Immunovant, Inc. (IMVT) Earnings Call Transcript & Summary

We're joined today by Dr. Peter Salzmann, the company's CEO. And in terms of format, there will be a presentation on the background and positioning of Immunovant FcRn inhibitors and then this will be followed up for some Q&A. And with that, over to you, Pete. Thanks, Sam.

And I appreciate the invitation to be a good amount of material. So I'm going to, as you mentioned, go through that material, then we'll have plenty of time for Q&A. We'll be making some forward-looking statements today, and I direct investors to carefully read this statement, which is part of the 8-K where we released this slide deck this morning. Just for a quick orientation. These are the programs that we have in development across our 2 assets, pitolimab and 1402 today, post education on a lot of preclinical biology related to 1402. And then also, you talk about chronic inflammatory demyelinating polyneuropathy or CIDP in our program there. which is clearly a lot of interest given potential data readouts from getting to the file in the first half of next year. We may touch on some of the other programs during the Q&A, but I won't cover them in [indiscernible]. [indiscernible] we to cover, and without reading everything, you'll see that the first 4 items relate to 1402 and also some foundational Fc [ biology ] so that we can draw some conclusions and some -- sort of interpret the data that we've shared with regard to our 1402 asset, and then I'll go to the CIDP design. Okay. So starting at the very beginning with autoantibody-driven diseases. This is a new slide put together because I think the class, which includes many, many indications, if you look at what is all being studied by 1 or more competitor, has grown to include not only classic autoantibody conditions, like myasthenia gravis, thyroid eye disease, warm autoimmune hemolytic anemia, but now also conditions where autoantibodies play a role and may play a role in disease pathogenesis directly like they do in myasthenia gravis, for example, or they play a role through forming immune complexes with their antigen and you get [indiscernible] auto antibodies and antigens kind of forming up a larger immune complex, which then activates other components of the immune system. Those are -- those biologies are -- have some important differences [indiscernible] and probably most importantly, that anything that's immune complex driven is likely to have a broader immune system activation, and therefore, may need a deeper and more prolonged production in the autoantibody in order to get the disease under control given the antibody is just going to compete. But we've already seen in our some of this data that even in classic IgG auto-driven conditions, there is a correlation between depth of autoimmune reduction and clinical response. So our takeaway is that it's important to be able to deliver a wide range, including saturating top of the curb reductions in IgG in order to -- in order to address the full range of clinical [indiscernible]. For those who are a little newer to the story, one of the things I love about this mechanism and what attracted me to Immunovant in the beginning, was it simplicity. Many immunologic mechanisms are complicated. There's an interplay between cytokines and cells. And so when you're in an early stage development, there is a fair amount of uncertainty in terms of how the change in the biology that you effect with a new medication actually leads to clinical impact. But in this case, it's very simple, which is, you see the green antibodies here. These are endogenous antibodies being recycled by an endothelial cells. So this will be a cell sort of remaining a blood vessel, for example. And this process of kind of constantly taking [indiscernible] out of the bloodstream and then breaking it down into its amino acids is important so that proteins in the bloodstream, which are [indiscernible] don't have a signal that lasts longer than a couple of hours. Signal proteins usually responding to some dynamic event and so you want the signal to be degraded. Immunoglobulins are different. The free floating of antiglobulin are just there waiting to see if there's a pathogen. And so recycling them and having a very long half-life is useful. FcRn inhibition evolves either an antibody [indiscernible] fragmented. Here in the Fc receptor prevents the endogenous antibody from being recycled. And so it then gets shuttled to the lysosome along the proteins and the grade into its amino assets where those can then be reused. So there are multiple FcRn inhibitors in development, and they have a lot of similarities, actually, in terms of the ultimate goal, which is the pharmacodynamics, but there are also some important -- there are important differences, both in terms of the foundational biology. And then there are maybe even more importantly, differences in terms of the degree of IgG reduction that can be achieved and how easily that can be achieved [indiscernible] a little bit later in the presentation. But because we have unveiled a new anti-FcRn, this is the first new anti-FcRn in quite a while, I have gotten a lot of questions back to the preclinical data, which was something I used to review in detail a couple of years ago and since there hasn't been a new NTFs FcRn lately, this has not been such a topic of discussion until we unveiled 1402. So we wanted to sort of just this information off and kind of organize it all in 1 place. So the first thing that you see is there are some differences in the backbone. Batoclimab and 1402 have a very similar [indiscernible] IgG1s, but beyond both IgG 1s they're very, very similar. They come from sort of the same family of antibodies that were in both cases, originally discovered or developed by at all and both were licensed [indiscernible]. [indiscernible] IgG1 fragment and batoclimab is also a human IgG1, whereas was Anelixizumab and Syntimmune antibody AstraZeneca, or IgG4s. So there's some differences in sort of the scaffolding or the structure of the antibody. In terms of Fc receptor potential, you see the information we've been able to find from public sources. And importantly, nipocalimab, agatigumod, batoclimab, IMVT-1402, when you test them in vitro and standard assays, which are used to determine whether the effect potential has been -- all score negatively. The mechanism of deactivating effector potential is a little bit different in the case of antibody by antibody, but the end result is [indiscernible]. Then we get to a topic that generates a lot of discussion and probably generates more discussion than it is actually relevant. But I think because it generates so much discussion, it's worth reviewing and that is what is the binding affinity at different pHs. So the pHs 7.4 and that's important because that's the pH in the blood stream, for example, with Fc receptor the cell surface and that endoscopic vessels first being formed. Once the vessel forms and it's -- and it brought intracellularly, then the pH drops. And that's important for the normal recycling of IgG because I don't have it on this slide, actually, but endogenous IgG does not bind to the Fc receptor at a normal pH, pH of 7.4, but does bind to the PA to the preceptor at a acidic pH. And that's what allows the recycling. Otherwise, IgG -- normalized IgG would just get stuck to the Fc receptor. But since it comes off the Fc receptor at a normal pH, it's protected intracellularly and released extracellular. So that's for a normal endogenous IgG binding at its Fc site. The Fc inhibitors, of course, don't bind their Fc site [indiscernible] the antibodies bind they're are variable regions, and that was