Immunovant (IMVT) 7 Nov 242025 Q2 Earnings call transcript

Good morning. My name is Terrence Obreski, and I'm your conference call operator.

As a reminder, this call is being recorded.

Before we begin, I would like to remind everyone that today's conference call will include certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, for example, statements regarding the potential efficacy and safety of Immunovant's product candidates, Immunovant's expectations regarding the timing, design and results of its clinical trials including the timing of future data readouts and the announcement of future indications and the market opportunity for Immunovant' product candidates, including Graves' disease and difficult to treat rheumatoid arthritis.

These forward-looking statements are not guarantees of future performance and are subject to various risk, events and uncertainties, assumptions known or unknown, which could cause the actual results to vary materially from those indicated or anticipated.

For more information, investors are encouraged to review Immunovant's most recent quarterly report on Form 10-Q filed with the SEC on November 7, 2024.

Joining me on this call this morning is Dr. Pete Salzmann, Chief Executive Officer at Immunovant.

Following his prepared remarks, we will open the call for questions.

With that, I would like to turn the call over to Dr. Salzmann.

Thanks, Tara. Good morning, everyone, and thank you for joining our call. At Immunovant, we're dedicated to enabling normal lives for people with autoimmune diseases. Today, I'm going to discuss 2 very exciting indications within the context of our overall development plans for our lead asset, IMVT-1402.

First though, I will highlight the very significant progress we've made in 2024 in advancing the development of IMVT-1402 since the Phase I data were presented at the end of last year. Graves' disease is, of course, an exciting first-in-class indication, and I will highlight some recently disclosed data that I believe you'll find very intriguing.

After that, I will have the great pleasure of introducing Dr. Peter Taylor from the University of Oxford. Dr. Taylor is a world leader in the field of rheumatology, and I look forward to properly introducing him later in the call. He will help me unveil our pivotal trial and acapositive, difficult-to-treat rheumatoid arthritis or 1402 has potential for best to have a pest in class profile.

I think you're all generally familiar with our lead assets 1402.

However, I want to emphasize a very unique combination of features. Other FcRn inhibitors might match 1 or even 2 of these features. But I believe only 1402 combines the ability for maximum FcRn-mediated IgG suppression in the neighborhood of 80%, being achieved with a practical amount of medication that can be given subcutaneously and doesn't have an impact on [ analytes ].

This trifecta of features is what makes IMVT-1402 so unique.

Given the strength of 102's profile and also given the potential breadth of indications that could be pursued with an anti-FcRn, there is no shortage of great indications we might choose to pursue. Since we are waiting to disclose the individual indications until they are more or less ready to go from a study start-up standpoint, I do want to provide our indication selection framework.

At the top of the list are first-in-class indications. There aren't many of these left, but there are some, and they are uniquely valuable specifically for 1402. What I mean by that is when an asset is not only first-in-class, but also best-in-class then it's very hard for the competition to catch up. A first-in-class program, which is not best in class can be matched with the later entrant. And in fact, that's what we hope to do with our best-in-class offerings.

Among the best-in-class assets -- sorry, indications that we might pursue, there are those which are classic autoantibody-driven conditions. These have the advantage of a lot of data supporting the idea that deeper IgG reduction can yield better clinical efficacy.

Another category of indications are more general autoimmune conditions where recent information suggests the importance of auto antibodies. In several of these indications, and we will review today ACPA-positive, difficult-to-treat rheumatoid arthritis, there is a strong suggestion from in his last data that deeper IgG reduction may yield better clinical efficacy.

So all 3 of these offer a lot of opportunity. And although we're talking today primarily about Grave's disease and difficult to treat rheumatoid arthritis, there is this wide portfolio of indications that we're working towards.

So far, in 2024, we have cleared 5 INDs across a range of therapeutic areas and with different FDA divisions. This includes announced and unannounced indications.

For anyone who's ever been close to the development of a pivotal protocol and the submission of an IND for such a program, you will appreciate that even a single or 2 INDs is a lot of work.

So to have achieved 5 INDs, all having been cleared by now is really a tremendous accomplishment, and I'm very, very proud of our team for having achieved that that's ahead of schedule that we set for ourselves, and therefore, we're well on track to launch 10 indications by March of 2026, with 4 or 5 of those indications being started as potentially registrational trials prior to March of 2025. Along the way, our experience with batoclimab offers many options to accelerate our 1402 development program.

Okay.

Let's take a quick look at the Graves' disease opportunity and some recent data that we shared.

As a reminder, for those of you who are following our story closely, you'll know this data well for everyone. We recently disclosed data demonstrating a strong response rate in a population of Graves' patients who had insufficiently responded to antithyroid drugs. This is ultimately the target population that we hope to serve with 1402.. This proof-of-concept study was, of course, done with batoclimab, but given the comparable IgG reduction between batoclimab and 1402, the findings that we have disclosed with batoclimab can be immediately translated to our 402 development program in Graves.

And on this slide, you see not only strong response rates in terms of normalizing T3 and T4 but a very strong response rate in terms of patients not only normalizing their T3 and T4 but being able to completely come off their antithyroid drug. This study employed a design where patients were treated with high dose batoclimab for 12 weeks and then standard dose batoclimab for an additional 12 weeks. And this design allowed us to explore the relationship of not only dose response, but also the relationship between depth of IgG reduction and clinical response given that there is some variability in IgG reduction on the 340-milligram dose.

This slide, I think, is maybe the most important slide from our Graves' disease program. and shows, I think, remarkably a large difference in patients who achieved the strict endpoint of ATD-free response, so normalizing their T3 and T4 while getting completely off their antithyroid drug. And you see for those patients whose IgG was lowered by 70% or more, they had a 60% ATD free response rate. Whereas for those patients whose IgG was not as suppressed, so their IgG was less than 70% suppressed at week 24, their ATD response rate was only 23%.

We chose this 70% cut point because it highlights, I think, something that 1402 is uniquely able to achieve, which is to get the entire population treated over this threshold, whereas other anti-FcRns, including our own at their standard dose would have a lesser IgG suppression on the left-hand side.

So this is what I mean by a first-in-class and best-in-class in Graves' disease.

