Good morning. My name is Tara Sobreski, 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 a 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 sixth, 2024. Joining me on the call this morning is Dr. Pete Salzman, 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. Salzman.
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 anti-thyroid drugs or ATDs. As noted on this slide, 25%-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 this same population studied 680 mg 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 three-quarters 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.
Viewed from several different angles, there is a consistently sized group of patients who are uncontrolled on ATDs. Specifically, each analysis indicates that about 25%- 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 activate the thyroid gland in Graves' disease. Since the autoantibodies aren't subject to a feedback loop, their presence leads to overproduction 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 anti-thyroid drugs or ATDs. The most common ATD, methimazole, was approved in the U.S. in 1950. The bad news for Graves' patients is that 25%-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%-30% of Graves' patients that don't respond well to ATDs? Today, there are two second-line therapies, both of which totally remove the thyroid, necessitating lifelong thyroid replacement.
These two procedures, radioactive iodine and surgery, or surgical removal of the thyroid gland, both carry important risks in addition to treating 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 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 four 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 four 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 mg for the first 12 weeks of the study, followed by 12 weeks of our lower dose of batoclimab , 340 mg 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 thyrotropin 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 just explained. The purple bar on the left shows that there were 76% responders after 12 weeks of 680 mg of batoclimab . The mean change from baseline in IgG at week 12 was 77%.
Recall that after 12 weeks of 680 mg of batoclimab , subjects were stepped down and received the lower 340 mg of dose, 340 mg 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 mg 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 were able to entirely cease ATD therapy by week 12. Remember, 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 mg weekly of batoclimab for 12 weeks....
Remember, the mean IgG reduction at week 24 was 65%, and this 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 mg 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 participant. We used this variability to separate the entire cohort into two 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 33% 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 two hormones that cause the symptoms of Graves' disease and also cause adverse medical outcomes. For competitive reasons, we aren't showing all the time points.
Rather, we're just showing baseline, week six, and week 12 values. In both charts, T3 and T4 rapidly fall within normal range by week six. Note that this is not driven by ATDs, which were already being significantly tapered by week six. Moving on to safety. No surprises here, with findings 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 preexisting 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 gallbladder surgery necessitated discontinuation of treatment per protocol.
There was one other patient who had heavy menstrual bleeding and consequently missed a visit and missed a dose. He 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 two 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 mg of 1402 or to matching placebo.
The primary endpoint at the end of period one or week 26 will be the proportion of participants who become euthyroid and stop ATD therapy. For treatment period two, group one will continue to receive 600 mg of IMVT-1402 sub-Q for an additional 26 weeks, blinded, of course. After period one, group two will be divided into a continued 600 mg of IMVT-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 two will continue on 600 mg of IMVT-1402 through week 52. Group three will remain on placebo throughout period one and period two.
A key secondary endpoint at the end of period two 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 IMVT-1402. We will test remission rates in participants who get 12 months of IMVT-1402 and in participants who are TRAb responders and receive 6 months of IMVT-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 five different approaches to size the market in Graves' disease and found that across these approaches, at least 25%-30% of patients relapse or 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 dataset 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 multi-year lookback 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 analyses without a very careful look back period might have characterized some prevalent patients as incident patients, potentially explaining this discrepancy. Turning back to our data, the prevalence and incident numbers suggest that the treatment of Graves' disease is more in the range of five years versus one to two 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 patient 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 adults in the US. The data shows that these patients take three paths. First, in the far right white box, we see that a 120,000 patients received ablative therapy, radioactive iodine, or surgery. The left two 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 300 and 30 ,000 ATD relapse 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 incidence population we've cited previously from the literature of a 100 and 16 ,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.
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 three, 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 a quarter of their patients qualified as uncontrolled while on ATD therapy, and another quarter relapsed and became uncontrolled after stopping their ATD. Because of these percentages are higher than the 25%-30% figure that we're generally quoting, probably because it's hard to fully separate the cases of incident and prevalent patients in a survey.
In other words, over time, total uncontrolled and relapsing group may be higher than 25%-30%. So that was what physicians said. In analysis four, we took a very careful look at what they did. Specifically, we 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. 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 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. 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 five different analyses is this: Having looked at the degree of unmet need from many different angles, we have consistently found that at least 25%-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've begun to talk about this opportunity, many have asked how a gap in care like this one can be addressed, or will be addressed in the commercial landscape.