kind of shown, applied as the other end of the antibody, which is where those variable regions are. So what is the binding affinity between the variable regions of different antibodies and the Fc receptor [indiscernible] the change, depending on whether you're a visual pH or an acetic pH. and you see that for the antibodies, our batoclimab, 1402, [indiscernible], in particular, really on those, for today, the binding affinity is pretty similar, whether you're looking at acidic pH or mutual pH. There's not a full order of magnitude difference. The largest difference, I guess, on a relative basis is for etokimab is a little bit more icebound and the acetic PH the neutral pH. But for [indiscernible], there is a pretty big difference. There's more than a tenfold difference per inning. And so the [indiscernible] will be less likely to find in this in vitro analysis just generally because a larger number is associated with the less tight binding or smaller numbers associated with the type finding. But at the neutral pH, the binding affinity is a lot lower than what you see for the other ones as represented by a larger [indiscernible]. So whether that has much impact or not on the ultimate thing we're all trying to do, which is lower IgG, it probably has some impact. And from the perspective of Immunovant, our 2 assets, you'll see that if we compare 1402 to etokimab that these binding KDs are a little bit lower for 1402 than teprotumab, meaning 1402 is a little bit more hopefully binding the Fc receptor [indiscernible]. I'm not sure these differences -- in fact, I'm pretty sure these differences aren't going to be big enough to matter, meaning that the amount of 1402 that will need to achieve the same degree of IgG lowering teprotumumab has shown is probably going to be pretty similar. But I suppose if they're going to be different, I'd prefer for the 1402 to be a little bit over, and that's what it is. The other topic that as a lot of discussion is half-life and half-life is very tricky for FcRns since there's a target-mediated disposition and there's a lot of variability based on the dose, whether you [indiscernible] Fc receptor or not since it's involved [indiscernible] disposition or recycling of the asset. So this is an area that I think is generally just not too helpful, particularly because there is so much data on the pharmacodynamics. And the pharmacodynamic curves, the slope of the curves are very similar across all these assets. The depth of the curve, meaning how much IgG you get is dose-dependent and asset dependent, but the time to peak reduction and then to recovery is generally a matter of weeks for all [indiscernible]. We don't see big differences even though there are some big differences in the PK half-life. Okay. This next section deals with crystal structure, and this, I think, is a very interesting information. There is some data available that we found publicly beyond just etokimab and 1402. We start out with just the endogenous proteins, the -- just to orient everyone here, the purple and the yellow ribbon structure is the FcRn receptor. And here's a structure of the FcRn receptor binding to the Fc portion of an endogenous IgG. So you can see that the IP mining site is over here, 4 o'clock or so. And then on the left side of the slide, you can see the crystals picture between Fc receptor and albumin. Albumin is also recycled via the Fc receptor and albumin also has a much longer half-life than many other routines. The binding side [indiscernible] is different. It's over here at sort of 10 o'clock on the Fc receptor in this orientation versus the IgG binding site with the other side. When you put the 2 -- when you overlay the 2 best structures, keeping the Fc receptor kind of the same so that you can do that overlay, you can see that the Fc and albumin don't appear historically to interfere with each other, which makes sense given that these are recycled independently. How does 1402 and how does etokimab bind to the Fc receptor. So here, we have some other cocrystal structures. We have the cocrystal of etokimab, cocrystal structure of 1402 with the Fc receptor, again, kind of always keeping the subsector in the same orientation and the binding site and the etokimab mining side are similar. They're not exactly the same, but they're slightly different episode -- epitopes within this general IgG binding site. And you can see that 1402 binds in a steroid orientation that's closer to this natural steric orientation of an Fc and indigenous Fc IgG binding. Whereas batoclimab, although it clearly inhibits IgG binding very well since you can get to a saturating dosage at reasonable milligrams, the 680-milligram, gets to a maximum IgG reduction, which is about 80% [indiscernible] locks the IgG binding site very well, but its steric orientation is in a different direction. And when we put -- I'm just going to skip ahead and then come back. When we put all 4 proteins together, you can see that the batoclimab is sterically interfering with albumin, which is probably how it -- why it causes a reduction now, and I'll come back to that in a second. So just looking at 2 other publicly available cocrystal structures. The teprotumumab the data that we were able to find is the Fc is in a slightly different orientation. So you can see we put it in a different color. It's not exactly lined up like [indiscernible]. But I think you get a general sense that it binds probably very similarly to an endogenous IgG, which makes a lot of sense because it's binding in the same way as an endogenous IgG. Syntimmune also mind similarly from a steric orientation standpoint as does 1402 and efgartigimod and the Fc receptor. So etokimab is kind of the outlier in terms of how it binding. We weren't able to find any publicly available information for nipocalimab's [indiscernible] don't have any idea how nipocalimab binds to the Fc receptor. Okay. And then returning to the -- our 2 assets and kind of putting everything together, starting on the right with batoclimab, which I already referenced briefly. Batoclimab binds to this IgG binding site. -- is steroid orientation is such that there's an overlap, probably the overlap here between albumin and batoclimab when they're both rebind the Fc receptor. So although it doesn't block the albumin binding so building into albumin and probably inhibiting or making it a little bit more difficult for albumin to buy [indiscernible], which is why you get a dose-dependent reduction in albumin [indiscernible]. On the other hand, 1402 in a moment, did not lower albumin at saturating doses in the cynomolgus monkeys. And then that makes some sense given that its organization is much more similar to [indiscernible] Fc and it's doesn't appear to be moving anywhere further. So those are all human co-crystal structures and that's all human data. We don't have human data yet for 1402, but we do have data from cynomolgus monkeys. And what we see in this head-to-head cynomolgus monkey study is data from 4 different test articles. So we tested batoclimab at 50 milligrams per kilogram, which is about 5x the saturating dose of etokimab when we study batoclimab and other monthly studies at 10 milligrams per kilogram, that's saturating monthly. So 10 milligrams per kilogram of batoclimab [indiscernible] 680 milligrams, [indiscernible] human. This was weekly basis. It's great here it's down here. So we chose 50 milligrams per kilogram on batoclimab just to make sure we had a very saturating dose and we wanted to be able to compare that very saturating dose of batoclimab to likely very saturating dose of 1402 with regard to albumin and cholesterol. So we wanted to flush any signal out if it were there. Remember, I