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

Good morning. My name is Tara Sobierajski, 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 with 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's product candidates, including in Graves' Disease. 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 August 6, 2024. Joining me on the call this morning is Dr. Pete Salzmann, Chief Executive Officer at Immunovant. Following his prepared remarks, we will open the call up for questions. With that, I would like to turn the call over to Dr. Salzmann.

Thank you, Tara. Good morning, everyone, and thank you for joining our call. I've been very excited about this day for a long time, and I think you're really going to enjoy this update. Today, I'm going to share additional data with you that we believe positions IMVT-1402 to be potentially best-in-class and first-in-class for people with Graves' Disease who don't respond well to antithyroid drugs or ATDs. As noted on this slide, 25% to 30% of Graves' patients diagnosed each year are uncontrolled on ATDs and therefore, have no good medical treatment options. With regard to clinical data, our proof of concept in the same population studied 680 milligrams of batoclimab given weekly by subcutaneous injection for the first 12 weeks. This therapy yielded results that I find very impressive. Specifically, at the end of 12 weeks, more than 3/4 of participants had a T3 and T4 value that had normalized without an increase in their baseline ATD. In fact, the ATD dose had to be tapered down for many patients in the first 12 weeks of the study, with more than half of patients not only normalizing their T3 and T4, but also completely stopping their ATD. It is also important to share that a strong correlation between depth of IgG reduction and response rate was observed, and this clearly positions IMVT-1402 to be potentially best-in-class. I look forward to diving into that data shortly. I have a lot of new data to share today regarding the real world disease course of Graves'. Used from several different angles, there is a consistently sized group of patients who are uncontrolled on ATDs. Specifically, each analysis indicates that about 25% to 30% of incident Graves' Disease patients are uncontrolled on ATDs with no or minimal medical options. Lastly, we now have an open IND with the Endocrine division and alignment with FDA to move forward with the start of our pivotal 1402 program in Graves' Disease. I will review the design of our first pivotal trial in Graves' Disease that we expect to start by the end of this calendar year. In the time we have today, I will cover these topics in greater detail, and then I look forward to taking your questions. Graves' Disease is a classic autoantibody condition. On the left, you see the illustration of normal thyroid function in which thyroid-stimulating hormone or TSH stimulates the thyroid gland to release thyroid hormones, T3 and T4. There is a feedback loop that keeps TSH and T3, T4 in balance. In the middle of the slide, you see that autoantibodies to the TSH receptor activates the thyroid gland in Graves' Disease. Since the autoantibodies aren't subject to a feedback loop, their presence leads to over production of T3 and T4. When T3 and T4 are too high, many organ systems are impacted, leading to substantial symptoms, including fatigue, diarrhea, anxiety, eye symptoms and heart palpitations. If left untreated or insufficiently treated as shown on the right, serious morbidity and loss of quality of life can occur. Many of these sequelae are serious and are more common in uncontrolled thyroid disease. As is the case for other autoantibody conditions, there has been a lack of innovation in Graves' Disease over the past many decades. The good news for Graves' patients is that many are well controlled on antithyroid drugs or ATDs. The most common ATD with methimazole, was approved in the U.S. in 1950. The bad news for Graves' patients is that 25% to 30% of them are uncontrolled on or intolerant to ATDs or they relapse after treatment with ATDs. ATDs also carry the potential for serious side effects including liver failure and agranulocytosis, meaning a loss of white blood cells. So what are the options for the 25% to 30% of Graves' patients that don't respond well to ATDs. Today, there are 2 second-line therapies, both of which totally remove the thyroid necessitating life-long thyroid replacement. These 2 procedures, radioactive iodine and surgery or surgical removal of the thyroid gland, both carry important risks in addition to trading one problem, hyperthyroidism or another problem hypothyroidism. In fact, as these risks have been more appreciated, the treatment paradigm has shifted away from the use of ablative therapies. The chart on the left shows that about half of Graves' patients were treated with radioactive iodine or surgery just 20 years ago. We recently completed a U.S. claims analysis with data from 2021 and 2022. The chart on the right summarizes this data and shows that ablation has fallen to approximately 11% of incident Graves' patients. Although, radioactive iodine and surgery have many issues, they do generally control the hyperthyroidism of difficult-to-treat Graves' Disease. As difficult-to-treat patients have shifted towards ATD therapy in order to avoid ablation, a new group has formed. This group that is intolerant to, or relapsing on, or uncontrolled on ATDs is avoiding ablation, but then remains persistently or intermittently hyperthyroid with an uncomfortable symptoms and with increased medical risk, as noted earlier. Now let's review the batoclimab proof-of-concept study in difficult-to-treat Graves' patients, specifically those who remain hyperthyroid despite ATD treatment. Taking a step back, we designed this study with 4 goals in mind: First, we sought to generate proof-of-concept data for FcRn inhibition in Graves' Disease. Second, we wanted to confirm our hypothesis that deeper IgG reductions would yield better response rates. Third, we wish to generate proprietary data to guide the tapering of ATDs in a 1402 pivotal trial. And lastly, we intended to leverage the data from this study to accelerate the development program of 1402 in Graves' Disease. We are excited to share with you today that we have achieved all 4 of these goals with the batoclimab proof-of-concept study in Graves' Disease. This study schematic shows that we enrolled Graves' patients who were hyperthyroid despite ATD therapy. To test our hypothesis that lower is better in terms of IgG reduction and clinical response, we studied our high dose of batoclimab at 680 milligrams for the first 12 weeks of the study, followed by 12 weeks of our lower dose of batoclimab, 340 milligrams weekly. This allowed each patient to serve as their own comparator over time. The key endpoint was the proportion of participants whose T3 and T4 normalized or fell below the lower limit of normal, and had no increase in their ATD. The response definition included those patients whose T3 and T4 transiently fell below the lower limit of normal in order to capture patients whose T3 and T4 fell so quickly that their ATD wasn't tapered fast enough, leading them to briefly become hypothyroid. Okay. This is a very important slide because you can see that the trial population was representative of an uncontrolled population despite ATD use. All of their Graves' Disease markers, T3, T4 and TRAb or thyroid receptor antibody, the antibody that causes Graves' Disease, were all elevated well above the upper limit of normal. We've included the upper limits of normal for T3, T4, and TRAb as you may not have these at your fingertips. In addition, their median time since diagnosis was well over a year. There were a couple of patients with a very long duration of therapy, which would have skewed the mean, which is why we'll provide the median, which is, as I said, already well over a year. This is important because a population like this with uncontrolled Graves' for well over a year and with high TRAb values is very unlikely to become euthyroid, simply with continued ATD dosing. On