Recently at the American Thyroid Association meeting in Chicago, we had a chance to disclose some additional data from this trial. And specifically during an oral presentation, finding extra thyroid findings Here, you're looking at a change from baseline in proptosis expressed in absolute terms, and this is the median change for the population, which was 2.5 millimeters already at 12 weeks and then 3 millimeters at 24 weeks. These are impressive changes in proptosis and they were matched by changes in lit aperture as well.

You do see a more pronounced impact during the first 12 weeks on the higher dose of batoclimab.

The changes both extrathyroidal and thyroid yielded impressive improvements in quality of life, particularly for those patients who achieved that high bar response of being off ATD with normal T3 and T4.

So among that group of patients, nearly 90%, 89% of them had a normal quality of life score.

You can see that on the left-hand graph by the end of 24 weeks.

I remind you that the population we're targeting to serve with Grave's disease is a common and important population because there hasn't been a lot of innovation in Graves' disease, you may get a different perspective on the degree of unmet need from different physicians, and that would be particularly true if you're speaking with endocrinologists that don't specialize exclusively or nearly exclusively on the treatment of Graves' disease.

This study here was done with 140 endocrinologists that do see predominantly graves patients.

So they have a lot of clinical experience in the treatment of Graves' disease. And we randomly pulled 8 charts from each of those physicians to generate 1,000 patient charts, which were objectively coded and analyzed.

So this is a very robust look at what's happening in actual clinical practice in the United States. And you see that 60% of patients did achieve a thyroid state relatively easily with antithyroid drug.

So antithyroid drugs worked well for a portion of patients with Graves' disease.

However, at the other end of the spectrum, there were 23% of patients who actually never even became used thyroid.

So they did not achieve any degree of control in terms of normalizing T3 and T4 despite being treated by an expert physician for a good period of time. And then in the middle, there were 16% who did achieve control, but it was challenging. There was a lot of titration required, a lot of extra visits, a lot of blood draws to manage their T3 and T4 and some patients just have a much narrower therapeutic window. What I mean by that is small changes in their antithyroid drug can lead to wide swings in their thyroid control. This is something that we would not expect to be the case with FcRn inhibition since you can't drive someone to become hypothyroid with FcRn inhibition, whereas you can drive someone to become hypothyroid with anti-thyroid-drug therapy.

So beyond just the ability to gain control, that's a primary benefit of anti-FcRn therapy having that control be achieved in a more -- in an easier way as a second benefit.

So in order to validate that benefit, that potential benefit, we've designed a pivotal trial. This is the first of 2 pivotal trials that will enroll a population very similar to the batoclimab proof-of-concept -- and those patients will be people who are hyperthyroid despite antithyroid drug therapy, and they will be randomized to for 2 or placebo, we're only using our high dose in this study because we believe that the lower dose may not be as successful based on the batoclimab data.

We really think the high dose is uniquely positioned to serve patients with Graves' disease by achieving that mean IgG reduction of 80% with nearly everyone above 70%.

So this is a trial that we're very, very excited about. There will be a second trial, which we are in the process of finalizing now and taken together, those will -- that will be our -- the primary data for our Grave's disease program.

Okay.

In addition to Grave's disease today, I'm excited to unveil our program in difficult to treat rheumatoid arthritis. This is, as I've said when I was reviewing our progress to date on our portfolio, 1 of the 5 indications that we have an IND cleared in. And it's one of our earlier indications because there are some unique elements of our trial design that we'll discuss in a moment. which allow it to provide not only an early data catalyst, but also for some parallel processing.

But before I get to that, I want to welcome Dr. Peter Taylor to the call. Dr. Taylor is the Norman Collison Chair of Musculoskeletal Sciences at the University of Oxford, and he is a fellow of St. Peter's College in Oxford. He is the Head of Clinical Sciences at the Botner Research Center, where he directs the biomedical research unit inflammation theme and leads the rheumatology clinical trials group and related translational research program at the Kennedy Institute of Rheumatology. Dr. Taylor has special interest, special clinical interest in rheumatoid arthritis and early inflammatory arthritis.

He has over 20 years of experience in clinical trial design and international study leadership for multiple biologic and small molecule therapies in rheumatology. And I'll also note is really an outstanding clinician with a very nuanced and fine appreciation of what patients experience every day with these conditions. That insight is invaluable for companies like us working to design a trial in one of these conditions.

So with that, I'm going to turn it over to Peter to talk about some of the background here.

Well, thank you very much indeed, Pete, for the generous introduction, and good morning to everybody. I have to confess that [ Time March ] is on. And in fact, it's probably well over 20 years of experience now, and we might need to add another decade to that. but that's another story.

But actually, it's an appropriate remark in some ways because I'd like to introduce our audience to how the landscape has changed over the course of a generation in order to contextualize contemporary unmet need and the relevance of the dialogue that we're having today.

So you'll all be aware that rheumatoid arthritis is a very unpleasant condition. There's no cure currently. It's a chronic progressive disease that's going to last a lifetime once it starts and it causes not only joint inflammation and pain, but potentially, it causes a great deal of joint destruction with accompanying loss of function.

Now a generation ago, when I started out in rheumatology, our clinics were full of poor souls in wheelchairs. Basically, if patients had developed rheumatoid arthritis, they were going to become -- or lose their employment within a very short time. People came out of work. They had a really awful quality of life, and they died prematurely.

Matters changed some years later when the first targeted therapies came about. And this came about really for 2 concurrent reasons. One was a much better understanding of the pathobiology of disease. And the second was the development of protein engineering, which allowed us to pick off key therapeutic targets. And of course, over more recent years, we've had advances in chemical engineering, which has enabled the development of small molecules.

So all of this has been a tremendous success story to a degree in as much that now we don't see this awful structural damage to the same degree as shown in the radiograph here. It can happen but it's less common than goodness. Patients do have functional deficits. It does impact on employment. But the reality is that many of the symptoms that patients have today are not so readily visible to the observer but certainly impact hugely on quality of life.

And this is a common condition, about 1% -- 0.5% to 1% of the population have rheumatoid arthritis, is the most common systemic autoimmune condition. And although we have this really quite expanded array of effective therapeutics now, the difficulty is that they're all similarly effective. And after failure of the first particular agent, if you don't have an adequate response to treatment, the switching to any of the others gives an almost exactly similar chance of response. And the chance of responding meaningfully is around about 50%.