showed you that the binding affinities between these 2 are pretty similar. So we expect the milligram per kilogram impact to be similar between batoclimab and 1402. And what we see is that the saturating dose of the -- supersaturation dose of batoclimab does what we expected and what we've known from prior homologous monkey studies, which is that it lowers albumin, these thresholds are referred to upper and lower [indiscernible] they are slightly different than in people. And you can see that curve that comes down in a couple of weeks and then recovers [indiscernible] weeks, which we're well familiar with. We looked at that high dose of 1402, and we did also a lower dose of 1402 that was more to see the impact on the [indiscernible], which we'll get to an amended and then placebo. If we look at albumin, there's some variability in albumin measurement for all 3 curves because there's just some variability, in fact it's a good but very little assay has some variability. The placebo, the high dose and the low dose 1402, all basically look the same and particularly after 4 doses here, you're looking at this fourth dose was given here in this -- the albumin right after the fourth dose was really pretty much overlapping central tendency between high-dose 1402 and placebo. The low-dose 1402 actually had a little bit higher albumin. I don't think that 1402 is raising albumin. Again, it just goes to show you the variability because I'll start here at the same point. [indiscernible] variability in cholesterol and LDL just as a measurement. Part of that probably has to do with the cynomolgus monkey biology and some of it may outside a little bit the assay. But again, we see batoclimab clearly separating from the other 3 lines, whereas the high dose, low dose, 1402, more or less overlapping placebo, particularly if we go out here at Day 4 , they're pretty much [indiscernible] Okay. So then 1 of the questions I get a lot of questions on is, remind me what did the data look like for the other assets? And how much can we expect this data in the monkey to translate -- in the cynomolgus monkeys translate to humans. And I think the trends have always been consistent. So efgartigimod does not show change, and this is all public data, we were able to find the proton down here, did not show any change in monkeys, didn't show any change in humans. [indiscernible], no change in monkeys, no change in humans For [indiscernible]. [indiscernible] there's not much data published, but we were able to find some commentary from [indiscernible] that they did show differences and really been in the multiple dose studies in the monkeys and that was shown [indiscernible]. [indiscernible] has very small changes, 1% to 13%, which is kind of within the range of variability in 1% to 5%. So either it's sort of no difference or maybe a very small difference, but in any case, it was consistent. Batoclimab observed differences and then there goes dependent differences [indiscernible] in monkeys and humans, and 1402, we also have a lumpy data [indiscernible]. So if we can buy on these trends of these other 5 assets that we would expect not to see change. The reason they have no or minimal is because, obviously, you can't say exactly 0 with a study of the size. But again, if we look at the end of 4 weeks, look at that central tendency, it really looks like there's essentially no change. Whether there's a tiny level change in either direction, we can't exclude that, but we're not seeing much there. Okay. How about on the IgG side, that's great as long as we're also reducing IgG as strongly as batoclimab. And here, we have the comparison. Again, these are both high saturating doses but they're essentially in the same. 5 milligrams per kilogram is not a saturating or modeling with the batoclimab also when we tested on these was 10 milligrams per kilogram. [indiscernible] low doses of a test article, which are doing safety studies in the monkey. But when we model what 5 milligrams per kilogram would do with batoclimab in a monkey, it looks [indiscernible] does here, which [indiscernible] similar time, I think of this as kind of the 340 equivalent, and this is like the 680 equivalent for batoclimab. So this all looks good and very consistent with what we would expect from an antibody that's likely to have very similar IgG [indiscernible]. What does that all matter? What does -- what do we get with IgG lowering? And what we get is a nice continuous relationship between the degree of lowering and clinical response across a range of conditions. So this is data from the efgartigimod myasthenia gravis Phase III trial. We have a similar curve from nipocalimab Phase II trial, which was a large Phase II with multiple doses, so they were able to really define this well. And essentially, we were seeing on x-axis is changed in IgG and along y-axis change in MPDL and there's a nice looking at this 1 is kind of a small picture, but the p-value is very, very, very low here, very strong [indiscernible] and same with the efgartigimod data. And it was a small trial, but even our small trial was consistent with [indiscernible] 340 and lesser IgG reduction and lesser autoantibody reduction. And although it was different than placebo and similar to what other antibodies or inhibitors have shown with a [indiscernible] patient reduction. The 680 [indiscernible] was better on IgG and better on MG-ADL which is why we included the 680 in the induction portion of MG trial. In thyroiditis, we actually tested 3 different doses and again, sort of same pattern, higher IgG reduction. This is through 6 weeks. So it was a 12-week study, but we're doing this [indiscernible] of 6 weeks because that's when we had the most patients had completed 6 weeks since the tie-up study was [indiscernible]. This slide refers to sort of a threshold effect of the stimulating autoantibodies if you get below [ 140 ] where they thought to go from having a stimulating effect to no boating a stimulating effect at the 140 threshold means that you would then be sort of similar to a normal for that didn't have salaries domain hormone receptor antibodies. And you can see that a greater percentage achieved that sort of normalization on the 680 dose, and that's not surprising because you had a lower overall reduction in IgG. And again, the proptosis response was stronger in 680, we also have CT scan data that we've shown previously, where we had a bigger impact in 680 versus the 340 ml versus the 250. So a lot of those rents there. Different conditions ITP. This is a nice large study that [indiscernible] with a lot of different doses, range of IgG reduction, again, dose-dependent [indiscernible] platelet improvement. And then the [indiscernible] pemphigus vulgaris study, they had different cohorts in terms of duration of therapy and frequency. The 2 cohorts that had the most IgG suppression for the longest period of time had, you can see here the max IgG reduction was lower and the complete response rate was higher and the relapse rate was lower. So [indiscernible] correlation across every disease where multiple doses have been tested between [indiscernible]. So we don't think that there's a threshold effect, by the way. There's not as much data when you get out [indiscernible] reduction. But I don't think that this curve suddenly flattens at 60% or 65% and there is no benefit to be had beyond 60% or 65%, which is sort of what most FcRn inhibitor deliver. And efgartigimod at the doses it's being studied generally delivers around a 65% reduction. At a much higher dose, it would probably also deliver a higher reduction in IgG, but the doses that are being studied delivered this 65-ish percent reduction, we