this slide, we're looking at the response rates, defined as T3 and T4 normalizing without an increase in ATD, as I've just explained. The purple bar on the left shows that there were 76% responders after 12 weeks of 680 milligrams of batoclimab. The mean change from baseline in IgG at week 12 was 77%. Recall that after 12 weeks of 680 milligrams of batoclimab, subjects were stepped down and received the lower 340 milligrams of dose, a 340-milligram dose of batoclimab weekly for an additional 12 weeks. The blue bar on the right shows that there were 68% responders at week 24 after receiving 12 weeks of 340 milligrams of batoclimab. The mean change from baseline in IgG at week 24 was 65%. Recall that we've discussed the bar for success for responders using this definition as being 50% and these values, especially the responder rate on high-dose batoclimab are meaningfully above 50%. Okay, this next slide has a very exciting headline. More than half of the patients receiving high-dose batoclimab not only achieved normal T3 and T4 levels, but also we're able to entirely ceased ATD therapy by week 12. However, these are patients who began the trial hyperthyroid on an ATD and with a median disease duration of well over a year. The chance of them becoming euthyroid with continued ATD therapy was already low. We believe that the chance of these patients becoming euthyroid and stopping their ATD in 12 weeks was essentially zero. So I'm really impressed by greater than 50% of participants achieving an ATD-free response on high-dose batoclimab at 12 weeks. The blue bar on the right shows the ATD-free responders at week 24 following the step down in dosing to 340 milligrams weekly of batoclimab for 12 weeks. Remember, the mean IgG reduction at week 24 was 65%. And the smaller IgG reduction was associated with a smaller ATD-free response rate of 36%. The next slide provides more evidence regarding the importance of deeper IgG reduction. Given that everyone received 680 milligrams of batoclimab in the first 12 weeks of the study, there was some pharmacodynamic carryover into the second 12 weeks of the study, and this varied, of course, by participants. We use this variability to separate the entire cohort into 2 groups. Those whose IgG reduction at week 24 did not reach 70%, shown on the left, and those whose IgG reduction at week 24 was more than 70%, shown on the right. Using the very strict criteria of ATD-free response rate, the difference between the groups is striking. On the right, we see a 60% ATD-free response rate at 24 weeks in the group that experienced 70% or greater IgG reduction at week 24. This is almost threefold higher than the ATD-free response rate of 23% in the group whose IgG suppression wasn't as deep at week 24. We believe that in order for many Graves' patients to achieve maximum benefit, an IgG reduction greater than 70% will be needed, providing a strong argument for lower is better and also a strong argument for a potentially best-in-class profile for 1402. On this slide, we're looking at what happens with thyroid hormones, T3 on the left side, and T4 on the right side over time. These are the 2 hormones that caused the symptoms of Graves' Disease and also cause adverse medical outcomes. For competitive reasons, we aren't showing all of the time points, rather, we're just showing baseline week 6 and week 12 values. In both charts, T3 and T4 rapidly fall within normal range by week 6. Note that this is not driven by ATDs, which were already being significantly tapered by week 6. Moving on to safety. No surprises here with finding similar to what has been previously reported for batoclimab, batoclimab was well tolerated. With one exception, all adverse events were mild or moderate. The single serious adverse event was not treatment-related. This patient who had a history of pre-existing gallstones had a flare of their disease leading to a surgery or cholecystectomy and gallbladder removal followed by an uncomplicated recovery. This adverse event was deemed serious as surgery was required and was deemed unrelated to batoclimab treatment. Of course, the gall bladder surgery necessitated treatment discontinuation per protocol. There was one other patient who had heavy menstrual bleeding and consequently missed a visit and missed a dose. She returned to the study after that and completed treatment. Menstrual bleeding was also deemed unrelated to batoclimab. Okay, these remarkable findings have been key to informing the design of our first potentially registrational trial with IMVT-1402 that I'll show on the next slide. As noted in today's press release, our IND for Graves' Disease has cleared. We expect to conduct 2 pivotal trials as part of our registration program. Inclusion criteria for this first study are similar to the proof-of-concept study. Participants must have antibody confirmed Graves' Disease and be hyperthyroid despite ATD therapy. These patients will be randomized to either 600 milligrams of 1402 or to matching placebo. The primary endpoint at the end of Period I or week 26 will be the proportion of participants who become euthyroid and stop ATD therapy. For treatment Period II, Group I will continue to receive 600 milligrams of 1402 subcu for an additional 26 weeks, blinded, of course. After Period I, Group II will be divided into a continued 600 milligram of 1402 arm and a placebo arm. Those who are TRAb responders whose TRAb is reduced a lot, in addition, of course, to being euthyroid and off ATD will go to placebo in a blinded fashion. The rest of Group II will continue on 600 milligrams of 1402 through week 52. Group III will remain on placebo throughout Period I and Period II. A key secondary endpoint at the end of Period II will be the proportion of participants who become euthyroid and stop ATD therapy at week 52. Importantly, this trial has an upside design element, specifically the study of remission, meaning maintaining a euthyroid state off ATD and off 1402. We will test remission rates in participants who get 12 months of 1402 and in participants who are TRAb responders and received 6 months of 1402. We expect to start this trial by the end of the calendar year. Okay, I want to come back now to the topic of unmet need that we started with and share with you how we see the market opportunity in Graves' Disease. We used 5 different approaches to size the market in Graves' Disease and found that across these approaches, at least 25% to 30% of patients' relapse who are uncontrolled or are intolerant to ATDs. As many of you know, it's very difficult or perhaps impossible to obtain precise prevalence and incidence figures for Graves' Disease using published literature. There just hasn't been that much work in this area. So the first thing we did was a rigorous claims analysis using the Inovalon database, which is a very large claims data set with more than 200 million unique patients in the United States. In order to determine the prevalence and incidence of Graves' Disease, we used strict criteria, including ICD-10 codes, medication history, a requirement for continuous data at the patient level in the dataset and a multiyear look-back period. Using these and other strict criteria, we obtained prevalence figures that are a bit higher than those reported by others and incidence figures that are a bit lower. Prior analysis without a very careful look-back period might have characterized -- might have characterized some prevalent patients as incident patients, potentially explaining this discrepancy. Turning back to our data. The prevalence and incidence numbers suggest that the treatment of Graves' Disease is more in the range of 5 years versus 1 to 2 years. Bottom line, this strict methodology yielded a U.S. prevalence of 880,000 and a U.S. incidence of 65,000. How many of these patients fall into the target population of uncontrolled on, relapsing on, or intolerant to ATDs? To answer that, we took a three-pronged approach, including, first, a quantitative in-depth survey of thyroid specialists. And then second, a detailed and objective review of over 1,000 patients' charts and finally, an