So on the one hand, you could argue that we have a perfect biomarker because it's just a flip of the coin. But in seriousness, the reality is that if you've got a 50% chance of responding at a not all that impressive level, we're left with a problem. And what happens is that patients cycle through different advanced therapies. And at each some point in the cycle, they often get more and more refractory responding to the next drug.

So this is a real issue in contemporary practice and the size of that population is increasing.

So that begs the question as to why might there be an interest in anti-FcRn in this situation? And so the advances in understanding the pathobiology that I mentioned really have been to note the role of cytokines and the key pro-inflammatory cytokines, IL-6 and CNF have become really very well-validated targets over the last quarter century and form the backbone of our therapeutic armamentarium biologics targeting these particular cytokines.

But of course, we also have other agents, B-cell depleting agents, co-simulation blockers, more recently JAK inhibitors. And each one of these agents has a different benefit/risk ratio with the nature of the risks associated with drug being somewhat different and we don't currently have biomarkers that will reliably inform which drug a patient will refer to or respond to.

Now is the neonatal FcRN is the neonatal Fc receptor and the biologists among you will know that, of course, the name comes because this is the molecule that enables transfer of potentially protective immunoglobulin from the maternal circulation to the fetal circulation.

So in the first few months of birth, a fetus has some degree of protection to environmental pathogens. But in that aspect, the FcRn receptor is also responsible for the homeostasis of immuno global NG. And IgG is in fact the most abundant protein or one of the most abundant proteins in peripheral blood of human beings because of this receptor because it rescues the IgG from being degraded within the cytoplasm of a whole variety of cells.

Now if you were to block the FcRn receptor, you would prevent that rescue process. And in the situation -- in the face of any condition that has autoantibodies that are driving the pathogenesis, this would be advantageous.

Furthermore, there'd be a theoretical advantage here because although you would diminish the concentration of pathogenic autoantibodies, you would not disable the ability of the whole cellular adaptive immune system to respond to another pathogenic insult.

And so there could be many advantages of inhibiting FcRn. But of course, it presumes that there would be an IgG that's pathogenic. And in rheumatoid arthritis, we've known for a long time about rheumatoid factors, which can be of any isotype but the majority that we measure are IGM, and that's not affected by the FcRn mechanism, IGG rheumatoid factor is also, we know, of interest and pathogenic relevance in rheumatoid. But there's also this interest in ACPAs and the role that ACPAs may play in the pathobiology disease.

So let's look at that a little bit more closely.

Sorry, it skip 2 slides, we'll just go back to ACPAs.

So there's been a lot of interest in ACPAs over the last 20 years or so. These are very good diagnostic auto antibodies. They're not so good and actually reflecting disease activity as rheumatoid factor is. But there are also poor prognostic antibodies, so patients with higher levels of ACPA and rheumatoid factor tend to have more destructive erosive disease. And we know that the whole process of developing autoantibodies against the [ tunilated ] proteins, it may be one of the initiating factors in rheumatoid.

The hypothesis is that there may be certain bacteria, the [ citrinilate ] proteins, particularly those in the lung. And in smokers, this is a problem. And smokers and the association with ACPA is very high.

If you have the 5 amino acid susceptibility sequence in the HLA Class II system. That's the DRB susceptibility allele that's referred to at the top right-hand of the slide.

And so one of the earliest speeches of rheumatoid arthritis can be ACPAs, anti-citruled peptide antibodies. And the presence of these antibodies, in fact, may predate the onset of clinical symptoms and signs by more than a decade. And what we find is that there's this regulation right across all arms of the immune system in rheumatoid but a proportion of patients will have these autoantibodies, about 2/3 to 3/4 of patients through the lifetime of disease. And we've learned that these autoantibodies play a proactive part in disease in many ways. There's data to show that they increase [ osteoclastogenesis ] and contribute to joint destruction in rheumatoid, there's also data that suggest that they're related to some of the pain signaling that occurs in rheumatoid through modulation of chemokines.

And among the contemporary patients that I described that have been better treated than was the case of generation ago, they've had earlier exposure to therapeutic doses of methotrexate and may have been experienced on one biologic, let's say, actually, the pain that remains for many of these patients may be related to chemokine production and ACPAs.

So ACPAs have a very interesting set of autoantibodies in rheumatoid.

And so there's undoubtedly a need to look at this so-called difficult-to-treat group of rheumatoid arthritis. And what do we mean by that?

Well, what we mean is that the ideal treatment targets from a clinician's point of view is to achieve low disease activity or remission. In early phase rheumatoid, we aim to achieve remission and can do that very successfully. But unfortunately, half of those patients will lose their remission status over time. And then of those patients who need to go on to an advanced therapy, meaning a biologic or a small molecule, such as a JAK inhibitor. A proportion of those will either not respond or will lose responsiveness over time.

And this is a huge problem with biologics, in particular, because they are all immunogenic being proteins.

And so the immunogenicity of administered proteins leads to loss of effect. About 50% of patients will lose effect to their first biologic anti-TNF over 2 years, sometimes even less time than that.

So the consequence of all this is in an era where the belief is that when the patient is not responding adequately to current therapy, that you should then switch and move on to another mechanism of action therapy is that over the course of time, there's an enrichment of patients who still have really very debilitating symptoms but nonetheless, have active disease.

And when we talk about active disease, in some cases, it might be highly active disease, but in other cases, it may simply be patients who are not achieving low disease activity. And by having moderate disease activity, that might be enough to increase the likelihood of needing orthopedic intervention. It increases the likelihood of joint destruction it majorly impacts on employment prospects, both in terms of what we call presentism, meaning being able to go to work, but being relatively nonproductive because of the impact of disease. And even in terms of absenteeism, those patients who simply can't get to work and of course, in terms of unemployment.

So difficult to treat rheumatoid has an impact on the individual. It has an impact on their families and carers, and it has actually a very significant impact on broader society because these patients who have inadequately controlled disease get all sorts of comorbidities. And of course, the health care costs in dealing with those become exponential.

So we really need to do something about it, and we need further therapies. And the problem with the existing array of treatment therapeutics is that we simply don't have the biomarkers to tell us which patient might respond best if you switch from one mechanism of action treatment to another.