think that ore is going to be required in many cases for different patients. And that's a big advantage of etokimab for a period of time of deduction and potentially a big advantage for 1402 for long term [ immune ] therapy. So again, multiple lines of evidence that greater IgG reduction yields greater clinical response and then, by this column here of IgG reduction. This is organized as sort of the different -- several different assets and then whether they impact albumin or LDL, whether they would [indiscernible], which they reduce round of administration, things like that. This is probably the most important column here because efficacy, we believe, is going to correlate to a degree of IgG reduction. It's not going to stop at 65% and efficacy differential differences are probably 1 of the biggest differentiators product to product [indiscernible], particularly and diseases that have a lot of unmet need. So most of the other assets are really delivering IgG reductions in the 65% range. [indiscernible] does get a little bit higher, but that's for short periods of time and the higher doses are associated with a pretty high rate of headaches. So that may be dose-limiting. It also has some limitations in terms delivery mechanism with a subcu fusion that takes quite [indiscernible]. So there are several -- although it does deliver a little bit higher IgG reduction, there's things that may limit that as a -- from a practical standpoint. Similarly, in nipocalimab, when you give it in high doses intravenously, also [indiscernible] IgG up to 80% or even a little bit filer that they reported. But in the dose that's being studied here, this refers to the nipocalimab dose in their MG trial because that's [indiscernible] publicly available, and it's 15 milligrams per kilogram every 2 weeks after [indiscernible] 30 mgs per kg, that dosing regimen, we estimate is going to also be in the 60%. So batoclimab can do that with the 340-milligram dose, but what we can also do with batoclimab is achieved this 80% reduction, which we believe is going to be important for differentiating on efficacy and the 1402 pans out in the in humans as it's looking very productive in the [indiscernible] to be we'll be able to do that similar reduction without having an impact on albumin and LDL, which would [indiscernible] in terms of product profile. Both batoclimab and 1402, and we plan to make available through [indiscernible] is already being used in the clinic as a simple subcu and by simple subcu, I mean it's normal preparation, normal, like a lot of other bio concentrated with regular excipients and deliver it in a [indiscernible]. We have a similarly concentrated form of 1402 that we'll use in our [indiscernible] trial and the viscosity and needle are same or similar same for the needle gauge, similar from viscosity. So we expect the dosing experience with 1402 to be [indiscernible] better than the dosing experience with competitors. Great. I'm just going to touch on CIP super quickly, and then I want to leave a lot of time, Sam, for Q&A. I know there was a lot of information, but we've been getting a lot of sort of second and third order question, so I wanted to have an opportunity to go through detail across the [indiscernible] lot of that data. With regard to CIDP, I'm not going to run through all these slides. They are available on our website, and we discussed some of this information. But we see this as a really exciting opportunity for patients and commercially given the amount of IVIg that's used for CIDP specifically. And although IVIg works well, it does have some significant limitations from a logistical standpoint and tolerability standpoint. The interesting thing about CIDP, of course, is that there's not as much clarity in terms of [indiscernible], which autoantibody is causing the disease. There's some nice science that [indiscernible] probably the most detail that shows the transferability of the sort of CIDP condition to animals using sort of a serum solution, which is a cellular and suggests that there must be some protein present in patients with CIDP that's causing the disease, and that's kind of almost certainly an antibody. With [indiscernible] hasn't been identified, it's the antibodies that have yet to be identified, but are probably causing the disease or some of the antibodies that have been identified are finding mostly to the [indiscernible], and that's going to reduce neuro conduction [indiscernible] CIDP. FcRn inhibition, as we've already shown, reduced the autocode by having them be degraded and not recycle which then can allow your [indiscernible] to recover. So that's the basic idea. We have a lot of respect for the careful thought that [indiscernible] put into their trial design. This is a tricky disease to design a study [indiscernible] for different reasons, and we think there are a lot of things that they did, which were really clever and we [indiscernible]. As we are looking to think how could we make our trial even a little bit better, we made a few changes. So the double enrichment, which is really the critical innovation, I suppose that argenx brought to study in this disease space with not only and with ratable to demonstrate that patients have disease activity [indiscernible] sufficient to show a difference when you eventually get to the test portion of the trial, but also that they will [indiscernible] on open-label investigational product, which we should screen for those portion of CIDP patients that have an autoantibody-driven condition. [indiscernible] we think actions, and we did that as well. We added a third enrichment, which is we're restricting our primary endpoint just at the IVIg, subcu IG or flex cohort. And the reason is that we believe the effect size is likely to be the largest for that group because you can completely remove that therapeutic agents. Whereas for steroids, it's a lot harder to fully taper steroids, assuming people are on or dose of steroids. Because if you fully taper them over a short period of time, you're going to have steroid [indiscernible] during the study. And the other enhancement we made to our trial was to include more than 1 dose in this open label period. That takes advantage of batoclimab's ability to deliver that higher level of IgG suppression along with the standard IgG suppression of 65% and really will be the first meaningful set of data that will allow us to understand whether there's a dose response or an IgG reduction response curb in CIDP. I think there probably is, but we don't know the size or magnitude that. If it turns out there is a response, which I believe there is, and that it's significant, then that would even more so support not only batoclimab, which can be used at that high dose in the -- in an induction period, but also potentially even 1402 in the maintenance period. [indiscernible] this trial design, I probably just won't go through a detail here, but Sam, if you have questions, we can come back to it. And it's something we've discussed previously. But at the end of the day, for CIDP specifically, we see this as a very exciting indication. We think that the argenx double enrichment trial zone is a really attractive way to provide really meaningful scientific information to physicians and patients about the global and CIDP, but we think we can improve on that even further with the changes that I mentioned that we've incorporated [indiscernible]. And those changes, not only are maybe some improvements on the trial design, but also taking advantage [indiscernible] properties of batoclimab, which is to deliver [indiscernible] to deliver all the IgG [indiscernible]. So with that, Sam, I will take the slides down.