in-depth quantitative survey of patients with Graves' Disease. Let me walk through those one by one. Let's look at the prevalent population here in a bit more detail. At the top of the figure, you see the prevalent population of 880,000 adults in the U.S. The data shows that these patients take 3 paths. First, in the far right white box, we see that 120,000 patients received ablative therapy, radioactive iodine or surgery. The left 2 white boxes are the patients treated with ATDs. What I want to draw your attention to is the dark purple box toward the bottom. This represents the 340,000 patients who experienced ATD treatment relapses, meaning they aren't maintaining control on an ATD, or they have to return to ATD treatment after a trial off of their ATD. About 10,000 of these patients received an ablation leaving an immediate cohort of 330,000 ATD relapsed patients who have not opted to pursue ablation. This represents a sizable prevalent pool of uncontrolled Graves' patients available at the time of launch, assuming, of course, success of 1402. Turning now to incidence. You may be aware of the incident population we've cited previously from the literature of 116,000 newly diagnosed patients in the U.S. The analysis that we've done here on a recent set of claims data is much stricter and results in a more conservative estimate of the incident population being around 65,000 incident or newly diagnosed patients in the U.S. each year. On this slide, the light purple boxes reflect the patient population that pursued ablative therapy, either first line or after first-line treatment with ATDs. We learned that this was about 9,000 or 13% of the incident patients in this dataset. Of the remaining patients who don't undergo ablation, there are about 20,000 who are uncontrolled on, relapsed on, or intolerant of ATDs. These are noted with the simpler titles of initial and late relapse on this slide. These 20,000 patients represent about 30% of the 65,000 incident patients in the U.S., meaning the annual market of second-line patients is about 20,000. And that is without considering the potential upside of patients shifting from early ablation to second-line medical therapy with 1402, again, assuming success and ultimate approval of 1402. Okay, in analysis 3, we took a different approach, directly surveying 140 endocrinologists, all of whom treat many Graves' patients. You can see the physician characteristics on the left. In this quantitative survey approach, these endocrinologists reported that nearly 1/4 of their patients qualified as uncontrolled while on ATD therapy. And another quarter relapsed and became uncontrolled after stopping their ATDs. Because of these percentages are higher than the 25% to 30% figure that we're generally quoting, probably because it's hard to fully separate the course of incident and prevalent patients in a survey. In other words, over time, total uncontrolled and relapsing group may be higher than 25% to 30%. So that was what physicians said, and in analysis 4, we took a very careful look at what they did. Specifically, we did conducted a detailed chart review of more than 1,000 patient charts. These charts were randomly selected in order to minimize bias, and data was extracted and coded to enable objective scoring. The results showed that 23% of patients based on their chart history, never became stably euthyroid. And this is even after excluding the 11% of patients who underwent ablation. Note that the 11% undergoing ablation aren't included in the pie chart, which is why there's 998 patients in the pie chart. Among the patients who were not ablated, 16% shown in blue, did achieve a euthyroid status but with some level of difficulty, as demonstrated by requiring many adjustments to their ATD dose, while their T3 and T4 fluctuated. And while they had frequent visits -- physician visits and multiple blood draws. In this cohort of 1,000 patients, just 61% achieved a euthyroid status without a lot of difficulty based on chart review. And finally, in our fifth analysis, we heard from Graves' patients. This blinded survey of 100 patients asked many questions. And this one I find particularly compelling. We learned that 35% of patients reported that they found it difficult or very difficult to achieve stable thyroid disease status while on ATDs. They described many dose adjustments, fluctuating thyroid hormone test results and generally feeling quite frustrated with their treatment. So the bottom line across these 5 different analyses is this. Having looked at the degree of unmet need from many different angles, we have consistently found that at least 25% to 30% of Graves' Disease patients are not achieving desired disease control on the current first-line standard-of-care antithyroid drugs. And we know that more and more patients are refusing to take the big step to one of the current second-line ablative procedures. I find it very impressive how similar the unmet need percentages are across these diverse methodologies. And we believe this gap in care between ATDs and ablation is ripe for new medical innovation. As we begin to talk about this opportunity, many have asked how a gap in care like this one can be addressed -- will be addressed in the commercial landscape. How does an innovative new medical therapy enter the space between cheap generics and invasive procedures. I want to share a recent and relevant example with you to address this. A few years before the launch of TEPEZZA, when teprotumumab was in development, there were similar questions about whether or not there was truly a market for Ted. I know that seems hard to believe right now, but if you were working in this area in 2017, 2018 and 2019, you'll know what I'm talking about. Leading up to the launch of TEPEZZA, as shown in the pre-TEPEZZA launch bar on the far left of this slide, the market was dominated by generic steroids. At that time, roughly 20% of patients were receiving second-line therapy with orbital surgery. Within just 2 years of launch, TEPEZZA had taken a 20% market share, similar to the 25% to 30% I've been quoting and that was achieved in just 2 years. As shown in the right half of the slide, net sales grew to about $2 billion for this rare disease with a roughly similar incidents and with pricing in the same range or higher than anti-FcRn. We believe this is very informative for a potential -- for the potential dynamic in Graves'. The standard of care consisting of a generic therapeutic option on the one hand, and invasive procedures on the other hand, with a large unmet need gap in between the two. Okay, we've covered a lot of ground today. Allow me to wrap up with a few closing thoughts. First and foremost, I believe that IMVT-1402 is well-positioned to be potentially first- and best-in-class in Graves' Disease, a long overdue innovation for the 25% to 30% of patients with Graves' Disease who have minimal to no other therapeutic option. Here are the reasons I believe this. Number 1, 2 and 3, the batoclimab proof-of-concept study exceeded the goals we had set out to achieve. Recap there, high-dose batoclimab delivered 76% response rate in patients uncontrolled on ATDs, meaningfully exceeding our 50% response rate bar for success, and 56% achieved an ATD-Free response rate, again, in patients previously uncontrolled ATDs, meaningfully exceeding our 30% ATD-Free response rate bar. Importantly, we also observed a strong correlation between the degree of IgG lowering and clinical outcome. With the 1402 Graves' Disease IND cleared, we expect to start our first pivotal study by the end of this calendar year. And finally, we have sized the potential market opportunity using multiple analyses to be about 25% to 30% of Graves' Disease patients who are not well controlled on ATDs and for whom no approved medical alternative exists today. Given this, Graves' Disease represents both an important opportunity to solve a real gap in the current treatment paradigm for patients and an attractive commercial opportunity with limited competition. With that, I'd like to thank you all for your time and open up the call to questions.

