. And the delta versus placebo is very limited on the ESSDAI. And despite that, this product will most likely be approved.

You okay on Sjogren's? Should we move on to other indications?

Yes.

Yes. Just talk a little bit about how you balance like the data from RemeGen in China for teli, and maybe what your thought process is as you move to other indications. You could take this into IgAN or a number of other indications, but maybe how does the probability of success sort of inform that?

So we've been very diligent. We have worked on indication selection, which starts with clinical development, the science first. Can the disease be addressed by the modality? And there are a lot of diseases which can.

Then there are the nuances in the mechanism and the modality. Jeremy spoke about APRIL versus BAFF, or BAFF versus APRIL. I mean there are some nuances that we are applying on the selection and the ranking. And then there is a commercial relevance and competitive edge we could get. It wouldn't make sense to start the study in RA, although it's approved in RA in China. So those are the kind of things.

So we have in mind a couple of other indications. But I'll just remind you that we already have 2 and, soon, 3 Phase III studies. So one which is soon to be complete. But Sjogren's will still run for 48 weeks, study -- 48-week study. So it's going to be longer. oMG will be probably 24 weeks. So we have our hands full. But we are ready to start when and if it makes sense.

So probably at the declaration of results for our gMG study, we'll probably be in a good place to decide what we do next. Because if we have a great outcome, for instance, we'll be probably, capital-wise, in a very good situation, and then we can decide on what we unfold. So all these parts are in flux, but we're ready to act as soon as we have the catalyst.

Okay. With that, thank you, guys. Appreciate the time.

Thank you very much. Thank you.

Okay. Well, good morning, everybody, and thank you so much for joining us for the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the biotech team, and it's really a great pleasure to have with us today Vor Therapeutics and Jean-Paul Kress, the Chief Executive Officer.

Vor telitacicept is a BAFF/APRIL inhibitor with really promising data in both Phase III in gMG and Sjögren's. The gMG data is going to come midyear and first patient in for the Phase III global Sjögren's study is going to be by the end of the first half of this year. We've written extensively about both opportunities. gMG looks really promising based on the data, and we're equally to, frankly, even more excited about Sjögren's, which is frankly a big white space.

So Jean-Paul, thanks so much for joining us. We appreciate it. We'll do a presentation and then Q&A.

Thank you, Yaron, and good morning, everyone.

Very pleased to be here and to update you -- presentation. Just trying to retreat the slides. So very pleased to be here and to tell you about our progress at Vor Bio. Thank you. I'll be making forward-looking statements during this presentation. This is our disclosure slide.

At Vor, our ambition is to significantly improve the standard of care in autoimmune disease. And for doing that, in 2025, in June, we in-licensed one of the most exciting opportunities in autoimmune, a late-stage asset called telitacicept. Telitacicept comes from the China biotech innovation engine. It's RemeGen, our partner there, who has developed this asset in a series of late-stage trials that I'll talk about in a minute.

And the great thing with telitacicept is that it has a very uniquely designed and differentiated profile. It's a BAFF/APRIL inhibitor, as Yaron alluded to, which has the ability to tackle the upstream and the downstream of the B-cell lineage. And with that, it remodulates the immune system without B-cell deep depression and unnecessary immune suppression. So this elegant mechanism has applicability in a series of autoimmune diseases, and it's been very well characterized in the RemeGen late-stage clinical program in more than 8 indications.

There is an impressive list of Phase III trials in the major autoimmune diseases and some at the forefront or in the white space like Sjögren's disease. We'll tell you more about that. So it's clinically validated, which is extremely precious for us. And it's also de-risked on the safety side because it's commercially available in China. It has been administered to tens of thousands of patients there commercially in several indications.

We have selected 2 indications for our global first trials. It's myasthenia gravis and Sjögren's disease. They are 2 very different diseases and opportunities, but they are both sizable and with unmet medical needs. And we think we can compete very effectively and provide great advances in these indications and achieve blockbuster status in these indications, obviously.

There is more than that, but we stay very diligent in our capital allocation. There is more than that with a series of autoimmune B cell-mediated disorders. In theory, telitacicept can cover most of them, if not all of them. We'll address that in time with the right discipline.