Awesome. Thanks, Pete. Next as mentioned, we'll go to some Q&A on some recent questions we've got in. I guess, first, regarding your crystal structures and preclinical data on albumin with batoclimab and 1402, there's been some questions recently on just minor immunoacid differences between nonhuman primates and humans and whether that could impact the translation of your data in cynos versus humans. I guess just any insights on this, in addition to just your confidence in the translatability of these animal data?

Yes. Yes. It's interesting as we've unveiled 1402, I've gotten kind of and myself in a lot of the details of preclinical models that are used [indiscernible] and others. So with regard to nonhuman primate study specifically, we're only using cynomolgus monkeys not [indiscernible] monkeys cynomolgus monkeys and humans have very high sequence analogy for their FcRn [indiscernible]. And for the IgG binding sign for batoclimab and 1402, there's 100% immunoacid homology between the cynomolgus monkey and the rhesus monkey Fc receptor. I understand from others that there may be some differences in the rhesus monkey, but again, we're not using a rhesus monkey in our studies.

Got it. And then in cynos, you showed multi-dose PD data earlier within the slide deck on IgG levels of 5 mg per kg and then 50 mg per kg for 1402, and then 50 mg per kg for batoclimab, which was a supersaturating dose to your point. I guess as we think about the translation of IgG lowering into humans, you mentioned that they're expected to be relatively similar. So I guess, is that kind of a per dose level in the sense that up to 680 mg or whatever you can fit in that amount of injection that should be relatively similar?