[Operator Instructions] So our first question comes from Alex Thompson at Stifel.

I guess maybe could you talk a little about what patients look like who had a response or an ATD-free response at 12 weeks and then lost that response in the second period?

Yes. Thanks for that question, Alex. So for -- if you look at the slides with the responder rate and the ATD-free responder rate, you can see that if you look down at the numbers, where the patients, there are 14 patients who had an ATD-free response rate at week 12 and then there were 9 at week 24. So 5 patients lost their ATD-free response rate on the lower dose. What happened to those 5 patients is that they remained euthyroid, but now they were maintaining that euthyroid state with what I might call combination therapy, so they needed an antithyroid -- they needed to restart their antithyroid drug on top of the 340 milligrams of batoclimab, whereas with high-dose batoclimab, they were able to become and stay euthyroid without any ATD.

Our next question comes from Derek Archila at Wells Fargo.

Congrats on all the progress here. Just two from us. I guess, Pete, maybe can you provide some insight on how the first pivotal trial on Graves' is powered? I guess, what's your expectation for the placebo response using the proposed ATD taper in the trial? And then the second question is I guess, can you give us a sense of how derisking you think the magnitude of the dose response that you're seeing here with beta on Graves' will translate to other indications?

Yes. Great questions. Thanks, Derek. So in terms of the powering, this study is very well powered because in the placebo arm, I think it's going -- the response rate is going to be very, very low. We've said before that we thought 5% to 15% of patients might become euthyroid with continued ATD dosing, but the percentage of patients over a 26-week period who start out the trial insufficiently responding to an ATD, so they're hyperthyroid and on an ATD like this population, then over a short period of time, 6 months is a relatively short period of time, not only become euthyroid, but also are able to stop their ATD because they have to do both of those to hit the primary and the placebo group. I think that's going to be a very low number. We saw the values for the FcRn-treated, batoclimab-treated patients at week 12, they might be even a little bit stronger at week 24, the placebo group is going to be low. So the powering, I don't think will be an issue. And we have a slightly larger number of patients than we would need for the powering and the primary in order to have a good pool for the -- some of the secondary metrics that I mentioned. In terms of the deeper is better, which we're observing here in this proof of concept, Graves' patients and how derisking is that for other indications? That's a great question. I think there's -- this is one more among many datasets that shows a correlation between IgG lowering, depth of IgG lowering and clinical response. And what's striking about this data is because we have the primary patient-level data, which isn't true for all the other datasets, we were able to cut it in many different ways. We have a lot of cuts that we didn't show, but they all are very similar to what we did show, which is when you divide patients who were above 70%, meaning they're deeper than 70% or less than 70% and you saw a big difference in the clinical outcomes. No matter which way we looked at that, we saw a correlation between IgG lowering and clinical response. So I think this bodes very well for other indications.

Our next question comes from Yasmeen Rahimi at Piper.

Congrats team for the great data as well. It's a really thoughtful presentation this morning to us. Two questions. I guess, given that two registrational studies will be run and you have said that they will be staggered, could you maybe talk about how similar the second study could look like? And then second question is, you were the first one in this field. And obviously, you've learned a lot through the study in terms of execution to ensure maybe a rapid enrollment, maybe we could talk about how you're thinking about executing on the study. I know it's difficult to give time frames for how long the study would take for enrollment on top-line data. But just maybe conceptually talk about what's being done, what lessons were learned from the open-label study that -- and now with this data on hand to really kick this off and move as quickly as you can. And I'll jump back in the queue for the long questions.

