All right. Good morning, everyone. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to have with us, as part of the next session, Vor Biopharma. We have Dallan Murray, who is the Chief Commercial Officer, and Jeremy Sokolove, who is the Chief Medical Officer. Thanks for joining us today, guys.
Thank you.
Any opening remarks you'd like to make before we jump into Q&A?
Well, firstly, thanks for hosting us, Steve. We're very excited to be here. We're very excited to be in the position that we're in. It's just about a year since we've created this iteration of Vor 2.0. We've just recently announced the completion of our global phase III study, and we have exciting data coming up at AANEM that Jeremy can point to later. We believe we have best-in-disease data in our beachhead indication, which is one of the most exciting, dynamic, and rapidly growing markets out there, the MG market. Jeremy also has a global study running very well in children to date. Lots of progress in our first year, but even more opportunity looking forward to the future. Looking forward to the discussion.
Yeah, me too. Great. Maybe just broadly, you can talk a little bit about how you think about the mechanistic differentiation of telitacicept, specifically within myasthenia. I know when you look at the current treatment landscape, there are novel therapies that are targeting either upstream B-cell depletion or downstream circulating IgG. You are kind of the first to combine the two via BAFF and APRIL inhibition. How do you think this differentiation reveals itself in the China data that we have seen to date, and then potentially positions you for commercial success in what is obviously kind of an increasingly competitive marketplace?
Yeah, Steve, that is a great question. Telitacicept obviously is a dual BAFF/APRIL inhibitor, and as such, it covers that upstream and downstream targeting of the B-cell developmental pathway, autoantibody production, all the way back to early B-cell maturation. We think that, often we are asked, "Why would there be such a differential efficacy from your mechanism versus a downstream mechanism such as FcRn or an upstream mechanism such as the CD19?" The answer is exactly as you implied, which we think is that dual mechanism, and it is the ability to have that additive benefit where we first initially see relatively rapid improvement in acetylcholine receptor antibody reduction, and it is that initial effect that is very similar, not identical, to that seen with FcRn. All that time, we are remodulating the upstream B-cell repertoire, and that does two things.
One is it prevents repopulation of that autoreactive B-cell pool, such that we have really turned off the source of that autoreactive B-cell clone and autoantibody-producing plasma cell. Also, we think that the more we see, the more we are convinced there is an antibody-independent mechanism for B-cell-driven pathology in MG. We think that the evidence for that is really drawn by the success, reasonable success, of CD19 targeting. UPLIZNA has a very nice efficacy profile, relatively similar to the FcRns, and the complement inhibitors, but it has a very minimal reduction in immunoglobulin, 9% total immunoglobulin. We do not think there is a directly disproportional reduction in pathologic immunoglobulin. Thus, there must be another mechanism by which this B-cell modulation is resulting in that magnitude of efficacy.
We think that when we look at the curves for the two different mechanisms, FcRns tend to improve relatively rapidly, and then have a period of stability where you do not see further improvement, or you might see a wave pattern where patients actually do get worse between cycles and then get better, versus the CD19 upstream B-cell depletion mechanism, where you see slow but gradual improvement, which tends to further separate even between 18- 24 and 24- 48 weeks. If you look at those two patterns and you superimpose them, that is the pattern we see with telitacicept. We think what we are capturing is that early momentum and increased depth of the FcRn mechanism, and then similarly, the durability and continued remodulation of the B-cell response through the upstream B-cell targeting through the BAFF mechanism. We think it is that additive mechanism.
One investigator used a term, he said, "We're really looking for combination therapies in MG, and telitacicept may be the first combination therapy." Again, it's one drug, but it has that dual targeting mechanism.
Yeah. Steve, to your question of where it positions us in the market commercially, we think this dual mechanism will. It's all going to come down to the data, and we think it will allow us to come into the market with best-in-disease data. I think you can look to argenx in the market earlier, who came in in 2021 with a differentiated profile. If you can show differentiation on efficacy and/or safety, they're dominating the market now. While it's an orphan market, there's no one-time gene therapies. If there's a better profile of a drug coming in, the physician and patient community will move to that new option.