Right, exactly. So I think there's probably likely to be some small differences that won't be in terms of the total milligrams and the [indiscernible] and those sort of things that we really care about. The advantage we have with batoclimab is we have a single prefilled syringe, 340 milligrams, that delivers standard IgG suppression standard is 65%. That's what you're getting with roughly with the argenx preparations and with others that are competitive. And then we have -- by using 2 syringes, we can get to a saturating level of FcRn suppression that gets you to the maximal IgG suppression of 80%. So that's very simple. You got 1 or [indiscernible]. You don't have to have different views. You don't have to measure different amounts of drug. It's very, very simple and straightforward. We expect to replicate that for 1402. The exact amount of medication might be slightly different. It might not be exactly 340, not exactly 680, but it'll be similar. I say they'll be similar, I predict it will be similar because the binding affinities are close, and to the best that we've been able to compare, the sort of a little bit larger set of monkey data we have in-house, batoclimab and 1402 look quite similar from an IgG lowering. [indiscernible]. So that's in terms of the potency piece. And then in terms of the concentration, the concentration of 1402 in terms of the milligrams per milliliter that we will be testing in our Phase I study is very close to what we're using for batoclimab, which is 170 mg per ml. So I think we're going to have a very similar form factor for 1402 than for 1402 and batoclimab.

Got it. Super helpful. And then going to indications because batoclimab and 1402 should work in all the same indications more or less. How are you thinking about the best indications to advance 1402 in versus batoclimab?