But in the case of an FcRn inhibitor, we've got some pointers that there may be a companion diagnostic that might not give a precise likelihood of response. But we'll give a point of a response because those patients with higher levels of anti-citrulated peptide antibody are the patients who are most likely to respond to this mechanism of action.

And as Pete alluded to earlier, there's already been a proof-of-principle study. I was the Chief Investigator for this study, which used another antibody called nipocalimab.

So that's an FcRn inhibitor. And what this study was designed to do was to look at short-term exposure in anti-TNF inadequate responders in a relatively small number of patients, 53 patients. It was a placebo-controlled study with an intravenously administered drug. And the idea really was to see whether in either rheumatoid factor or CPA positive patients, whether or not there was any benefit of the drug.

And in fact, when we looked at the primary endpoint, the study missed its primary endpoints looking at the cohort as a whole. But nonetheless, when we look at some of the other outcomes that were actually in the statistical analysis plan, we can see that looking at those participants with a higher than median ACPA, but there's really a very striking response at ACR50.

You can see that in the histogram on the left-hand side of this slide.

So in the subgroup with above median ACPA, you see this very nice response that differentiates from placebo. And if you look at all comers on the left-hand side of that histogram, you can see again, there is a difference between placebo and looking at the patients on [indiscernible].

Now that was looking for ACR50 responses which as rheumatologists, we would consider to be really a very clinically meaningful response. The primary endpoint in this study was looking at absolute change in [ DES 28 ], and that was the outcome measure that didn't meet statistical significance for the study as a whole.

But if you now look over on the right-hand side of this slide, what we're seeing here is that there's a relationship between the magnitude of improvement either in terms of [ DAS28 CRP ] remission, which is the type of outcome we'd like to see or ACR responsiveness, which again is a type of outcome measure that we would like to see and are difficult to treat patients. And there's a very striking relationship between the reduction in CPA IGG level, the ACPA is IgG, whether as most of the rheumatoid factors or IGM, as I mentioned earlier.

So you can see this striking relationship. And in fact, the implication of that from a pathobiology point of view is that this is probably one of the first pieces of data outside of in vitro data that directly implicates as one of the key drivers of disease in this subgroup of patients. And we've learned that rheumatoid arthritis is in fact, a very heterogeneous condition, and there are probably many different sub diseases that have a similar clinical phenotype.

So the attraction of FcRn in ambition is that we've got a biomarker that's available in the clinic, but might identify those patients who are most likely to respond.

We have the potential to inhibit driving autoantibodies, but without actually disabling other aspects of the adaptive immune symptom, and that also is an attractive possibility.

So really, this is the reason for our interest and the interest of Immunovant. And if we look at the size of the patient population that might be affected, the data that are shown here, they are for a United States population, but in fact, I can I tell you that the proportions are very similar as we look at Europe.

So the proportion of patients of the total involved that are autoantibody positive is around about 3 quarters, particularly that's the case when they get to what we call the established phase of disease.

The proportion of patients who have an inadequate response to prior exposure to a biologic or targeted synthetic DMARD is around about 20%. And that figure tends to go up, if anything, over time.

So the longer the disease duration, the higher the fee tends to become. And what we can see is that this emergence of more and more patients were difficult to treat disease.

So despite the enormous therapeutic advance over my lifetime in rheumatology, we've also seen this rapidly accruing number of patients who failed to respond adequately to multiple therapies.

And really, we have this enormous problem of what do we do next. At the present time, they just tend to cycle through a number of drugs unsuccessfully incur the various adverse effects that might be associated with these drugs, but without the benefits of improvements in quality of life.

So there really is a very major unmet need right around the globe, let alone in the U.S.A. And you can see here that the likely target addressable population is thought to be about 70,000 and climbing, I would say, in the U.S. I would have thought it's very similar in Europe, probably a higher figure across Europe as a whole.

So really those are the points that I wanted to make today. And I'm going to hand back over to Pete, who's going to talk you through the path forward from the perspective of Immunovant. Thanks for your attention.

Thanks, Peter. That was a tremendous overview I really appreciate that.

So taking those learnings that Peter just shared with all of you and some additional thoughts, for example, that there are many studies in rheumatoid arthritis, where medications have been studied versus an active control. And the reason that's important is it gives you a sense for the response that patients might be expected to have in a non placebo-controlled trial, which helps from a trial design standpoint, taking all that into consideration, we designed this trial that you see before you.

I will -- starting over on the left-hand side, I want to highlight a couple of important things. This study will investigate a group with and then they will have had an inadequate response to a couple of different classes of medications.

So that's a group that I think is right in the bull's eye of what Peter was just describing. We then have a, what I would say, is a little bit of a unique approach within rheumatoid arthritis, but it is an approach that's been used in other rare disease studies. And it's a common approach actually in pediatrics, which is to begin with an open label and that has several different advantages for us.

One is that from a patient and clinician standpoint, these are people who are really struggling who might be considering either a therapy that's a little bit of a shot in the dark without a biomarker in clinical practice or enrolling in a label lead-in at the beginning, they know that they're going to at least have active therapy right upfront and not only active therapy, but active therapy with our most potent dosage form of 1402.

So that's nice from an enrollment perspective.

Also by having that open-label lead-in, this allows us to generate data both for internal decision-making in terms of when we would start a second trial in rheumatoid arthritis. And also from a catalyst perspective, prior to the eventual top line readout of the placebo-controlled regulatory component that I'll talk about next.

So that open-label period really has a lot of advantages.

So for patients who have an ACR20 response in period 1, so they meet a minimum threshold of response, then they advance to period 2, where they will be randomized. That's essentially the beginning of the actual controlled experiment, the regulatory portion of the trial or primary regulatory portion of the trial, and they're randomized to then maintain their dosing with 600 or step down to 300 or go to placebo so that you have a control group to compare.

And then the primary actually for the study is how many of them maintain that response 12 weeks out.

So of course, we will also look at more stringent measures of improvement, and that will allow comparison across different trials and also be ultimately really interesting and important for clinicians. But ACR20 is the primary kind of to maximize the ability of patients to move through the trial. We do expect that we'll need 2 trials for approval in rheumatoid arthritis.