How does an innovative new medical therapy enter the space between cheap generics and invasive procedures? I wanna 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 two years of launch, Tepezza had taken a 20% market share, similar to the 25%-30% I've been quoting, and that was achieved in just two 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 incidence and with pricing in the same range or higher than anti-FcRns. We believe this is very informative for the potential dynamic in Graves'. A 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%-30% of patients with Graves' disease who have minimal to no other therapeutic options. Here are the reasons I believe this. Number one, two, and three, the batoclimab proof of concept study exceeded the goals we had set out to achieve. To 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 on 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 outcomes.
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%-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 yo ur time and open up the call to questions.
Great, so at this time, we'll be conducting a question and answer session with our speakers. Please hold for a brief moment while we poll for questions, so our first question comes from Alex Thompson at Stifel. Please go ahead, Alex.
Great. Thanks so much. I guess maybe could you talk a little about, you know, what patients looked like who had a response or an ATD-free response at 12 weeks and then lost that response in the second period? Thanks.
Yeah, 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. For the patients, there are 14 patients who had an ATD-free response rate at week 12, and then there were nine at week 24. So five patients lost their ATD-free response rate on the lower dose. What happened to those five patients is that they remained euthyroid, but now they were maintaining that euthyroid state with what I might call combination therapy.
They needed an anti-thyroid. They needed to restart their anti-thyroid drug on top of the 340 mg of sotolimonab, whereas with high-dose sotolimonab, they were able to become and stay euthyroid without any ATD.
Great, thanks for the questions, Alex. Our next question comes from Derek Archilla at Wells Fargo. Please go ahead, Derek.
Hey, good morning, and thanks for taking the questions and 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 in 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, you know, can you give us a sense of how de-risking you think the magnitude of the dose response that you're seeing here with batoclimab and Graves will translate to other indications? Thanks.
Yeah, 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 gonna be very, very low. You know, we've said before that we thought 5%-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 in insufficiently responding to an ATD, so they're hyperthyroid and on an ATD like this population, then over a short period of time, six 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 in the placebo group. I think that's gonna be a very low number.
We saw the values for the FcRn-treated, batoclimab-treated, patients at week 12. You know, they might be even a little bit stronger at week 24. The placebo group's gonna 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 on the primary in order to have a good pool for some of the secondary metrics that I mentioned. In terms of deeper is better, which we're observing here in this proof of concept, Graves' patients, and how de-risking is that for other indications? That's a great question. I think there's this is one more among many data sets that shows a correlation between IgG lowering, depth of IgG lowering and clinical response.
What's striking about this, you know, this data is because we have the primary patient-level data, which isn't true for all the other data sets. We were able to, you know, 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%, 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.
Thanks for the questions, Derek. Our next question comes from Yasmeen Rahimi at Piper. Please go ahead, Yas.
Thank you. 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're the first one in this field, and obviously, you've learned a lot through this study in terms of execution to ensure maybe a rapid enrollment. Maybe we could talk about how you're thinking about, you know, 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 two studies. We'll run them in parallel, meaning the second study, you know, will start sometime in the near future. And, you know, we'll work to have the two trials finish about the same time. The second trial is likely to be reasonably similar in terms of the design, but maybe 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 anti-thyroid drug. And one example, of course, are patients who not only have hormonal implications relative to their 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 what that one, 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'll 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 one-time speed bump at the very beginning. These trials aren't gonna 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 enroll much more quickly than in other rare disease trials.
And in terms of something that's within our control to maximize enrollment, you know, one of the things that's helpful for any trial is being able to articulate the trial design in a really convincing manner to physicians. And we have, you know, a variety of proprietary information that would be shared with physicians confidentially who are participating in the trial. I think it'll 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.
Yes, thanks for the questions, yes. So our next question comes from Brian Cheng at J.P. Morgan. Please go ahead, Brian.