Mm-hmm. Maybe just another quick commercial question. I know that we've seen some recent literature that's been talking about the contribution of IgA and IgM antibodies to the pathology of MG. What are the commercial implications of these findings for Taly? Is this something that clinicians are looking for via serology at time of diagnosis, or is it just really you're an adequate FcRn responder, it might be due to this?
Yeah. Yeah, it's a great question, and Jeremy can talk to what's available diagnostically today. This data that's come out of Yale showing IgA and IgM, is resonating with the physicians because about a third of patients have these antibodies that are fixing acetylcholine, and that correlates with about a third rate of non-response to the FcRn's. There's not a commercially available assay to test this.
But I think that this advantage that we have, that we target IgG, but in addition, we target IgA and IgM, is a key advantage, and it speaks to the unique opportunity we have here. Even if you are on the conservative side, and you don't believe we're going to come in with best-in-disease data, we have a response rate that we think is driven by this broader immunoglobulin coverage, and 100% of patients are getting at least a two-point or greater response on the MG-ADL, and that's unique and differentiated in the market. And we think this is what's driving that. So even if you're a little bit more conservative on the expectations of what our efficacy might be, this IgA and IgM coverage positions us very well for second-line use, even if we don't replicate the delta from China.
Even if we come in with a delta, we lose it entirely, that looks similar to the rest of the market, we have a $3 billion opportunity in second line that we can target. So that speaks to how de-risked the asset is. And the recent launch of UPLIZNA gives us even more conviction on this opportunity because the delta on MG-ADL was lower than what you see in the market.
Okay
Was low too.
Yeah. And their launch is exceeding all expectations, and the company themselves have said they're getting about 50% of their usage is in first-line patients. So it really speaks to the appetite in the market for targeting upstream, a new modality.
Until UPLIZNA launched in December, the biologic market in MG had really just two modalities of FcRn's and complement. So it speaks to that unmet need and the demand in the market for a different modality. Clearly, the current options aren't working for all patients.
Okay. I know you recently completed enrollment in the upstream MG trial. Congrats. I believe this study was already actively enrolling patients when you assumed control from RemeGen. What can you just say about the consistency about the types of patients that were enrolled throughout the change in sponsorship here? I know it's a question that we get from investors sometimes.
Yeah. There was very few patients enrolled during RemeGen's ownership of the study, so the vast majority of patients were enrolled during our oversight. The patients are not particularly dissimilar. I think there was a more rapid uptake in Europe and South America early on during the RemeGen phase. The U.S. sites hadn't really come on board and been aware of the mechanism. I think one of the things that we did, which I think was helpful, was really engaging with U.S. investigators, KOLs, scientists, and really showing them why a BAFF/APRIL mechanism scientifically was a good opportunity in MG, and also making up a good partnership with all of our sites and investigators. I think there's so many good sites and investigators globally, they're just looking for a good partner.
I think really what it was making that partnership both operationally and scientifically, and so most of the patients were enrolled under our leadership. I think that that really will represent a typical, potentially optimal global population.
Okay
-final analysis.
What are some of the key differences in terms of the patient baselines in the global phase III in the upstream study relative to the phase III China trial? How should we think about these differences potentially impacting expectations on the clinical efficacy side?
Yeah. I think the two demographics that are different are the age. It is a little younger in the China population than the global population.
The disease duration is often a little bit shorter in the China population than the global population. That just really represents the referral patterns in China. Patients are referred to tertiary care academic centers that conduct clinical trials very quickly
than community neuromuscular docs. I think that is the main reason we see that. Really, I think the other difference is just there are some cultural differences. Dallan and I traveled to China, went to a couple of the largest sites that were involved in their study and are also involved in our study as well. What we learned was patients in general in China have a slight reluctance to over-report it, to over-reporting. They tend to be a little more stoic, which is why the placebo rates tend to be a little bit lower. It also tends to blunt the active response in patient-reported outcomes. What we find is that in the physician-administered outcomes, like called the QMG in myasthenia gravis, they tend to be pretty similar to the global population.
We hope that the results observed in China will be very similar to the results observed globally for the QMG and the results for the MG-ADL. We anticipate some increase in the placebo globally relative to the China study, but we also anticipate a relatively proportional increase in the active arm relative to the China study. Hopefully, that delta, that effect size is maintained in the global study.