We have a healthy balance sheet with $450 million, which gives us the runway until mid-2028 and the mean for our midterm catalysts, especially our global Phase III. So a great opportunity I'm going to tell you more about now. And I should also say that we reentered the company completely mid-'25 around this asset with a brand-new team of experts, great talents who have been executing on turbo boosting our Phase III trials. And preparing for the launch because the MG launch is not so far.

Let me tell you more about the modality or the mechanism of action of telitacicept. BAFF and APRIL are 2 key cytokines in the B-cell lineage pathway. They are important for the development, the maturation and the survival of B cells. By blocking BAFF and APRIL selectively, telitacicept inhibits the abnormal development of the hyperactivated B-cell clones and it reduces the secretion of autoantibodies. So by acting on BAFF and APRIL on the upstream and the downstream, it basically remodulate the immune system without, again, deep B-cell suppression, which allows the immune system to function against pathogenic agents for instance.

So this elegant mechanism or modality has a great applicability because you don't need to interrupt treatment time to time to help the system to restore and you can treat chronically and in a very reliable way on the long term. In these diseases, the patients need to be treated chronically and on a regular basis. That's very important.

I mentioned the impressive clinical program, late-stage program from RemeGen on telitacicept. And it's been obviously well characterized here with a very consistent and clinically meaningful efficacy profile, 3 commercial approvals there in systemic lupus first and then rheumatoid arthritis and most recently, myasthenia gravis. 2 more BLA submissions late 2025 in Sjögren's disease and IgA nephritis. And it has achieved in at least 3 indications, best-in-disease status with the Phase III results. So a very compelling set of data, which give us a fantastic bearing point to select and carve our own global Phase III trials at Vor.

This is true for efficacy. The de-risking is also obvious for safety because tens of thousands of patients have been treated in China, either through the program or commercially. And the safety profile is very consistent and manageable. There is no burdensome vaccination requirements like complement inhibitors. There is no signature B-cell depletion associated serious adverse events like with depleters, CD20s and others. And there is in a consistent way, mostly mild-to-moderate adverse events observed in the clinical program and in the commercial endeavors.

So the safety profile is very important because it enables long-term treatment and chronic treatment in these diseases, which is extremely -- it's actually one of the most important high unmet medical need in autoimmune disease, the ability to treat chronically without having to do drug holidays.

This slide shows you the important and impressive list of clinical trials with telitacicept. There is a wealth of Phase III data between RemeGen in China and ourselves globally now. You see we cover a large amount of autoimmune indications, and it gives the picture of a true pipeline and a product opportunity with obviously multibillion dollar sales potential. And again, a strong cash position, which makes us -- which puts us in a very good position to deliver on these opportunities.

Now let me tell you more about myasthenia gravis, which is our midterm opportunity. And first and foremost, why did we select myasthenia gravis our beachhead indication? For mainly two reasons. MG, despite the fact it sounds busy as a market, is a sizable market. It is forecasted to be in excess of $10 billion of sales in the U.S. only by the end of the decade. And that's very much the case with most immunology or autoimmune indications.

Remember that atopic dermatitis was forecasted to do only a few billion dollars of sales. Dupixent product is probably going to top EUR 25 billion at the end of the decade. And it's only 1/3 of the patients treated by biologics. Same in MG. When the first FcRn was launched, nobody thought that it would be as important market at the end of the day. So we have a lot of playground here to increase the sales in this market.

Number two, there is still high unmet medical need in MG. The patients are treated by new agents, okay? But these agents don't fulfill all the needs, which are mostly about the possibility to treat chronically with a holiday break with a better safety profile. It's true for complement inhibitors, true for FcRns. And our agent, telitacicept ticks all the boxes here.

The China Phase III trial, which was communicated last year by our partner, RemeGen is extremely impressive in its results. The MG-ADL primary endpoint, placebo-adjusted results compared to the other agents on the market or being investigated show a very strong magnitude of improvement, minus 4.8 placebo-adjusted improvement here, which is almost double their agents at 24 weeks with a very consistent safety profile and very manageable.