And the second trial would of course, need to be a more standard trial where patients who meet inclusion criteria are immediately randomized to therapy or placebo. There are some different advantages of that style, more classic trials designed from a regulator perspective.

So they're going to want to see that information. But this allows us to get started and generate data more quickly. And again, is sort of nice for patients who are who are struggling with disease control even after having been treated with multiple therapies.

Because this is kind of a unique trial design, I'd love -- Peter, if you don't mind to jump back in and give your perspective just on the trial design itself.

Yes. Thanks, Pete. I mean I actually think this is a terrific trial design for this particular population for a number of reasons.

The first comment to your question regarding disease activity, to set these entry criteria as given here, historically, we've always seen that if you use the hyperventry criteria, the average patient will, in fact, have high disease activity. But nonetheless, even if some were included within the moderate disease activity range that's still really relevant because these are patients who have had an inadequate response to a couple or more drugs and actually have a pretty miserable quality of life because there are so many different ways in which the disease activity impacts on quality of life.

So that's important to note that these are patients with genuinely active disease at baseline. But the second point to note is that from a recruitment and feasibility point of view, and I'm very sensitive to this, having spent many years trying to recruit patients to clinical trials, it's always challenging. People worry about a lot of things. But one of the things they worry about most of all is will they be exposed to placebo for any length of time and could their disease flare and get even worse than it has been.

And this particular study design is very attractive from that point of view because everybody is exposed to test drug. And therefore, is likely if there are benefits of this to receive them.

Of course, they're aware that this is a test drug. But then going into period 2, we'll also drive very good data about the durability of response to drug as well as the optimal dose for maintaining response.

So it's a very attractive clinical trial design because it addresses exactly the type of things that contemporary physicians need to know whilst at the same time talking to the needs that are necessary for regulators from the point of view of trials that are relevant to registration.

So if it turns out as we all anticipate that this will potentially form a valuable part of the future therapeutic momentarium, this way of actually going about a trial in the more difficult to treat from refractory patients can potentially catalyze how rapidly the drug might get through to clinic. And that's also really important, I think, because some of the more traditional routes may be very protracted indeed. And the sooner we can get effective and safe new therapies for this particular tranche of patients the better.

So I hope those comments have some use, Pete.

Yes, that's excellent. Thanks, Peter, for that insight. Great.

So then in summary, and I'm not going to read through this because Peter has made them so eloquently. But we've got a biomarker-driven strategy for a high unmet need population where there is evidence from another FcRn inhibitors trial of the relevance and potential impact of FcRn inhibition in this group. The study design is enhanced in a couple of different ways that we just highlighted.

And based on the data that Peter shared which showed a correlation between the degree of ACPA reduction, those who started out at a higher level were more likely to be the ones who got a deep response and those who got a deep response or more likely to have a larger change in their ACPA.

So kind of looking at the correlation between ACPA changes and clinical improvement from 2 different angles. There was good evidence that deeper reduction yields, better efficacy. And then we're really excited to have this IND cleared and to get this study started in the early part of next calendar year.

There are some similarities between the 2 programs that we've so far highlighted the Graves' disease program and the rheumatoid arthritis program in the sense that we really first and foremost, are looking for a group of patients that really need a new therapy.

So that's kind of always our starting point. We -- from a clinical and market opportunity standpoint. Then we're looking for scientific evidence that FcRn omission is going to matter and that actually deeper IgG reductions for a more potent prn inhibitor could matter even more.

And we have evidence, I didn't review it today, but you'll be aware of the data that batoclimab lowered not only IgG, but [ trab ] levels and today, Peter review the information showing the reduction in ACPAs in the [ nipocalimab ] trial, which we expect to not only replicate for those patients in the 300 dose during the randomized withdrawal but potentially exceed for those patients on 600.

And then finally, from a trial design standpoint, we're really looking hard at how to have the most informative trial design possible because in rare diseases, the number of patients is lower, and you don't have study programs that have thousands of patients where when you do have thousands of patients, there are many, many different questions that could be asked. But even if the trial is a relatively straightforward design, when you're looking at trials that are more in the 100 to 200 range. The trial design needs to be done very thoughtfully so that not only do you generate information required by regulators for approval, but also you're able to generate data that can differentiate the product for clinicians.

So with that, I want to loop back to where we started, which is maybe one of the main points of today, even though we didn't spend as much time on it because a lot of the information is yet undisclosed. But behind the scenes, there's just been an amazing amount of work to ensure that we stay on track for our development program for 1402. And I think, again, to highlight that 5, having 5 INDs already cleared, which exceeded our goal. We're hoping to have 3 by the end of the year to be well on track to launch 4 or 5 indications by the end of the fiscal year, which is March 2025. To already have 5 of those cleared is just an amazing accomplishment by the Immunovant team that gives us a lot of confidence in our broad development program.

We also have data coming up from our MG and CIDP programs. Both of those are fully enrolled in terms of the people who will contribute to the initial data readouts. In the case of MG, that's the entire trial. In the case of CIDP, it's all of the participants who will contribute to the period 1 data release.

So both of those are closed from an enrollment standpoint and the patients are just moving through the studies for that data disclosure. And then in the case of our Thyroid Eye Disease program, that data will now be expected in second half of next year.

Thyroid eye disease is very interesting. The primary focus in the last several years has been around those patients with high disease activity and to are acute, meaning they're very early in their journey with thyroid eye disease, and they haven't been diagnosed with thyroid eye disease for very long. And that's actually a relatively narrow slice of the entire thyroid eye disease population, but it's where all the clinical trials are currently happening.

And so there's a lot of competition for those patients specifically.

Having attended multiple thyroid conferences this year, including most recently ATA, where there's always a good discussion around thyroid eye disease, even at the thyroid clinics -- sorry, conferences, it's clear that the clinical opportunity, I think, is kind of moving sort of out in both directions. What I mean by that is there's a large prevalence of more chronic long-term thyroid eye disease. That's a population of patients who have had proptosis for a while may or may not have residual inflammation, but the key thing is they've had the condition for quite a while.

And those patients are probably going to remain best served either by surgery or in the case of the medical therapy, insulin growth factor inhibition. But the real excitement is to treat patients earlier in their disease course remember that people who qualify for a thyroid eye disease trial have not only active disease but have to achieve certain thresholds of severity in terms of their [ ex ophthalmos ].