Thanks, Yas. Two great questions. So for approval by the Endocrine division with an indication for Graves', we will need 2 studies. We'll run them in parallel, meaning the second study will start sometime in the near future. And we'll work to have the 2 trials finished about the same time. The second trial is likely to be reasonably similar in terms of the design, but may be different in terms of the populations. There's some interesting different populations within the broad Graves' Disease population that's intolerant or insufficiently responding to an antithyroid drug. And one example, of course, our patients who not only have hormonal implications relative to the Graves' Disease, but thyroid eye disease as well. We purposely excluded patients with moderate to severe TED from this first trial because the trial infrastructure would have to be different to accommodate studying that as well, and we wanted to really focus this first trial just on Graves' Disease. But our second trial will likely have the ability to look more closely at the overlap between Graves' and TED. So stay tuned for how that one shapes up. In terms of enrollment, there's one really, really positive tailwind and then one small hurdle that we'll need to work through. The tailwind is that there's a lot of unmet need. And as we speak with physicians, potential investigators who treat a lot of patients with Graves' Disease, it's easy to bring that need into focus with more detailed discussions with them. And that will be a real big positive and there aren't competitive trials. On the hurdle side, many of these physicians have not run a lot of clinical trials recently. So there is some level of trial infrastructure that will need to be set up. That's kind of a onetime speed bump at the very beginning. These trials are not going to be overly complicated, but there are a few things that need to be put in place in order to run them. So I think the trial may take just a little bit longer to get started an extra couple of months to get the sites up, but then once they're up and running, I'd expect them to roll -- enroll much more quickly than in other rare disease trials. And in terms of something that's within our control to maximize enrollment, one of the things that's helpful for any trial is having -- being able to articulate the trial design in a really convincing manner to physicians. And we have a variety of proprietary information that would be shared with physicians confidentially who are participating in the trial, and I think that will give them extra confidence in terms of how to manage the trial and that kind of thing helps a lot with enrollment. So thanks for those questions.

So our next question comes from Brian Cheng at JPMorgan.

Congrats on the data. Can you give us a sense of the average ATD dose at entry and at time to ATD-free? And just on -- when you think about the competitor dynamic here, now that you have decent insight in Graves', particularly, how do you think about the competitor barrier entering the space? In other words, how confident are you that you have built enough of a barrier to protect yourself against potential competitors?

Yes. Thanks, Brian, for those questions. So in terms of the ATD dose at baseline, we didn't -- we left out some of those details for competitive reasons. But patients were on a -- they were on a good dose of ATD. So they weren't on low doses of ATD. They were on doses that I think the vast majority of physicians would consider moderate or high. And in terms of time to stopping their ATD with 56% of them totally off their ATD by week 12, you can -- you would be right to infer that the down tapering started pretty early in Period I. In terms of barriers to competition, there's -- on the one hand, there's so much unmet need here when you really roll out to your sleeves and do your homework. And as I think we've shown with today's information, the market sizing information, and more detailed and careful discussions you have with physicians and patients, you really realize there's a lot of unmet need. So I expect that to draw others to this space as it comes into focus. However, I think what we've also shown is pretty convincing information that if you don't have a highly potent FcRn inhibitor, if you're not confident that you can get above 70% at the population level, not for an occasional patient who gets above 70%, but that you can get the average patient in your trial above 70%, I think that would make me nervous. We're not including the 300-milligram dose in our pivotal trial because, frankly, we don't think it would work. So that is a pretty significant barrier, I think, for any competitor that can't get there, which is pretty much all competitors right now in terms of the doses that they're actually using in clinical trials.

Our next question comes from Sam Slutsky of LifeSci Capital.

Congrats on the data update. I guess, so there seems to be obvious benefits for a therapy that could work in both Graves' Disease as well as thyroid eye disease given the overlap of the two conditions. Could you just discuss the strategy for 1402 as it relates to getting either TED data directly on a potential label for Graves' Disease, generating data that could be discussed and potentially market physicians or just running a separate thyroid eye disease study in itself to kind of interplay those two?

Yes. Thanks for the questions, Sam. So obviously, as you point out, the root cause of both conditions is the same. It's the autoantibody, the TSH receptor. Thyroid eye disease is, therefore, a subset of Graves' Disease. And there's a high overlap between the group of Graves' Disease patients who are harder to treat and those who have thyroid eye disease. So there's definitely a lot of reasons to think about these two distinct but overlapping conditions together. In terms of our strategy for how we address that in the context of our 1402 development program, as already hinted at, we're likely to include patients with more severe TED in a subsequent Graves' study. And if we go that route, that will definitely generate data in thyroid eye disease patients who have Graves' and so TED data in the context of a Graves' label. Over the next quarter or so as we finalize that study and then reveal its design, that will come into focus. But directionally, that's how we're thinking about it today. Thanks for that question. It's a good one.

So our next question comes from Samantha Semenkow at Citi.

Congrats on the data. A few for me. I know the treatment duration was limited in the Phase II, but do you have a sense of the durability of the high dose of batoclimab over the first 12 weeks. Were there any patients that met the response criteria and then subsequently lost it and curious how you're thinking about the durability in the Phase III? And relatedly, what are the patients that didn't respond look like? Do these patients tend to have a lower IgG reduction than the average? Or did they just need more time on therapy, do you think? And then just lastly, the Phase III trial design you shared, it includes TSH normalization as part of the primary endpoint definition for euthyroid. Did you look at TSH in the Phase II? And how does it impact the Phase II data when you add in that criteria?