But importantly enough, what is true at 24 weeks is even more true on the longer run. If you look at the open-label extension period, which is not 24 weeks in the China study, you can see that the MG-ADL score continues to improve and the patients continue to feel better and be better and do better. So again, this duration of effect and efficacy is extremely important because it leads to disease modification, which is probably the main unmet medical need in myasthenia gravis.

On the right hand-side, you can see that around 87% of the patients achieved MG-ADL absolute score improvement of 6, which is best-in-disease definitely very impressive. So these results are a fantastic opportunity for us to replicate that in our global Phase III trial, which we have started and actually are enrolling at a good pace.

You can see -- actually, I forgot to mention that in the Phase III trial in China, it's an important differentiating point of telitacicept versus existing agents like the FcRns, there is no need for drug holidays or breaks because you might know that with FcRn, you knock down the IgG by such a magnitude that you need the system to recover time to time. Otherwise, the patients don't have immunity anymore. You don't want to leave with only 10% left of IgG to fight your COVID or other agents. So that's why they have to stop and do a break and come back.

And during these breaks, beyond the fact that it's not convenient and obviously not very reliable, you expose your patients, especially in MG to myasthenia gravis crises, you can have acute episodes with life-threatening events. So that's not good. And with telitacicept because of the consistency of the treatment scheme and the mode of action, you don't need drug holidays. That's a key differentiating factor for us.

So I was going to tell you that our AMG global Phase III trial is enrolling very well. It's a very similar -- 180 patients, very similar protocol than the China Phase III trial, randomized between the active arm of 240 milligram of teli versus placebo and with an extension period. Here, we have made some improvements in the protocol, learning from the China study, trying to improve it, especially in the duration of the OLE. We've made it from 24 weeks to 48 weeks. And even with the opportunity for the patients to stay longer, depending on the patients and the physician wish.

So we really want to see that as a long-term opportunity. We believe this duration of treatment and of effect is key to study and that will add to our unique differentiating profile. So we have guided for readout of the top line results of this study by the H1 of 2027. So more to come, great opportunity in MG, well-studied indication, larger than thought with a great differentiating opportunity. And we'll keep you updated on our progress here midterm.

Let's pivot to the next white space, as Yaron said, I like the expression. It's not -- it's white space in the space that is probably the next frontier in autoimmune disease. This is an indication or a disease which affects more than 100,000 addressable patients in the U.S. So it's very large, and it's probably much larger than that. It's typically an underserved indication with no approved biologic modern treatment yet, which has underdiagnosed patients. And it's going to be larger than that, and the market will grow as with all these indications pre-biologic going to biologic era.

This is a much more complex disease than initially thought. It's usually traditionally mentioned as a dry eye, dry mouth disease affecting mostly female patients. It's actually multi-organ, multi parts of the bodies, joints, lungs, liver, skin with pain and fatigue, which are debilitating for the patients. They evolve in stages, and they end up with a very debilitating late-stage disease with very importantly, the prognosis, which can be very affected by the transformation into malignancies of these patients and insignificant portion of them transform into B-cell lymphoma, DLBCL, which is obviously a very different prognosis.

So that also underpin the fact that this disease is not only about purely just an IgG shutting down solution. It will be way too simple, which actually it has a deep B-cell origin, which you have to tackle in the upstream. So there are FcRn agents being investigated there, but we believe that our action, mode of action on the upstream has a very important relevance here.

So that's important to characterize the disease and spend a bit of time because it's new. People don't know it yet well. Even the physicians had to learn how to investigate this disease and study this disease and conduct the trials. It's very important, and we are at the perfect timing for our global Phase III. But first, let me tell you more about the incredibly impressive results from RemeGen.

At ACR last fall, they have presented their Phase III on [ 300 ] patients randomized into 2 active dose of telitacicept and placebo. and they have shown incredibly stunning results on the 2 key endpoints, the physician endpoint, ESSDAI and multi-domain and the patient endpoint symptom score ESSPRI.