But earlier in the course of Graves' disease, there's many more people who have mild thyroid eye disease, they will generally -- some of them will progress to moderate to severe thyroid eye disease, along with their thyroid specific autoantibodies remaining high and/or their Grave's disease remaining uncontrolled.

So the big opportunity we see in thyroid eye disease is actually to catch it earlier and treat it along with Graves'.

Peter mentioned in some ways, there's an analogy to rheumatoid arthritis. Peter mentioned that earlier in his career, patients who he saw in the clinic or was enrolling in trials would come in wheelchair bound or he would be worried that if they didn't already -- they had already become that disable that, that might be right around the corner, whereas today, with more advanced therapies, we're not seeing people generally with that degree of visibility, even though he highlighted that they have other disability.

And I think we have the same hope for thyroid eye disease over time that if the graves that these program works as we expect, then the numbers of people who are progressing to that moderate to severe had requiring surgery in many cases, will be much reduced because you mentioned earlier yourself.

So that -- with that, I think that concludes our sort of prepared remarks on a lot of different topics. And I will turn it back to Tara to open the line for questions.

[Operator Instructions] So our first question comes from Samantha Semenkow at Citi.

Sorry, I toggled back and forth on mute for some reason. I have actually a couple for Dr. Taylor on RA.

First off, do we know much about the heterogeneity of RA patients that have high ACPA? Is this a more homogeneous population based on their ACPA status? Or is this group still quite diverse in terms of pathogenesis? And then just building on that, what are your thoughts on how effective and how CRN could be as a monotherapy in this population dependent on how heterogeneity it is? Or do you think we'll need a combination therapy to better control it as one of the competitors in the space is running?

Yes. Thanks, Sam, for those questions. Peter, I think those are 2 good questions we've talked about before and the heterogeneity, I guess applies to broadly to patients with rheumatoid arthritis. Sam asked specifically about any heterogeneity within the ACPA positive. And then your idea is on drug development with monotherapy versus combination therapy would be appreciated.

Yes.

So thanks, Samantha. It's an important question. There's been a very considerable advance in our understanding of rheumatoid in recent years and it's complex.

So it's clear that the CPA-psitive patients and the PAR-negative patients are very different in many respects. But we have also learned that one can subdivide the syndrome we call rheumatoid. In other words, people meeting classification criteria according to synovial histomorphology and a number of other markers.

But it would appear that the ACPA positive patients and particularly those who are strongly activositive are more homogeneous than the enormous heterogeneity that we observe in the seronegative patients. The traction really of looking at FcRn as a target, therapeutic target, is related to the sub analysis that I referred to earlier, where we were seeing a very nice proportion of patients hitting ACR50 criteria and even DAS28 remission criteria. And that, of course, was the monotherapy antibody.

But what was also publicly disclosed as part of the nipocalimab data was that the magnitude of total IgG reduction was a lot less than the magnitude that Pete has been talking about in the various studies where the Immunovant antibody has been explored.

So in terms of how well patients might respond to monotherapy, Well, of course, that's the reason we do clinical trials to address hypotheses and find out that the expectation based on information we already have and based on theoretical knowledge about this new antibody would be that a good proportion of patients would respond to exactly the type of level that people like myself as practicing clinician on a day-to-day basis would like to see.

In other words, significantly relieving the aspects of life that are impacted by rheumatoid arthritis. But really further comment than that can't be made because, of course, that's precisely why these sorts of novel trial designs are necessary and then carefully scrutinizing the data that arises.

So our next question comes from Sam Slutsky at LifeSci Capital.

Got kind of one for Dr. Taylor and then for the Immunovant team for follow up for that.

So I guess for Dr. Taylor, for the population that IMVT-1402 is being studied in, I guess, what level of efficacy would be clinically relevant to make this an interesting therapy to you? And then also just given the novel trial design they're using, would that have any impact at all on interpreting these results versus drugs that have used other trial designs for RA?

Yes. Great questions, Sam.

So I think I'll reference a point and then I'll let Peter to comment on whether he agrees or not. There's I mentioned that one of the benefits of studying patients with rheumatoid arthritis, there are so many other trials that give you some benchmarks. And there have been some meta-analysis, which when you look at patients who fail the biologic. Generally, the average across a lot of different trials in terms of ACR 50 is about 25%. And of course, the -- looking at the active -- the higher ACPA positive patients that Peter showed those had a ACR50 of 27% or so.

So something that I think would be a very competitive response in this difficult-to-treat patient.

I guess just generally, Peter, would you agree without getting into all the details today that it's going to be possible for clinicians and investors to form an opinion about what sort of response rate would be a really good response rate in this trial?

Yes. Absolutely.

I think the key point here is that in order to really understand the relevance of the findings of the study, 1 has to look at the totality of data. And if, for example, you were just to take the ACR categorical levels at any 1 time point, as being the sole indicator that would have a very limited value, but it's important to stress that even a 20% improvement for these people who have not had an adequate response to other therapies may be very impactful in terms of improvements in their quality of life.

But when you look at the totality of the data, which will include other measures some of which will be continuous measures of response where you can look at maintenance of response, for example, area under the curve and so on, will be extremely informative.

So I think, in fact, this is a very clever study design because it will give us that total set of data that will point in the right direction to allow nuancing of design for any study that follows. But at the same time, it will also allow the type of ballpark in direct comparison because of the choice of regulatory endpoints that's going to be used.

So it's an [indiscernible] outcome, for example, which will allow indirect comparison and benchmarking with other mechanism of action drugs.

Awesome. Thanks, Peter. Sam, maybe just to quickly the Immunovant question in the interest of time.

Yes. actually going to the Graves' disease data that you recently presented.

For the patients who had grades orbitopathy, what was the range of severity kind of at baseline? Was it all moderate-to-severe patients or milds mixed in? Just any additional clarity on that?

Yes, yes. I'm glad you asked that. I didn't mention that. but I should have.

So these were not patients, for the most part, who had moderate to severe disease. Those -- more of them were mild they might have been moderate to severe on one dimension.

So for example, maybe the -- and by moderate to severe, I'm using like the criteria that are typically used for enrollment inclusion criteria in an ED trial, whether ours or others, you generally require short duration of disease, high cat and proptosis finding that meet a minimum threshold among some other things.