Good morning. Thanks for taking our questions this morning, and congrats on the data. Can you give us a sense of the average ATD dose at entry and the time to ATD-free? And, you know, just on, you know, when you think about the competitor dynamic here, now that you have decent insight into Graves', particularly, how do you think about the competitor barrier in the space? In other words, how confident are you that you have built enough of a barrier to protect yourself against potential competitors? Thank you.
Yeah, thanks, Brian, for those questions, so in terms of the ATD dose at baseline, we left out the, you know, some of those details for competitive reasons, but patients were on a, you know, they were on a good dose of ATD, so they weren't, 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, you know, with 56% of them totally off their ATD by week 12, you would be right to infer that the, you know, down tapering started pretty early in period one. In terms of barriers to competition, there's...
On the one hand, there's so much unmet need here when you really roll up your sleeves and do your homework, and as I think we've shown with today's information, the market sizing information, and the 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't get the average patient in your trial above 70%, I think that would make me nervous.
We're not including the 300-mg 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, to my knowledge, is pretty much all competitors right now in terms of the doses that they're actually using in clinical trials.
Great. Thanks for the questions, Brian. Our next question comes from Sam Slutsky at LifeSci Capital. Please go ahead, Sam.
Hey, congrats on the data update, and thanks for taking my question. I guess so there seems to be obvious benefits to 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 can be discussed and potentially marketed to physicians, or just running a separate thyroid eye disease study in itself to kinda interplay those two?
Yeah, thanks for that question, Sam. So obviously, as you point out, the root cause of both conditions is the same. It's the autoantibody to 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 distinct but overlapping conditions together. In terms of our strategy for how we address that in the context of our 1402 development program, as I already hinted at, we're likely to include patients with more severe TED and 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, you know, it can come into focus, but directionally, that's how we're thinking about it today. Thanks for that question. It's a good one.
Thanks for the question, Sam. So our next question comes from Samantha Semenkow at Citi. Please go ahead, Samantha.
Hi, good morning, and thanks very much for taking the question, and 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 do 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? Thank you.
Yeah, great questions, Samantha. Thank you for those. So, 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'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 a pretty lower, much lower level on the 680 in the batoclimab study.
And then, of course, 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, you know, that I think is lends itself to sort of a short-term induction and maintenance. I think it's you're going to need to keep the antibody suppressed for a while, a year or so before testing remission, and that's what we've designed into our pivotal phase II-B trial. In terms of the non-responders, you know, there, 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.
And many of the 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. It's possible that just with longer duration of the, you know, more potent agent, the 600 mg given for 26 weeks, that will, you know, 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, 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, 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 II- B 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, it'll track. Thank you for those questions.
So our next question comes from Andy Chen at Wolfe Research. Please go ahead, Andy.
Hey, good morning. Thank you for taking the question, and 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 six, 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, I'm just guessing. Can you talk about your best guess on what happens to response rate or remission rate between week six and week 12 and week 26? Is there any reason to believe that extending to 26 weeks or to 52 weeks would net you a higher rate of euthyroidism? Or maybe is this simply just giving patients more time to become ATD free? Thank you.
... Yeah, good question, Danny. I think it's, it's a little bit of all those things. You know, the if we 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 and that 12 to 18 months therapy. And there are some recently published papers on anti-thyroid 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, you know, patients who's more difficult to treat and being treated longer.
In the past, if you didn't get a 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 three or six months, and so that's the first point. Second, point is that, you know, everything looked like it was continuing. You have saw a lot of improvement in the T3 and T4 between week zero and six, and then some additional improvement if you look at the curves on our slides between week six and week 12. And of course, the other thing that's happening between weeks six 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, you know, need a six-month study design to inform that. So those are all the reasons that we went for six months in the pivotal IIb trial.
Thank you.
Thanks for the question, Danny.
So our next question comes from Jason Gerberry at Bank of America. Please go ahead, Jason.
Hey, guys. Thanks for taking my question. 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 frame—you know, 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. Thanks.
Yeah, great questions. Thanks, Jason. So we set this trial up to be, you know, up to 45 patients, and originally, that was because we weren't sure how much heterogeneity there would be. You know, would we see, you know, 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, you know, 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, you know, about 20 patients, it was very clear that everything was kind of looking the same, everything, which was good. This population is actually relatively homogeneous in terms of their response to the high dose of sotolimonab over that first 12 weeks.