Okay. I know in talking to KOLs, we've heard more of an emphasis on this minimal symptom expression, so MSE, as kind of an important differentiator on the efficacy front, just given that the disease itself is so heterogeneous, and all of these phase III studies are delivering this 2-point MG-ADL delta. How do you think about the competitiveness of Taly on this MSE endpoint? Then maybe particularly as it pertains to this sustained MSE and not just MSE at any time.
Yeah, Steve, I think that's really important. MSE, just minimal symptom expression, just for reference, is an MG-ADL of zero or one. Basically, it's remission. It's great that that's the goal, and that should be the goal. Everyone wants to be free of disease. The reality is the way MSE has been reported has been very variable. It's obtainment at any one point over 24 weeks, any one point over 48 weeks, any one point over four years. Again, that's really not the best way to think about it. Again, like you suggested, we think that patients want to be in MSE, and they want to stay in MSE. That's the sustained durability of minimal symptom expression of remission. That's how we're measuring it.
I think one thing that, I don't want to speak to how other people did it, but I'll just say that anytime you have an MSE report, the question is, over what duration and of what consistent magnitude do you want to see that MSE maintained? In our study that we'll be reporting out at the AANEM meeting next week, actually, we'll be showing both the rate of MSE, but also the durability of MSE. Of those patients who attain MSE, who gets to keep it? The analogy we use is like giving a child a toy. If you give a child a toy and take it away, you really didn't do them any favors. They get pretty upset.
Whereas if you let them keep it, I think that's really the goal for minimal symptom expression and disease remission.
Okay. I know this similarity in, I guess, MG-ADL effect sizes across a lot of these studies has
Yeah
placed a bit of an emphasis on things like safety, convenience, administration. I know there's a lot of patient data to support the safety profile of telitacicept at this point, but can you just talk about where you are with respect to formulation?
Yeah.
The longer-term administration profile you're hoping to bring to the commercial setting and just what the timelines are to get there.
Yeah. Right now we're giving two subcutaneous injections weekly. They're low volume injections, 1.5 mils. At the end of the day, we are looking to reformulate. In fact, we have a reformulation which is active right now. We will launch, anticipated to launch with the current formulation, which is the two shots weekly. That will rapidly be replaced by a single prefilled syringe weekly and an auto-injector option as well. We're leaving both options on the table because we know patients like to have that optionality, both for the providers as well as for the patients. Again, we haven't had a whole lot of complaints about the double injection right now. We don't think that the double injection will be very long in its launch cycle, and we're excited to get a single injection weekly.
Notably, the single injection is kind of the timetable that most people are comfortable with for Myasthenia Gravis , and we think that by following that cycle, we're not at a significant disadvantage. That said, we are doing everything we can to make it more convenient for patients to administer at home.
Yeah, and given our confidence about our value proposition in the market, Steve, we're actively doing life cycle planning, and once we have that once-a-week shot, we'll move very rapidly into an auto-injector.
Okay
For more convenience for patients as well. More to come. We're in this market for the long term.
Mm-hmm. Maybe Dallan, where are we with respect to just the percentage of MG patients who are on a biologic now? Do you think a disease like MS, where I think three-quarters of patients are on a biologic, is that a good proxy for where the MG market expands to over the longer term? I guess, if so, what are the TAM implications of that?
Yeah. It's certainly where we would like to go. We would love to replicate the success of the MS market. It's a great question, Steve, because you do hear different numbers from different companies out there.
The general consensus is that there's a huge runway still to go in MG, that about 20% of the patients with MG are currently treated. As the market leader, argenx, starts to expand out, different companies may have different denominators because argenx is moving to ocular MG, as we will be doing as well, and seronegative MG. Generally speaking, we spend a lot of time talking about differentiation between the drugs here, but the biggest opportunity is the penetration in the market. I think there is a pathway to get there. The market's been growing at a rate of about 60% per year. It's an orphan market with high-value therapies in the market. Part of the— As in any market, there's friction, and that friction slows the rate of patients getting on therapy.