Many of these patients had 1 or maybe 2 of those, but most didn't have all 3.

So they would -- it's generally a group that had more mild disease. Nevertheless, you see a meaningful change in their proptosis values, which really is a whole interesting separate discussion that the population averages for what is a normal amount of [ x ophthalmus ] most, it's a little bit like anything else in the population, height or something where there's variability.

So some people clearly add x ophthalmus that was abnormal for them because they improved a lot on therapy even if they didn't weren't above the average value for the population based on their gender and race.

So it's also what gives us a lot of encouragement that we can see some benefit in a more Grave's enriched program that we're going to be running that will -- those are mostly going to have mild or TED, but yet we expect to see some findings based on this data.

So our next question comes from Brian Cheng at JPMorgan. Brian.

Good morning. I'm [ Miriam ] on for Brian.

First for Pete, can you talk about how the extra thyroidal benefits that you presented last week at [ ETU ] [indiscernible]? And any comment on the timing of the updated time line for the test readout? And we have a follow-up.

Sorry, I couldn't quite hear you.

You said the extrathyroidal findings, how they -- and then I missed something.

Yes.

So how the extra there benefits that you presented last week at ATA read through to your ongoing TED trial with [ Beta ]? And any color on the timing of the updated time line for the TED readout? And we also have a follow-up.

Right.

So the thyroid eye disease program is obviously blinded.

So -- and as I just highlighted to Sam, the populations are different because the TED trial is enriched for moderate to severe, whereas the Graves' trial was selected for Grave's disease activity in spite of antithyroid drug therapy and those patients happen to have, for the most part, mild disease, but mostly not moderate to severe.

I think at the end of the day, though, the fact that we're seeing not subtle changes in proptosis even in that graves population is encouraging for our overarching goal within our program for 1402 in Graves', which is to address thyroid eye disease before it gets to be that severe. And that relates to the comments I made around the thyroid eye disease program, which has by tugging along, but there's been increasing competition for patients who are in that narrow slice of acute and very active.

And we will -- we wanted to keep our trial consistent with others and just maintain that narrow slice of patients for the TED trial, so that cross-trial comparisons but also may be most easily done. But I think the bigger picture is that 1402 will -- has an opportunity through its Graves' program to get to TED or early in the disease course, which was maybe the main value driver there.

I'm probably going to have to ask you to have your second question short, we do need to finish by 9:15 for -- and we have some other questions in the queue. I'm going to ask your second one, Mary.

Yes. And for Dr. Taylor, down the line, how do you think about sequencing SCR in the real world? Do you see any potential for it to move into earlier line?

Theoretically, absolutely, there could be. And certainly, given that we may have the biomarker to indicate responsiveness. But of course, it's important to point out that in a world where we're seeing many biosimilars now and many of the small molecules will become generic. A lot of the potential prescribing choices restricted in many health care economies. And actually, the area of a biggest unmet need is potentially around this difficult-to-treat population. But in principle, yes, that's a possibility.

Yes.

So our next question comes from Alex Thomson at Stifel.

I guess sort of at a high level heading into the CIDP and MG readouts early next year. Maybe you could sort of talk about like what you want to see to really validate the best-in-class profile you're thinking for 1402? And then sort of with that, are there any scenarios at this point where batoclimab moves forward towards FDA registration? Or is it really still all 1402 at this point?

Yes. Thanks, Alex.

I think you see in the data that was presented today, particularly in the graves data, a strong correlation between degree of IgG lowering. We didn't go into all of the various dose cuts that I presented a couple of months ago. But when you look at the totality of that data, there's a lot of evidence for deeper IgG reduction correlating with better clinical response, which is a fundamental thesis of Immunovant's value creation story. And then in the nipocalimab data that Peter presented, you see you see that correlation as well. And the reason you're able to see that correlation, although the average reduction is Peter pointed out, was closer to 60% at the population level, there was variability.

So you see some small number of patients who got a deeper response. And we see that in our low dose as well.

So I think what we want to show with MG and CIDP data is the same thing that in the case of myasthenia gravis and CIDP deeper IgG reduction correlates with clinical improvement across multiple parameters. Peter made a very good point about assessing the -- particularly the impact of a biomarker and the correlation between that biomarker and disease is that any single time point, any single measurement is not going to be convincing one way or the other.

But the totality of data, when you look at endpoints over time and you see a correlation, particularly over time between a biomarker and disease activity, that's the kind of information that gives you a lot of confidence that there's a there's a correlation there.

So that's what we're looking forward to seeing with -- and plan to see. That's why we designed the trials to be able to pass this correlation across a lot of different dimensions.

So our next question comes from [ Andy Chan ] at Wolfe Research.

So one question for Dr. Taylor. In these ACPA positive patients to antibodies, do they account for the majority of disease pathogenesis and disease activity. is much more so than other pathways inside the clients from PH1, Th17 and maybe CDA 80 cells? Just trying to understand how much more important IgG may be in disease activity? And then maybe just one follow-up for the Immunovant team. The 70,000 U.S. prevalence, is that the diagnosed population? Or is that the estimated prevalence?

Yes. Thanks, Andy. Maybe I'll start with that one.

So patients with who are difficult to treat almost by definition, they're in the health care system because they need to be seeing physicians getting treatment in order to tick off those boxes of having disease activity, having failed different therapies.

So these are -- this is essentially the current population estimates of people who are in the clinic with meeting those criteria.

As Peter pointed out, that prevalence may be growing over time as people cycle through the anti-cytokine therapies and as more people possibly due to availability of biosimilars and things like that, get more advanced therapy earlier and then some fraction of them will unfortunately progress to being difficult to treat.

So that group could be growing in size.

I think the disease -- Peter, I'll toss it over to you for the disease heterogeneity question, that's a really big, big topic. Maybe you could just give your thoughts on -- which I think you kind of already did, but again, on the relative homogeneity of an ACPA positive difficult-to-treat population.

Well, Andy, thanks for the question. In brief, I don't know the answer to the exact question you posed, and I don't think anybody does. What we do know is that when you look at all the different mechanism of action agents that are currently approved, that they all have similar benefits in a similar proportion of patients. But the groups of patients who respond to each are not necessarily the same. And furthermore, for patients who become refractory to one, the responsiveness to another different mechanism of action may vary.