Right, right. That's a really important question that we're spending a lot of time thinking about it, and we will continue to spend a lot of time thinking about over the 6 months as we prepare for success with our Phase I trial and plan to be ready for that. I think it's both an important sort of short-term and medium-term question. The short-term question is what to do with our current 4 programs that we're running for batoclimab? So let me start with that 1 because it's kind of concrete and I think relatively straightforward. So if I take the 2 really straightforward ones first, for Graves' disease, that's a proof of concept, which we need in order to know how to design a pivotal anti-FcRn trial in Grave's disease. That trial will finish -- batoclimab will finish about that similar time frame that our Phase I data is available for 1402. And as I said before, I think there's a good chance that we'll pivot to 1402 for Grave's disease and run the pivotal trial with 1402 So the batoclimab proof of concept can accelerate our development program of 1402 in Graves, assuming [indiscernible]. The next one, I think, is pretty straightforward in thyroid disease. That's fixed-duration therapy. And over a 6-month period of treatment, the difference between batoclimab and 1402 has been so significant. So 1402 is, obviously, just going into healthy subjects beginning of next year, where [indiscernible] starting up a Phase II program in thyroiditis [indiscernible] running the book program in thyroid disease makes a lot sense. CIDP, you saw that we have 2 doses in our open-label lead in. So that will give us a hint of dose response even with the final trial is completed. [indiscernible] there's been the subsequent randomized [indiscernible]. And then we'll have data from argenx to give us also some [indiscernible] in terms of the effect size of FcRn inhibition and CIDP. Depending on what we see there at the end of the day, if we think that more is definitely going to be better in CIDP then we may pivot that program to 1402. If, on the other hand, we raised, and I would be surprised, but if we're surprised and 65% delivers kind of everything you could ever hope for in CIDP. And it seems that we've reached a ceiling of efficacy with 65% reduction, then batoclimab probably is -- we just keep going with batoclimab and CIDP and it will compete on a better [indiscernible] with argenx there. So that leaves myasthenia gravis. Myasthenia gravis is a really important indication for the FcRn mechanism. It's a little bit larger patient population than many of the others. It's [indiscernible] most -- there's the most data. The standard of care is hard, I think what an FcRn can offer. Our myasthenia program has many points of differentiation that take advantage of batoclimab's ability to provide flexible IgG lowering kind of deploring upfront, lesser IgG lowering over the long term, both of those, I think, the flexibility [indiscernible], I think, is important. So I see batoclimab is really competitive at the time of launch, assuming our Phase III hands versus [indiscernible], which is the [indiscernible]. So that's why we're continuing that program with enthusiasm. Will we eventually [indiscernible]? Yes, maybe, I mean it's a really important indication. So whether it's in the first wave of indications comes later [indiscernible]. So that's kind of the program by program answer. Conceptually, 1402 offers an advantage whatever you need deep IgG suppression for longer than 12 weeks, because we're using 680 just for 12 weeks of batoclimab. And I think that's going to be a lot of different indications where that could provide [indiscernible]. If we take a couple of categories of indications where I'm quite certain there'll be that need for longer [indiscernible], it's indications in rheumatology because you have [indiscernible] immune activation and there's immunocomplex, as I said earlier, those [indiscernible] a little bit longer to bring to disease quiescence. Hematology because you have a lot of the antigen burden, there's just a lot of glycoproteins or many, many blood cells. And then in Grave's disease, based on the land bit of information we have from our thyroid disease program, it looks like variety to production for a longer period of time is probably going to be [indiscernible] IgG reduction. And given how exciting it integration that is because it's a bit larger and first in class and there's really not much innovation there, that one is probably better [indiscernible].

Got it. That's helpful. And then for the upcoming CIDP study, just kind of what gives you confidence that the trial could be registration-enabling? And then depending on whether it is registration-enabling or not, how are you going to think about that switch between batoclimab versus 1402 for that next stage?

Right, right. So each division approaches the requirement for substantial evidence [indiscernible] trial data a little bit differently. Neurology division is generally amenable to a single adequately -- a single adequate well-controlled trial that's specifically and statistically persuasive to use in the FDA's language there. And I think that's been shown to be true in myasthenia with [indiscernible] assets, and it's probably true in CIDP as well [indiscernible] I say probably is because, again, the effect size of CIDP is not as clear as it is in myasthenia. Randomized withdrawal trial design is a little less standard. But all that being said, I think the -- you see from the actions of argenx, Janssen and Immunovant, companies that care a lot about this condition in this class and they've had [indiscernible] a single pivotal trial. Our trial is a little bit smaller, and we designed that as a little bit smaller so that we could react to data that was coming out from competitors as they release data and anything else we learned along the way. That gives us the flexibility to either simply upsize the trial if it makes sense to have a little bit reference, which is a little bit larger. Alternatively, if we learn something along the way that says a different trial design might be complementary either from the standpoint of achieving registration or from having a differentiated data package, we haven't committed to a very large trial, and then we're in a little bit trickier spot to add on that second trial. We're having a smaller trial [indiscernible] because of the perfect size that we predict in the IgG-only cohort. We have the flexibility to either upsize [indiscernible] or have a different trial. That's why I sort of [indiscernible] CIDP. Since then, of course, we've unveiled 1402. So then the other option that we have built in [indiscernible] it looks like more is better for [indiscernible]. We consider [indiscernible] program to 1402. So what are the most important [indiscernible].

Got it. Understood. And then for WAIHA, I guess, when can we expect an update on that indication and potential both forward plans?

Yes. Thanks. Great question, Sam. We'll make an update for next year? So what we have been saying with WAIHA is that we are going to make a decision on whether to study 1402 or batoclimab in WAIHA, based on an FDA interaction -- the second half of this year and year. So that interaction has occurred, and we're now kind of taking a look at the feedback that we received. We had a very good discussion with the hematology division, which allowed us to explore different trial designs and some creative ideas to begin with. So now we're taking that team back together with, again, what we know about batoclimab and what we predict for 1402 to make a final decision about how to go forward in WAIHA. I expect we'll make that decision earlier [indiscernible].

Got it. Okay. And then you showed some informative slides on just a correlation between IgG lowering and clinical activity. I guess, is it expected that lower is better across autoantibody-driven indications? Or is there a threshold effect in some diseases?