Yes, great questions, Samantha. Thank you for those. In terms of durability, when you look at the individual patient curves, their response really tracks their IgG curves or their TRAb curves, which track together. So we were confident that with high-dose 1402, we would -- we'll have steady IgG suppression and therefore, a durable response. You're not seeing a lot of fluctuation, except at the beginning of the therapy where the IgG is falling from normal to pretty lower, much lower level on the 680 in batoclimab study. And then, of course, when you -- this study has the special feature of lowering the potency during the second 12 weeks, which, of course, we're not planning to do in our 1402 study. This isn't a disease that I think lends itself to sort of a short-term induction and maintenance. I think it's -- you're going to need to heat the antibodies suppressed for a while, 1 year or so before testing remission, and that's what we've designed into our pivotal Phase IIb trial. In terms of the nonresponders, the people who didn't get off their ATD, so they were not an ATD-free responder, but they were a responder, which is most of the rest of them, they dropped their -- as a general rule, they dropped their ATD. So -- and many of those markers look like they were still improving at week 12. They were just moving a little bit more slowly than some of the patients who did get to an ATD-free response already by week 12. So it's possible that just with longer duration of more potent agent, the 600 milligrams given the 26 weeks that, that will bring some of the people who weren't responders into responding. Of course, for our pivotal design, we've chosen to stick with the strict responder definition, which is you need to not only normalize your T3 and T4 but also come off of your ATD. That's very, very helpful in terms of comparing with the placebo group, where we don't think there's much chance at all that they will come off of their ATD. And then you asked an astute question about TSH. So the -- what I can say about TSH is that at week 24 in the batoclimab proof-of-concept study, the average TSH had normalized. So we expect the response rates in the Phase II study to be predictive of the response rates in the pivotal Phase IIb trial even with the addition of TSH because it's basically tracking with the other thyroid hormones at week 24. It takes a little bit longer to normalize. So it wouldn't necessarily fully track at week 12 but by week 24 they'll track. Thank you for those questions.

So our next question comes from Andy Chen at Wolfe Research.

Congrats on the data. My question is mainly on your Phase III design and the primary endpoint at week 26. So you appear to see thyroid response by week 6. And the relatively high response rate that you reported today is on week 12. So I'm guessing remission rate will plateau after maybe week 12. I'm not sure what I'm just guessing. Can you talk about your best guess on what happens to response rate or remission rate between week 6 and week 12 and week 26? Is there any reason to believe that extending to 26 weeks or 52 weeks, would net to a higher rate of euthyroidism or maybe is it simply just giving patients more time to become ATD-free?

Yes, good question, Andy. I think it's a little bit of all those things. The -- if you take a step back, the recommended duration of treatment in terms of guidelines, both in the U.S. and Europe is generally 18 months, sometimes people will say 12 to 18 months, but I think it's moving more to people emphasizing the 18 months in that 12- to 18-month therapy. And there are some recently published papers on antithyroid drug use, suggesting that many patients actually need a lot longer than 18 months. And given that a lot of people are avoiding ablation, then you have this large group of patients who are more difficult to treat and being treated longer. In the past, if you didn't get the sort of problem solved in 12 to 18 months, then those patients, pretty much all went to ablation, but that's not happening anymore. So although the treatment of Graves' Disease is not decades, it's not short. It's not a short fixed-duration treatment of 3 or 6 months. And so that's the first point. Second point is that everything look like it was continuing. You saw a lot of improvement in the T3 and T4 between week 0 and 6 and then some additional improvement. If you look at the curves on our slides between week 6 and week 12. And of course, the other thing that's happening between week 6 and week 12 is ATD use is going down and people are coming off. So -- but I don't feel like at week 12, we've captured all of the responders and certainly not all of the ATD-free responders that we will be able to capture by week 24 or 26. And so that's a big part of the reason. And then finally, of course, if you're going to study a therapy for chronic treatment, you generally need a 6-month study designed to inform that. So those are all the reasons that we went for 6 months in the pivotal IIb trial. Thanks for the question.

So our next question comes from Jason Gerberry at Bank of America.

So you end up enrolling about 25 patients at a single site. I think initially, you had targeted 40 to 45 patients. So just curious, did something change? And I'm just curious how to think about enrollment timelines in a population like this, given the severity of disease, I'm wondering if this is a quick to enroll type of study population or if this could be a slower to enroll study population? And then just second question for me is, can you just bring -- as you think about the addressable Graves' population, what proportion of that is under the care of an endocrinologist. I'm just curious how concentrated of a call point this market is, from a prescriber standpoint?

Yes. Great question. Thanks, Jason. So we set this trial up to be up to 45 patients. And originally, that was because we weren't sure how much heterogeneity there would be, would we see, for example, in patients who had a markedly different disease duration or baseline TRAb levels or baseline ATD level or degree of hyperthyroidism that there were certain subgroups that performed one way and other subgroups that performed another way. So we wanted to have the trial large enough that we could figure that out. Once we got about 20 patients. It was very clear that everything was kind of looking the same, which was good. This population is actually relatively homogeneous in terms of their response to the high dose of batoclimab over that first 12 weeks. So at that point, we sort of slowed down the enrollment. We still have a couple of more people that are in the trial that will finish, and they give us some information on methimazole tapering, that will be helpful for the finalization of that methimazole tapering protocol for the pivotal trial. But at this point, I think we've learned what we need to learn from the POC with the 25 patients through 24 weeks. In terms of the addressable market, so patients who are easy to treat with Graves' Disease, so the group that we're not targeting because they go on to an ATD and after some short period of relatively easy adjustment, they get stable, those patients usually have at least a visit or 2 with an endocrinologist unless they're in a very rural area. But often, they return to their primary care provider for maintenance therapy because easy to treat Graves' Disease is definitely something that either a general endocrinologist or a primary care provider can do. But for this harder-to-treat group, and it's really striking when you see the chart review data that I described, these patients are often -- they're being seen as frequently as every 2 to 4 weeks because their T3 and T4 levels are fluctuating pretty dramatically. They're being tapered up and down. Those patients are not being seen by primary care providers. And actually, they're not being seen by general endocrinologists, even within a large endocrinology practice, that type of patient will be referred to the couple of physicians in the group that really specialize in Graves' Disease because these are hard iteration schedules to put together. So from a call point standpoint, I think this will be very efficient. Thanks for those questions.