Very important point in this study, these patients in China were clear of any background therapies. There was no steroids, no immunosuppressants. They were pure patients. So what you see is what you get with this study, pure patients and just the effect of telitacicept. It's a perfect proxy for us. We know that on the West, we will not be able to replicate that. We'll have to have patients with some background therapies, but we know how to control that. We learned that.

But here, what you see is the effect of telitacicept. And you see the incredible achievement at the high dose of 160 milligram, minus 4.4 ESSDAI placebo-adjusted improvement and minus -- almost minus 2 of ESSPRI, which is even more impressive on the symptoms. This shows you that it's true at 24 weeks, but it's also like for MG true in the longer run at the end of the OLE period. You can see that the effect -- the impact continues to improve, which shows, again, the potential of the duration of effect of the drug.

Another way to look at it is the -- if you take the percentage of patients achieving a certain amount of reduction in the 2 scores, 90% of the patients report improvement on their symptoms on the right-hand side of the chart here. It's very important. And usually, when the more than 1 point ESSPRI score is achieved, that's clinically meaningful. So the results are clinically meaningful and statistically significant. And we are the only ones having been able to achieve that.

If you -- so fantastic results. The KOLs actually are very impressed by that. And if you want to put in perspective with other agents, you see on the right-hand side of the slide, the Phase IIs available, the data available on the Phase IIs, us in dark blue and other modalities or products. You can see the magnitude of difference on the ESSDAI.

On the left-hand side, only 2 agents have communicated or published Phase III data. It's us and the BAFF receptor inhibitor. And you can see also the incredible separation of ESSDAI placebo-adjusted results, minus 3.8 for us, around something for the others. There is a placebo component, as you might know, in this, but it shows that when the study is well run, the results can be absolutely amazing with telitacicept.

And on that point, we have turbo boosted the start of our global Phase III trial in Sjögren's based on these remarkable results from our partner. We are in the position to announce that we will dose our first patient by the end of the first half. This trial will enroll 250 patients, randomized between active arm of 160 milligram of teli versus placebo during 48 weeks and will follow up for an extension period.

The endpoints will be ESSDAI, ESSPRI and a series of more investigational endpoints, which are very important to characterize the disease because it's an evolving space, again, the white space. There is also a need to accompany the stakeholders in this disease. I'm talking about the KOLs, the partnership, but also the regulators. And again, the timing couldn't be more perfect because others are just ahead of us to kind of clean up the path for approval for this disease.

So fantastic opportunity. And if we talk about business here for a minute, just MG and Sjögren's are multibillion-dollar opportunities for telitacicept. Sjögren's is very difficult to quantify right now because, again, it's a white space. There is -- there are much more patients that we don't know yet. And with our probably best-in-disease profile, we ambition to be definitely multibillion dollars with Sjögren's only.

I'm not talking in this presentation about potential other indications as signified by RemeGen, many others, but we will be disciplined. We'll think about that with time. But keep in mind that the blockbuster pipeline and the product approach is very tangible with telitacicept.

Now to conclude, we have, once again, one of the most exciting opportunities in autoimmune disease with a de-risked asset on the clinical and the safety side. We have 2 great opportunities, one well underway like myasthenia gravis and one where we are pioneering but with an incredible set of assets in our hands here. They are both multibillion dollars. And the midterm catalyst will be top line data for the Phase III trial in MG in the first half of '27. The global Phase III initiated for Sjögren's with the first patient dosed by the end of the first half, and the expansion opportunities that we work on in the next months and years with the right capital allocation discipline. Again, $450 million on the balance sheet, which puts us in a good position to fund our Phase IIIs and the runway into mid of 2028.

On that, thank you very much. And Yaron, open for the Q&A session.

So maybe the first question would be, can you give us just an update? So the myasthenia gravis, you'll have data in the first half next year. Enrollment will conclude first half this year, I assume. Maybe give us a little bit of a sense on that.

Yes. We're trying to stay away from the granular dissection of the metrics on the patient enrollment and everything. It's a spot. It's an art, as you know, with different forces. It's going well. It's very competitive. But what we can say is that we will read out for the top line, but you're in the ballpark.