As we see, there's been a predictable 60% or so growth every year. I think the docs are fighting for access for their patients. Just through new entrants like Amgen coming into the market, and we will come into the market, you're going to see that grow and the penetration hopefully get to levels similar to what you see in the MS market. We'll keep fighting for patients and for access for patients. We think there is a huge existing unmet need in this market, both in the biologic-treated portion, but more even in the biologic-naive segment of the market.
Okay. I know that there is another dual BAFF/APRIL competitor that is following you into MG. This is Vertex's povetacicept. I know that they are guiding to, I think, a disclosure of phase II data in the first half of next year. How would you characterize the differences between povetacicept and telitacicept? I guess, how do you think about that data reading through to what you are doing in MG, specifically if we happen to get that before your phase III?
Yeah. Telitacicept and povetacicept are similar. They are both based on that TACI framework. Telitacicept is more similar to the native TACI, which has a 2-to-1 BAFF to APRIL potency ratio. Povetacicept is slightly more engineered for higher potency, but it ends up with a higher potency for APRIL relative to BAFF, and that becomes relevant in a moment. I think operationally, I cannot anticipate too much. What we know publicly is that they are doing a 12-week study. At a 12-week endpoint, I think you may see some significant efficacy. But what you will not have a chance to see is the amount of continued reduction after 12 weeks from that upstream BAFF mechanism, as well as the durability of response. So I would not read through too much from either a highly successful or a highly unsuccessful study with povetacicept should they read out before us.
I think the key thing to understand is that APRIL is a good mechanism for decreasing autoantibodies. We see it with our mechanism, and we will see it with povetacicept. The real ability to differentiate, we think, comes down to the ability to remodulate that upstream B-cell pathway and get that long-term durability that is seen similar to the CD19s on top of what is seen with the FcRns. So we think that there may or may not be the ability to get that long-term durability and continued improvement over time with a molecule that has less targeting of BAFF relative to APRIL. We all dose to APRIL as our goal.
cannot overshoot APRIL, because if you do, you end up with hypogammaglobulinemia, and that has been a risk with several BAFF/APRIL inhibitors. We do not see that because we dose exactly to the right level of APRIL, knowing that we are overdosing on BAFF because BAFF is a relatively safe area to go higher than your target and supersaturate that target. BENLYSTA taught us that 1 mg per kg, 10 mg per kg, similar efficacy, similar safety. Whereas with APRIL, if you go over on APRIL, even by two or three-fold, you can very easily end up with hypogammaglobulinemia. So when we all dose to APRIL, some molecules may under-target BAFF relatively and end up with a loss of some of that long-term remission and that long-term remodulation that we are looking for. On a timeline perspective, again, we think there is an advantage to being roughly three years ahead.
We're completing phase III. They're somewhere middle of phase II. Dallan Murray can speak to some examples of where that first-mover advantage, especially in a rare indication like MG, has just really been a massive separation commercially.
Yeah, Stephen, we think the first-mover advantage is huge here, especially in this orphan market where you've got a small number of neuromuscular KOLs driving the market. Again, we don't need to look beyond MG to see the importance of that. argenx was the first FcRn. They had less than half the lead we'll have over Vertex Pharmaceuticals. The second and third FcRns have hardly made a dent in their market leadership position. So we think it's very important here. As Jeremy Sokolove said, there's important mechanistic differences. Then Jeremy alluded to the dosing to APRIL and the safety potential implications. One of the underappreciated advantages we have is the 3,000 patients that have been studied in randomized control trials with this mechanism in multiple indications and tens of thousands of patients treated in China, so a very well-characterized safety profile at the doses we're going in.
In MG, it's our higher doses, the 240 mg per week. So I think that is going to be important in a market like MG, that long-term safety data and the reassurance that comes with it. So in addition to the three-year head start we have, we have a lot of other advantages that will set us up.
Okay. Maybe just on the ocular opportunity that you talked about. So I know a lot of patients will initially present with ocular symptoms, and then most of those patients will progress to the generalized form. So when you enroll this phase III, are you going to be including some of these early presenting patients with ocular symptoms, or is it just going to be the pure documented ocular pathology? Then do you think that there's a scenario whereby if you intervene early and treat the ocular symptoms, that you can somehow prevent progression to generalized disease?