So the current hypothesis is that there's an immune disregulation in both the adaptive and innate immune arms that the -- there's a sort of bottleneck hypothesis whereby TNF and IL-6 may be the key cytokines that are driving but the reason for the aberrant control of those cytokines may be multiple and that perturbing those disregulations within the entire immune network at any point may give rise to similar outcomes.

But what we do know already is that FcRn is a validated target in a subgroup of individuals.

And so we'll learn more in terms of answering your question through studies with drugs that optimally decrease pathogenic autoantibodies and particularly, obviously, IgG. It's also important to mention that rheumatoid factor whilst it's predominantly IgM rheumatoid factor that we measure. It's long been known that IgG rheumatoid factor plays a role in the pathogenesis.

So we'll learn more in answer to your question.

I guess the other thing to maybe -- as it's a good question that's been asked by a couple of different people. Maybe a follow-up point, Peter, could also be that -- again, this strong hypothesis has been generated with the nipocalimab data. We're going to test it. If it pans out as we expect, then it's readily implementable in the clinic.

So this isn't just like a [ posterior ] biomarker that's going to be hard for rheumatologists to get their head around, right? This is this works. It's the translatable to kind of castability to clinical practice, I think, should be high.

Exactly.

Our next question comes from Yasmeen Rahimi at Piper.

Congrats on the really brilliant design and thank you, Dr. Taylor for your thoughtful comments. I guess this is directed to Pete. Pete, could you talk about given that it has an open-label portion, would you be in a position to provide updates from the open label before you go into Part 2? Or is the strategy to finish Part 1, go into part 2 and then the top line data will be post Part 2? That's sort of question number one, just for housekeeping.

And then in regards to it's a very difficult-to-treat populations, you would think in terms of a treatment effect, any statistical separation in the primary and trends in key secondary would be very, very attractive opportunity. But could you maybe -- am I thinking about this the right way? Or is there a siftically magnitude of change that could be clinically meaningful for this very tough population.

So what are we powered for and part 2 of the study, I guess, that's what I'm trying to get at.

And sorry for the long-winded question, I'll jump back in the queue.

Yes, yes, no problem.

So I think to the first point, yes is the answer, and this is part of the reason we chose this design. It wasn't the main reason. The main reason was based on the scientific rationale and the ability to advance our program quickly to registration if we're seeing good data as we expect. But there's a nice side benefit of having this open-label period, which is we'll be able to define a certain number of patients less than the -- potentially less than the entire 120 where there's enough information to warrant disclosure.

So that will be a nice side benefit from a catalyst standpoint.

This is a potentially registrational pivotal trial, so it's fully powered for the primary. And many of the secondaries are reasonably equally powered because the placebo arm is likely to have a very low rate of response and the placebo-corrected delta is often kind of in a similar order of magnitude no matter which cut point you're using.

One of the things maybe I'll say in terms of the -- as Peter to comment on the clinical magnitude, in the DAS28 remission was shown in one of the slides, could you put that in context, Peter, for a group that starts out? I don't know what the mean or median was, but I'm guessing it was maybe 5 or more in the nipocalimab trial, for a population like that, how meaningful is DAS28 remission as an outcome?

Well, it's enormously meaningful.

Just for the benefit of the listeners, there are many different definitions of remission. But basically, we want to approximate as closely as possible to the absence of symptoms and signs that impact on quality of life. And perhaps it is only fair to point out that one of the findings from the nipocalimab studies was that it didn't impact significantly on CRP, which is one of the components of the DAS28, but there's another measure called the CDI, the Clinical Disease Activity Index, which doesn't include an acute phase marker that's probably even more meaningful.

And what really matters is that the patient's quality of life is significantly better.

So the sort of proportions we were seeing with the DAS28 remission I would say, were pretty impressive in the difficult-to-treat population. But in fact, when you look at metrics that don't include a CRP, then that becomes even more impressive.

Yes, that's a really important technical point. A lot of the anti- maybe all of the anti-cytokine therapies tend to move CRP a lot. The patients don't necessarily feel CRP, but it is a part of a lot of the scoring criteria because of that because of that point. And when you look at the -- as you did, I know in a study and data we didn't show today, when you sort of disaggregate the [ deaths ] into these component parts and also ACR pain and to all in joint changes, there were many, many, many changes across all those subparts, which gives you a lot of confidence.

So that's a very important point you just made.

I think we have time maybe for just one last question, and then we'll wrap up.

Great. 2Thanks, Pete.

So our next question comes from Louise Chen at Cantor Fitzgerald.

Just wanted to ask you, if you saw your FCR in for RA would always be in a refractory patient population based sort of on the premise of how you're designing your study? Or does it have opportunities in earlier lines of treatment?

Yes. Thanks, Louise.

I think there's an overwhelmingly practical component to the answer and give you which is the anti-cytokine therapies are already some of them available as biosimilars and many others will become available as biosimilars. And they have a proven track record in a certain percentage of patients and before them, even methotrexate works in some patients.

So I think health care systems are going to require patients to go through those therapies, which will be much less expensive because they're generic or biosimilar prior to using an advanced therapy like an FcRn.

And I think for most patients, that's probably reasonable. And therefore, our program is targeting the subpopulation of patients who are difficult to treat, which makes sense from a clinical standpoint, but it's also something that health care systems can absorb from the standpoint of the difference in price between a modern therapy in a generic or biosimilar. Excellent. Well, I appreciate everybody joining today, and a robust dialogue. We had a huge thank you to you, Peter, for providing such a really nuanced and detailed an engaging overview of the history of rheumatoid arthritis, also the specific subpopulation of ACPA positive, difficult to treat RA and your thoughts on our clinical trial, which I'm really, really excited about.

And I guess I'll close again with where we started, which is that maybe what I'm most excited about is the -- just the progress we've made across multiple indications, including many that aren't yet disclosed. But we wanted to let everybody know that we -- that, that progress is real in the sense that we have 5 indications have now been approved by the FDA, which is a big, big step forward.

For those whose questions we didn't get to today, I do apologize just in the interest of time prior to market opening. We need to wrap it up. But thanks again to everyone, and I'm sure we'll be talking to you soon.