So at that point, we started, you know, slowed down their enrollment. We still have a couple more people that are in the trial that will finish, and they give us some information on methimazole tapering. You know, that'll be helpful for the finalization of that methimazole tapering protocol for the pivotal trial. But at this point, you know, 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 two with an endocrinologist, unless they're in a very rural area. But often, they return to their primary care provider for maintenance therapy 'cause easy-to-treat Graves' disease is definitely something that a, 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, you know, these patients are often. They're being seen as frequently as every two to four 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.
You know, 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 titration schedules to put together. So from a call point standpoint, I think this will be very efficient.
Got it. Thank you.
Thanks for those questions. Yep.
So our next question comes from Corinne Jenkins at Goldman Sachs. Please go ahead, Corinne.
... Morning, everyone. Maybe, maybe a couple questions from 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? Whereas 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 a quarter 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? Thanks.
Yeah, 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 . You know, we've looked at drivers or predictors of IgG suppression extensively, separate from Graves, just to try to figure out, you know, can you identify the people who aren't going to respond as more and therefore might need a higher dose? And, you know, 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.
Otherwise, there's it's hard to predict in advance who's going to get, you know, let's say with 680, we get a range of 75%-85%, with 80, you know, 78-ish being the mean for the population generally. In this study, we had, 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. The good news about the, you know, the 680 of batoclimab, and we also expect this to be true of 600 of IMVT-1402, is pretty much everybody is well over 70%. That's great. And, you know, at a lower dose, you're also gonna have variability.
So the ones who are above 70% after the 680 followed by 340, they're just the group, you know, 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 reviews. I kind of referenced this a little bit in response to Jason's question. These are patients who are being seen very frequently. You know, they have often a period of a 3-4-month period where they're seen every two to four weeks, getting their blood drawn all the time. They go from being hyperthyroid to euthyroid, to hypothyroid, then back to hyperthyroid.
Their anti-thyroid methimazole dose is being tapered up and down, and the physician is just really struggling to get them onto a stable dose and 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, you know, non-compliant or something like that. They're just really struggling. Why that happens? You know, it's not 100% clear, but because methimazole has a narrow therapeutic window where, you know, 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 and hypothyroid, that really makes the treatment difficult, and the symptoms basically track with those hormone levels.
So when they're hyperthyroid, you know, 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 that steady control. It's not requiring the titration that methimazole requires in these difficult-to-treat patients, so that's like a two-level breakthrough from a solution standpoint.
Thanks for the questions, Corinne. So our next question comes from Louise Chen at Cantor Fitzgerald. Please go ahead, Louise.
Hi. Congratulations on all the data, and thank you for taking my questions here. 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? Thank you.
Yeah, thanks for those questions, Louise. So I think remission is a possibility if 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. Then in terms of when the top-line results will read out, so the top-line results from this study read out at 52 weeks. So everybody remains blinded for 52 weeks, even though the primary is at 26 weeks. There's blinded movement between 1402 and placebo within group 2, and you also want to get 52-week data with a clean data set. So the study will stay blinded until 52 weeks. However, the remission part, that will be separate. So it, you know, the first-...
Registration that we would hope to seek would be just based on the becoming euthyroid and off ATD. The remission would come later. Thanks for those questions.
So our next question comes from Ashwani Verma at UBS. Please go ahead, Ashwani. Ashwani, you may be on mute.
Okay, sorry, can you hear me now?
Yes, we can.
Yes, yes.
Hey, good morning. Thanks for taking our question. So I had two questions just on the data that you presented. So the T3, T4 normalization that you showed, by week six, 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 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, could be because of the residual effect of the higher dose in the first period? Thanks.
Yeah, 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, you know, of methimazole, and meaning it's not going to make you hypothyroid. And we had a highly skilled physician at a single site doing the 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, a kind of a book to guide their methimazole tapering. So I think we'll be able to preserve that in the pivotal trial.
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, you know, if you think about the IgG curves, everybody starts period two, well, on average, they're 77% depressed from baseline, and so they're starting very low. In the first, it takes four, five, six weeks for them to go from the 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 less potent than 680.