Yes. I think when you're try to get initial control, to me, all the data suggests for us better. And when I think about the fundamental biology, you have a -- the disease-causing auto antibody and you're, on average, reducing it by 65%, I say out of [indiscernible] we look across all the different assets, including the 340-milligram batoclimab, which is a good reduction, but it's not 95% or 98% or something like that. So I would have -- I would have expected prior to seeing any data that more would be better, but particularly between the range of 50% or 60% reduction and 80% reduction and I think all the data supports that. So I think both pretest belief and the test as shown that more is better. Now what about in the longer term there, I think the answer could be different. A really interesting paper that looked at some of the more complete responders or people who achieved remission in the pemphigus in the Phase II pemphigus trial with [indiscernible]. And some of the patients who were treated with a higher dose, there are more patients who are treated with a higher dose and were treated longer through [indiscernible] remission as defined by the disease activity was absent for a while many weeks after stopping efgartigimod therapy. And when they look at those patients who had a remission or a deep response compared to those who [indiscernible] than relapsed or those who didn't have a response. The ones we had a deep response in the state and had a remission, their auto antibodies didn't come back with that same pharmacodynamic curve that [indiscernible] IgG came back. So total [indiscernible] recover antibodies stayed lower. And then they did some really interesting science where they actually looked at auto antigen-specific B cells and found them to be dramatically [indiscernible] therapy was stopped. So potentially, the FcRn inhibition was somehow sort of resetting the immune system to use a kind of [indiscernible]. In those patients, specifically around the auto antibody-producing B cells, we do think that there's a lot of reason to believe that once you've achieved disease control, maintaining it will require less IgG suppression, whether that [indiscernible], meaning you only need 50% or so or whether just the curve shifts and you just don't need as much. That's maybe a little bit semantics. But I do think in the -- when you're trying to get patients well who are sick, more is going to be better, generally speaking. When you're got people who've achieved the clinical response and you're trying to maintain it, I think in those cases, there'll be [indiscernible] people will be able to go down or potentially even come on the FcRn inhibitor [indiscernible].

I guess, with that in mind, for the maintenance dose that you're using in studies with dupoclimab, do you expect that it will compromise efficacy at all versus using a dose that is continually maxing IgG lowering such as 1402?

Right. Not in -- so I is fixed rate therapy. So MG, I think, no, because MG is not a very inflammatory condition. And I think if the achieving deep clinical resilience via deep IgG reduction in the first 12 weeks, I expect 300 milligrams to be strongly able to maintain clinical response. And even 340 every week, which we're testing, I think, is going to maintain response in many people. so CIDP, I don't know. CIDP might be a little bit more like a rheumatology condition. It's a little bit more evidence that there's sort of -- the immune system is more activated. So 12 weeks of deeper IgG depression might not be enough. And 65% IgG reduction might not be enough to achieve from a moment could be changed with this mechanism in this disease. So I think there's a decent chance that 1402 is better than batoclimab. Batoclimab is better than other assets because you can get deeper reduction at least for 12 weeks.

Got it. I guess just lastly, over the next year or so, what kind of an important update should we expect from Immunovant? And I have one more question after that actually.

So in terms of data, we have that we'll have initial results from the Phase I 1402 study in mid-'23. The reason that, that is a little bit vaguer commitment than what you usually hear from us is we unveiled the 1402 and the data package before we have the protocol finalized. We're doing that now. We're finalizing the protocol, and that will be submitted as part of the IND in the very early part of next year. And once we have that protocol finalized and agreement with the FDA, then we'll know kind of when -- which data is coming. What I've been saying is probably that mid '23 data package is the single ascending dose data from the Phase I trial, but we'll see when we have that protocol finalized. And then the other important data from Immunovant specifically next year will be the Grave's data, initial data from our Grave's proof of concept. So those the 2 data points to expect from Immunovant.

Okay. And then just lastly, so you touched on it earlier, but over the years, there's been some discussion around pH-dependent binding for FcRn inhibitors and kind of impact on PK/PD, albumin, et cetera. I guess, at this point, we have a bunch of data points across assets. What's to kind of tell us in terms of those parameters? Does it really have that much of an impact just looking at IgG reductions across the board and so forth?

Yes, I think the short answer is no. The -- we don't have -- there's only 1 asset that has strong pH dependence and that's efgartigimod. The antibodies are all pretty pH independent, meaning even at 7.4, the binding is pretty tight. But the dose -- all the assets, whether efgartigimod monoclonal antibodies have dose-dependent reductions in IgG and time on, time off from [indiscernible] standpoint, time to match reduction, whatever mass reduction is for that asset of that dose and then time to recovery that are very similar. So it's -- I can't really see what the pH dependence or independence is doing in actual practice. You can note in the metro study, but I don't link to the clinical difference.

Got it. Great. Well, Pete, thanks for joining us, and thanks to everyone for tuning in.

Yes. Thanks, Sam, for hosting us. I really appreciate it.

Take care.