So our next question comes from Corinne Johnson at Goldman Sachs.

Maybe a couple of questions for me. One, can you help us tease out like any drivers for the patients that didn't maintain higher IgG suppression through that second 12-week period versus obviously some of them were able to stay over 70%. And I'd be curious, mostly in terms of read-through to other populations and studies. And then one of the considerations, obviously, that comes a lot, up a lot in this discussion is like unmet need where you highlighted about 1/4 of patients aren't well controlled. But could you expand a little bit on what that means for them clinically and what kind of the symptoms and risks are for that patient population?

Yes. Great question. Thanks, Corinne. So in terms of those who didn't maintain their IgG, we have looked at -- it's basically people who didn't get as deep on 680 and then they also didn't stay as deep on 340. We've looked at drivers or predictors of IgG suppression extensively separate from Graves' just to try to figure out can you identify the people who aren't going to respond as more and therefore might need a higher dose. And some programs have used weight-based dosing. There is a correlation to weight, but it's pretty small. So you don't have very big differences unless the weight differences are really extreme, which is why we don't use weight-based dosing. And otherwise, there's -- it's hard to predict in advance who's going to get, let's say, with batoclimab 680, we get a range of 75% to 85% with 80-ish being the mean for the population generally. In this study, it was 77%. Who gets 75% and who gets 80%, it's hard to tell in advance, but some people do. Some people get a little deeper, some people get less deep. So the good news about the 680 of batoclimab and we also expect this to be true of 600 of 1402 is pretty much everybody is well over 70%. So that's great. And at a lower dose, you're also going to have variability. So the ones who are above 70% after the 680 fall by 340, they're just the group, it was 10 out of 23, so that's just the -- those are the 10 people who are just a little bit more FcRn responsive. In terms of the unmet need, so what does that look like? What's the texture of that unmet need? You really get a sense from this from the chart review as I kind of referenced this a little bit in response to Jason's question. These are patients who are being seen very frequently. They have often period of a 3-, 4-month period where they're seeing every 2 to 4 weeks, getting their blood drawn all the time. They go from being hyperthyroid to the euthyroid to hypothyroid then back to hyperthyroid, their antithyroid -- the methimazole doses being tapered up and down. And the physician is just really struggling to get them on to a stable dose in euthyroid. And you get the sense from a lot of these charts that the patients are working hard with the physician. It's not like they're just noncompliant or something like that. They're just really struggling. Why that happens, it's not 100% clear. But because methimazole has a narrow therapeutic window where you can give -- increase the dose just a little bit and you go from somebody who wasn't controlled and therefore hyperthyroid to somebody who's overly controlled than hypothyroid that really makes the treatment difficult. And symptoms basically track with those hormone levels. So when they're hyperthyroid, they're anxious, they're having trouble sleeping, diarrhea, flushing, heart palpitations, and then when they become hypothyroid all the opposite happens. They get lethargic, fatigued and just feeling slow. So people are very symptomatic and there's a lot of vacillation and uncertainty. And the nice thing about the FcRn profile for physicians when we've tested it is, of course, that it looks like you get euthyroid control, as we described with these results. But also, it's a steady control. It's not requiring the titration that methimazole requires in these difficult-to-treat patients. So that's like a 2-level breakthrough from a solution standpoint.

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

Congratulations on all the data. So just two quick questions for you. First one, is there a potential for a remission claim on your label? And why or why not? And then secondly, do we have to wait for 52 weeks to see all the data? Or will you show an interim look at 26 weeks?

Yes, thanks for those questions, Louise. So I think remission is a possibility that the data supports it. And that's why we have this extra period of 52 weeks of off-drug follow-up built into the study. And then in terms of the when the topline results will read out, so the top line results from this study read out at 52 weeks. So everybody is -- remains blinded for 52 weeks, even though the primary is at 26 weeks, there's blinded movement between 1402 and placebo within Group II, and you also want to get 52-week data with a clean dataset. So the study will stay blinded at until 52 weeks. However, the remission part of that will be separate. So it's the first registration that we would hope to seek would be just based on becoming euthyroid and off ATD, remission would come later. Thanks for those questions.

So our next question comes from Ashwani Verma at UBS. Ashwani, you're maybe on mute.

Okay, sorry. Can you hear me now?

Yes, we can.

Yes, Ash.

So I have two questions just on the data that you presented. So the T3, T4 normalization that you showed at by week 6, like, just curious, is that happening relatively smoothly? Or are you seeing any kind of big fluctuations to get to that point? And then secondly, just on the response rate, like I wanted to show -- I wanted to ask just how much of the efficacy boost in the second period with the lower dose that you're getting at like 68% response on the primary would be because of the residual effect of the higher dose in the first period?

Yes, great questions. At the individual patient level, the normalization is pretty smooth. And that is of course, because batoclimab doesn't have the overshoot potential of methimazole and meaning it's not going to make you hypothyroid, and we had a highly skilled physicians at a single site doing methimazole tapering. Based on the methimazole tapering experience, we're going to be able to provide as part to our much broader set of investigators in the pivotal trial, kind of a hook book to guide there methimazole tapering. So I think we'll be able to preserve that in the pivotal trial. And in terms of how much of the response in the second period is due to the first period I think there's a decent chance that a good amount of it is due to the carryover IgG suppression. Of course, if you think about the IgG curves, your -- everybody starts Period II, well, on average, they're 77% suppressed from baseline. And so they're starting very low. And in the first takes 4, 5, 6 weeks for them to go from 77% on average to 65%, which is different than someone who would be starting on a less potent FcRn inhibitor or starting on 340 of batoclimab, which is a less potent than 680, they would start at 0 and then it would take them 6 weeks to get to 65% and then they would only have the next 6 weeks to be at 65%. So I think there is a very good question. I think there's a good chance that if you just studied great low dose or standard dose from IgG suppression, you wouldn't replicate our second period results. Thanks for the questions, Ash.