They would start at zero, and then it would take them six weeks to get to 65, and then they would only have the next six weeks to be at 65. So I think there's... It's a very good question. I think there's a good chance that, you know, if you just studied straight low dose or standard dose, IgG suppression, you wouldn't replicate our second period results. Thanks for the question, Ash.
So our next question comes from Nat Charoensuk at Leerink. Please go ahead, Nat.
Good morning. This is Nat Charoensuk on for Tom Smith. Congrats on the data and the progress. So in the phase I-A study, you measured the antibody or TRAb level at baseline, which was highly elevated compared to the upper limit of normal. Do you analyze its changes throughout the study or observe its normalization? And how's the reduction dynamics compared to changes of T3 and T4 levels?
Yeah, 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 did start out very elevated.
Got it. Thank you.
Thanks for the questions.
Yeah, thanks for the question, Nat.
So our next question comes from Yatin Suneja at Guggenheim. Please go ahead, Yatin.
Hey, guys. Thank you for taking my question. Nice presentation. Just a quick one for me. I understand you are not disclosing the length of ATD at baseline, but have you checked and showed if there is any correlation between the length of ATD therapy and the response to the treatment? The reason I ask is because, you know, usually it takes somewhere between 6- 12 weeks for hormone levels to normalize. So just curious if in the first period there was any effect from the ATD at baseline for patient that had just started on it. Thank you.
Yeah, that's a, that's a really good question, Yatin. So, it turns out that there weren't many patients who had 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, not improving. But there were very few patients like that. As you can imagine, the patients who, who enrolled and who were attracted to the- to being in a trial design had generally a longer period, most of them more than six months of antithyroid drug therapy and were still hyperthyroid. And by six months, once you get beyond about six months, you know, things have kind of stabilized wherever they're going to be. People have either gotten better or they're, they're sort of where they're at.
Consequently, we didn't have the really short duration patients. I think although the pivotal trial does allow them, I expect that'll be a small. There'll be some special cases, you know, the more severe patients or something. Most patients are going to have a longer duration. So the phase II results, net of all that, is that I think these phase II A results are predictive for what we'll see in the phase II-B pivotal trial, except, of course, that we'll have more potent FcRn inhibition for longer in the 2b, 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?
Yeah, absolutely. I mean, we're at the super, super early front end of that. And, you know, the discussions remind me a little bit of talking to some physicians about thyroid eye disease in 20 19. So, what's pretty universal is among endocrinologists, and, you know, the ophthalmologists aren't very important for Graves' disease. The endocrinologists are really the, not only they're the center of the universe and the periphery of the universe in Graves' disease. They're super excited about the mechanism of action because it gets to the root cause of the disease. So that part, I think there's really no debate on or, you know, much variability.
When you go to physicians that are just general endocrinologists, and you ask them about treatment of Graves' disease, many of them will say, "Yeah, it's pretty easy to treat." But if you go to true 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, well, yeah, I've got this group. They're either 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 needed to take Synthroid for 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'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, you know, 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 gonna come much more into focus. And, you know, of course, we'll have medical education efforts around that as appropriate. Thanks for those questions, Yatin.
So our final question comes from Leland Gerschel at Oppenheimer. Please go ahead, Leland.
Yeah, great to see the solid data set. Thanks for taking the questions. Just wanted to ask, in terms of these patients, who go on ATD, I mean, how long does it take for them to sort of establish themselves as being refractory or non-responders? And do they, you know, go through kind of the, you know, this couple of oral options? You know, what does that sort of look like before they're deemed as refractory? Then I have a follow-up.
Yeah, it's basically six months for the vast majority. So when you look at the chart reviews or anything else, within six months, these patients sort themselves out one way or the other. So that's, that makes it... That's pretty easy.
Yeah. And then with respect to using an FcRn such as yours, you know, 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 this scenario, where they would use 1402 and then still have to remain on some level of oral?
Yeah, I'll just super quickly because we're getting close to the end of time here. But you know, the number one 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, that's - they're still getting a benefit, but the ones who get totally off ATD, they're the ones who are getting the home run. So 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.
Yeah, 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 promising emerging profile of IMVT-1402, to have a potentially best-in-class and first-in-class offering here in Graves' disease. So thanks, everyone, for your time today.