Okay. And for the Phase III in Sjögren's, can you maybe give us a little bit of a sense on the ESSDAI? How are you thinking about powering it? And kind of what are your assumptions on both?

Right. Remember that the China Phase III trial studied 2 active doses. So they needed more patients. They are 350 patients. We've done the modeling on the bio stat for our own Phase III and with 250 patients, we are well powered. We don't communicate on the numbers here, but we are -- with knowing what we saw on the China data and the fact that we'll have our 160-milligram dose studied versus placebo, 2 arms, we are well off.

And also, the thing is that the next question might be, do you need 2 or 1 studies? Well, we believe that with all the data we have from China, including their Phase III trial in Sjögren's, but also our -- we will have by then our global MG trial, we are very confident that 1 study will be enough.

And the secondary endpoint is ESSPRI. Would patients have symptomatic disease? Or is this mostly in systemic patients? And then would you also do later on a symptomatic study?

So that's actually a great question. We're thinking about the possibility of having other studies segmenting more the patient population because the field will evolve in Sjögren's. ESSPRI is one of the secondary endpoints. We have others that we'll be looking at. And we have been working very hard with the KOLs to try to improve from the learning from actually the BAFF receptor inhibitor, which has published their data at ACR last year. They had actually results that were very interesting to dissect, try to understand why they had such a high placebo rate and stuff like that. And we have optimized our protocol in all dimensions for that.

When we compared your data in China, I'm now moving to the RemeGen data in gMG, and we compared it to, let's say, VYVGART, there is about data in about 27 patients or so that Zai Lab's reported. And we looked at the placebo, the placebo, as you showed, did about 1.6, which is actually fairly typical of other Chinese studies. I think VYVGART actually historically sort of -- there was a little discrepancy between U.S. and international. But if you -- as you think about the global data that you will show, what would you expect to see in the control arm? And then to the extent that you can think about what decrement, if any, would you expect in your active/because I mean you had, to your point, almost a 4-point difference. So you have plenty of room to go in both directions.

Yes, that's the point. Actually, the plenty of room is the message here. We'll probably not have such a low placebo rate. China is usually with low placebo for several reasons. Patients are extremely compliant, I would say, and it's easier to do clinical studies there. But what we know is that we have the room to have a higher placebo rate because we know that our active arm works very well. So we're very confident we can still have best-in-disease. And we have modeled also our outcomes depending on a couple of scenarios here, and we feel very comfortable because it's -- one is the magnitude of the results. But also remember that one of the key differentiating factor is the possibility to dose the product on a regular basis with the drug holidays and with a compelling safety profile. So it's not just only on the pure efficacy. We were very confident on the efficacy side, but you also have to look at how the total package will deliver.

When we looked at UPLIZNA, UPLIZNA showed about a 1.8 point difference and continue to progress and get better with time between 24 and 48 weeks or 52 weeks, you have a broader activity in terms of the long-lived plasma cells and you have continuous therapy to your point, where UPLIZNA is periodic. Does that mean that we can take the UPLIZNA data as sort of potentially a benchmark and that your data might be better with the caveats across trial differences?

Well, that's a very good point to try to make a comparison with the upstream agent. I think the great thing with UPLIZNA is that they are opening -- they are breaking the paradigm of the only IgG effect from -- and very downstream narrow flushing IgG from FcRns.

Now UPLIZNA is actually putting a bit of church in the middle of the village back, which is we have to tackle the upstream thing. Now that being said, they are a bit too much on the upstream because they deplete. And this is where we come because we have the best of both worlds. We have the upstream and the downstream, and we don't deplete. UPLIZNA depletes like rituximab depletes. It's carpet bombs. And I mean, the CD19, I was the CEO of MorphoSys. I launched tafasitamab in what? In DLBCL. It's only recently that the CD19s have been investigated in autoimmune, but it's initially agents for heme malignancies where you really want to blast, basically take away all your B cells.

So I mean I think we will differentiate with a more balanced profile and with the no carpet bombing approach and huge immune suppression, which is not always easy to manage. But again, we welcome UPLIZNA to open the market to upstream agents, which we are part of.

Thank you very much and looking forward to update you on our progress later.