Yeah. In general, our approach is to enroll what is called MGFA Class I, which is basically an ocular population with minimal generalized symptoms. The goal is really to show the ability to improve ocular symptoms and access that early patient population, which is a gateway to the MG population, larger gMG population. Your second question is a great one, which is, we do think that our mechanism gives the opportunity to have some degree of abrogation of progression from ocular to generalized MG, and that is one of our exploratory outcomes. We are running a 24-week randomized study. We will have an open label extension for at least a year, and so we will hopefully be able to see some separation.
We are not counting on that as our primary approval point, but it is definitely something we think is both mechanistically probable, but also something we can potentially demonstrate during that long-term extension period, which is something that probably won't be demonstrated with FcRns.
Yeah, we are super excited about ocular MG. We are going to be third to market here, and we are going to be first with the upstream targeted mechanism of action. We feel like we got fortunate with ocular MG because if you talk to the KOLs, they will tell you, ocular MG is just an earlier. It is all on a spectrum. It is all MG. I think probably part of the reason that there is only two other companies there is that people probably felt that you were going to get the ocular MG opportunity by default.
But the payers have made it such that you need to do the work here, you need to do the studies, and you need to get the indication for these patients. That has all resulted in us going from being 12th in generalized MG to third in ocular. We are really, really excited.
As Jeremy alluded, it does get us access to these patients earlier. It puts us on an even footing with argenx in what we believe will be a battle for the first-line patients in this market.
Okay. I know we're running out of time here, but maybe you can squeeze in a Sjögren's question. I know you have the phase III that's ongoing. The placebo response, I think, also comes up here, and I think you've got two disparate examples, right? You have the phase III telitacicept China data that had a very muted placebo response. You had the Novartis NEPTUNUS data which had a very inflated placebo response. How do you connect the dots on the differences between those two studies, and then how do you just incorporate those assumptions into your power?
Yeah. We obviously are powering for an effect size that's lower than the one observed in the China study.
We don't think we will phenocopy the China study in terms of Sjögren's. We know we're going to have a higher placebo. If you look at the NEPTUNUS study, it was obviously the high end, somewhere in the range of five. The population tends to, when you remove NEPTUNUS, be somewhere in the range of 2-3. I think we would anticipate that that would be a global population placebo that we'd observe. Whether our active goes up proportionally, we maintain the delta, that would be ideal. But even if it narrows, having a delta that's 2.5-3.5 would be really still a game changer in the field of MG. We anticipate a higher placebo. We're doing a lot of things that we learned from the NEPTUNUS studies and from other studies how to mitigate that placebo.
We've incorporated them into our clinical design, into our study oversight, and we're just going to do our best to make sure that we enroll the right population of patients. We think we have the right investigators on our team, and we're fairly confident that mechanistically, this telitacicept will demonstrate significant efficacy and presumably differentiate efficacy from the two reportedly successful studies that we've heard about, iscalimab, and now more recently, the CD40 from Amgen.
Yeah. Any quick thoughts in the last 30 seconds on CD40 ligand as a target?
Again, the nice thing about the BAFF/APRIL mechanism is it targets the breadth of the underlying immunobiology of Sjögren's. Sjögren's, yes, there's autoantibodies, and those autoantibodies cause disease, but there's also a significant amount of antibody-independent B-cell-driven pathology. One of the things that those B- cells do is T-cell co-stimulation. That's something that also is abrogated by telitacicept. Then there's just the upstream biology of cytokine production, which a small portion of the pathology driving Sjögren's. We think that autoantibodies and FcRns and those type of mechanisms are limited to a proportion of the underlying pathology of Sjögren's, and we think that iscalimab targeting BAFF and B-cell depletion targets only a small portion of the pathology underlying the Sjögren's pathobiology.
We think you really, to get that maximal efficacy in Sjögren's, you need a mechanism that covers the breadth of that B-cell immunopathology, and we think BAFF/APRIL is an ideal mechanism that does that. There's translational data to support that. There's the China efficacy data, and hopefully there'll be our data shortly to show that as well.
Wonderful. Well, we are a little over time, but I appreciate you guys taking the time to speak today, and we're really looking forward to what should be incredibly interesting next six to nine months.
Yeah. We are really excited for our readout in the spring, and we are looking forward to taking you along with us.
All right. Thanks again, guys.
Thanks for hosting us.
Bye.