So our next question comes from Nat Charoensook at Leerink.

This is Nat Charoensook on for Tom Smith. Congrats on the data and the progress. So in the Phase IIa study, you mentioned that thyroid receptor antibody or TRAb level at baseline, which was highly elevated compared to the upper limit normal. Did you analyze it changes to other study or observe its normalization? And how's the reduction dynamics compared to changes of T3 and T4 levels?

Yes, thanks for that question. We didn't share the TRAb data for competitive reasons, but it largely tracked IgG and both in terms of the degree of response and the kinetics. And you're right, it can start out very elevated. Thanks for the question, Nat.

Our next question comes from Yatin Suneja at Guggenheim.

Nice presentation. Just a quick one for me. I understand you are not disclosing the length of ADT at baseline, but have you checked and showed if there is any correlation between the length of ADT therapy, and the response to the treatment. The reason I ask is because usually it takes somewhere between 6 to 12 weeks for hormone levels to normalize. So just curious if in the first period, there was any effect from the ADT at baseline for patients that had just started on it?

Yes, that's a really good question, Yatin. So it turns out that there weren't many patients who had a short duration of antithyroid drug therapy. We allowed in this trial, patients who had been diagnosed as recently as 12 weeks ago as long as they were on a stable dose of ATD for a period of time and not improving. But there were very few patients like that. As you can imagine, the patients who enrolled and who are attracted to being in a trial design had generally a longer period, most of them more than 6 months of anti-thyroid drug therapy, and were still hyperthyroid. And by 6 months, once you get beyond about 6 months, things have kind of stabilized wherever they're going to be, people have either gotten better or they're sort of out where they're at. And consequently, there wasn't -- we didn't have the really short duration patients. And I think although the pivotal trial does allow them, I expect that will be a small -- there'll be some special cases, more severe patients or something, most patients are going to have a longer duration. And so the Phase II results, net of all data set, I think these Phase IIa results are predictive for what we'll see in the Phase IIb pivotal trial, except of course, that we'll have more potent FcRn inhibition for longer in the IIb, so that might help.

Very good. One more question, if I may. This is more around the commercial dynamics. So you highlighted this big prevalence pool and over 20,000 incidental pool. Could you just talk about where we are on physician education standpoint, their adoptability on a new mechanism, given that there has been just limited development in this space?

Yes, absolutely. I mean we're at a super, super early front-end of that. And their discussions remind me a little bit of talking to some physicians about thyroid eye disease in 2019. So what's pretty universal is among endocrinologists and ophthalmologists aren't very important for Graves' Disease. The endocrinologist are really the -- not only they're in the center of the universe and the periphery of the universe in Graves' Disease -- they're super incited about the mechanism of action because it gets to the root cause of the disease. So that part, I think there's really no data on or much variability. When you go to physicians with them -- if you go to physicians that are just general endocrinologists and you ask them about treatment of Graves' Disease, many of them will say, it's pretty easy to treat. But if you go to through a thyroid specialists who treat hundreds of Graves' patients, and you ask them to describe, for example, patients that they're seeing today for whom they're recommending ablation, but those patients are refusing it, then you get much more easily into a dialogue of, "Oh, yes, I've got this group there. Either they're on a persistently high dose of ATD, which makes me nervous because of the severe side effects or they're going up and down and they're really hard to control." Basically, they describe what we showed from the survey and the chart review. And 20 years ago, those patients just went to ablation. And then they had a new problem, which was hypothyroidism and they need to take Synthroid the rest of their life, but they were much easier for the physician to treat at that point. Now with patients refusing ablation because they're worried about radiation or physicians have become more attuned to the risk of precipitating TED with radioactive iodine, all those things are definitely leading to a huge decrease in the use of ablation, which creates this pool of patients that are hard to treat. And I think the other thing -- the final thing I would say in terms of the physicians really being attuned to and recognizing this need is when you don't have a good solution, which is true today, if you have a -- if you're a thyroid specialist treating Graves' patients, you don't have a good solution for your difficult-to-treat Graves' patients. So when you don't have a good solution in those types of situations in market research, you don't tend to hear the unmet need articulated quite as crisply. I think once physicians start to see this data, I think the unmet need is going to come much more into focus. And of course, we'll have medical education efforts around that as appropriate. Thanks for those questions, Yatin.

So our final question comes from Leland Gershell at Oppenheimer.

Yes, great to see the solid dataset. Just wanted to ask in terms of these patients who go on ATD. How long does it take for them to sort of establish themselves as being refractory or nonresponders? And do they go through kind of the -- the couple of oral options, what does that sort of look like before they're deemed as refractory. And then I have a follow-up.

Yes. It's basically 6 months for the vast majority. So when you look at the chart reviews or anything else, within 6 months, these patients sort themselves out one way or the other. So that makes it -- that's pretty easy.

Yes. And then with respect to using an FcRn such as yours, obviously, it would be the holy grail to get them off those drugs, given their limitations. But in sort of the scenario where you have dose reductions, how do you see 1402's opportunity in the scenario where they would use 1402 and then still have to remain on some level of oral?

Yes. Just super quickly because we're getting closer to the end of time here. But the #1 need for patients and physicians is to become euthyroid. It's a really, really, really nice icing on the cake to also get off your ATD. So the patients who become euthyroid and need to maintain a small amount of ATD, they're still getting a benefit, but the ones who get totally off ATD, they're the ones who are getting the home run. Thanks for those questions, Leland.

All right. This concludes our Q&A session. I'll turn it back to you, Pete, for some closing remarks.

Yes. Thanks, Tara. So I think we've covered a ton of ground today. This is a very exciting opportunity. Frankly, first and foremost, for patients who today don't have a good option. And secondly, for Immunovant, given the information we shared about the character of the unmet need and the emerging profile of 1402, which have a potentially best-in-class and first-in-class offering here in Graves' Disease. So thanks, everyone, for your time today.