Roivant Sciences Ltd. (ROIV) Earnings Call Transcript & Summary

Good morning, and thanks for joining today's Brepocitinib investor call. We expect this call to run for approximately 60 to 75 minutes, with prepared remarks around 40 to 45 minutes and the remainder spent on Q&A. Presenting today, we have Matt Gline, CEO of Roivant; and Ben Zimmer, CEO of Priovant. You can find the slides being presented today on our IR website at www.investor.roivant.com. I would like to remind you that we'll be making certain forward-looking statements during today's presentation. We strongly encourage you to review the information that we have filed with the SEC for more information regarding these forward-looking statements and related risks and uncertainties. And with that, I'll turn it over to Matt.

Thank you, Steph, and thank you, everyone, for joining today. Really excited for this opportunity. We're going to spend most of today talking about the brepocitinib program, and in particular, our ongoing late-stage studies in dermatomyositis. And one of the purposes of today's call is for you all to hear from the Priovant team from Ben Zimmer directly. So I'm going to shut up pretty soon but I'm going to do a brief introduction first. Starting on Slide 4. So look, I think we are in a pretty exciting and unique position here with an opportunity to set bluntly a new standard of care for patients, frankly, across multiple areas of high unmet medical need. Starting with our VALOR study, which, if positive, we think, has the potential to improve standard of care treatment for over 40,000 patients currently living with dermatomyositis. And then with over 200,000 patients across other indications, including our ongoing Phase III program in non-infectious uveitis, and our proof-of-concept study ongoing in cutaneous sarcoidosis. So the expected readout in the second half of this year, just in the next few months here, is the first of, we think, a number of really exciting clinical and regulatory milestones expected for the program in the next couple of years. On the next page, we see brepocitinib really as the latest evolution of a really important mechanistic theme that's evolved over, at this point, several decades. Brepocitinib is the first dual selective TYK2/JAK1 inhibitor, the first-in-class of those. We think should represent a new generation of treatment for inflammatory disease. Obviously, if you go back in history, you have tofacitinib and baricitinib, now XELJANZ and Olumiant, these sort of nonspecific pan-JAK inhibitors that have been really important treatment for inflammatory disease, but the fact that they're not specific to certain JAK isoforms limited their ability to dose to maximal efficacy and ultimately was in part responsible for the class-wide black box warning on JAK inhibitors. Now since then, we've got 2 single JAK isoform inhibitors like upadacitinib, RINVOQ, obviously, an enormous drug at this point, and deucravacitinib for TYK2 inhibition. Both of them really exciting drugs with extraordinary efficacy but still limited in that they only impact 1 of the 2 isoforms of JAK. And brepocitinib finally is designed to impact both TYK2 and JAK1, which should give us potentially very robust efficacy across highly morbid heterogenous autoimmune disease. So on the next slide, as a reminder of this pathway, there are 4 human isoforms of JAK, JAK1, JAK2, JAK3, and TYK2 and distinct combinations of each, we'll talk about this more in just a second, are required for specific cytokine signaling. And so depending on which JAK isoforms you pick, you get a distinct pharmacologic effect in terms of which pathways are suppressed. So on the next slide, you can see this laid out, where JAK1 is responsible for signaling an interferon gamma, IL-2, IL-6, and then is partially responsible for interferon alpha and beta and IL-10. And the TYK2 is also responsible for interferon alpha and beta and IL-10 as well as IL-12 and IL-23. And so by hitting both JAK1 and TYK2, we get this full range of cytokine suppression as well as particularly strong inhibition of interferon-alpha and beta, which are relevant to interferonopathies potentially including dermatomyositis. So finally on Slide 8, before I hand it over to Ben, I just want to say I'm super proud of this clinical program. First of all, brepocitinib has been an incredible molecule in clinical development thus far. We have 7 positive Phase II studies across a wide range of doses, many hundreds of patients. Some of the largest autoimmune diseases were successful data generated by our partner, Pfizer. We have obviously been focused now on orphan immunological conditions, but we're able to rely on the safety profile across over 1,500 patients. Our expansion of brepocitinib, and this is where I give an enormous amount of credit to Ben and to Priovant team has been rapid and robust, starting from the first in-licensing just a few years ago through the pivotal programs initiated in dermatomyositis and ultimately in NIU. And now we're finally about to harvest the first fruit of that labor with the upcoming data from the VALOR study, as I said, in just a few months. So with that, I'm really excited to hand it over to Ben to take you through the program in detail and to answer some important questions about the program. So Ben, take it away, and thank you, everybody, again.

Perfect. Thanks so much. Really appreciate the into. And if you go to the next slide. Dermatomyositis is one of the most significant unmet needs in autoimmune disease today. And the VALOR trial, if successful, would represent the first pivotal trial of any modern therapy for this disease and the first 52-week successful trial for any therapy at all. And so we're really looking ahead to a very exciting milestone for the field. I think a lot of patient groups and physicians are very excited about it and we are as well. I'm excited to tell you more about it today. First of, just give a bit more background on the disease for those who aren't familiar with it and then go into the study rationale and design. Next slide, please. So DM is an inflammatory condition of the vasculature in the skin and muscles. Very severe patient burden on both skin and muscles. As you can see here, muscle weakness in DM patients results in extremely debilitating impact on basic activities of daily living, walking, carrying simple objects. And over 1/3 of patients require mobility aids. Next slide, please. In the skin disease, it is also not just a kind of afterthought symptom. The skin disease carries extremely high patient burden of its own. These are rashes that cover a large body surface area, lead to itching, pain, disfigurement, hair loss, calcinosis and across multiple different dimensions when comparing disease burden across skin disease, DM consistently ranks at or near the top in terms of patient-reported burden. And so you stack that on top of the muscle weakness and you're really looking at one of the most debilitating diseases in inflammatory -- of the different inflammatory conditions out there. Next slide, please. So given this burden, it's hardly surprising these patients are highly treated. And we see today in the claims data, approximately 35,000 patients in the active treatment pipeline for dermatomyositis. As you can see on the pie chart on the left, approximately 80% of these receiving some form of oral or injectable steroids and approximately 60% receiving multiple different therapies, so heavily treated patient population. And as you can see on the bar charts on the right, these therapies are not working all that well. This chart shows the percentage of patients receiving, in bright red, oral high-dose steroids of greater than 10 milligrams per day chronically. And you can see independent of contaminant therapy, whether patients are on IVIg, off-label biologics or immunosuppressive therapies, half or more of patients are requiring these large-dose chronic steroids. So this speaks both to the fact that these patients are not doing well in spite of all the treatment they're on. And then also, of course, steroids have significant side effects and health burdens of their own. These are generally very well documented and known so I won't go into them in too much depth. But if you go to the next slide, I do want to call out specifically that in myositis patients, specifically DM and other myositis, not just patients more generally, there's significant data around the rates of adverse health impacts for patients, both in terms of long-term chronic steroid use as well as even short-term use. And you can see these rates of different events being extremely high. So the steroid burden in DM actually creates a lot of health impacts of its own and is one of the things that is needed for new therapies is to treat this burden along with the underlying disease symptoms. And then if you go to the next slide, I'll just wrap up by kind of reinforcing that point that it would be 1 thing if these steroids were actually solving patients' underlying disease, but they're not. Patients continue to experience large flare rates, high rates of reported pain, high use of opioids. And so we really have a very significant challenge for patients today in terms of skin disease burden, muscle disease burden and side effect burden of steroids all coming together at once. So an extremely high need for new efficacious treatments. Next slide, please. So against this backdrop, we set out on the brepocitinib program in DM a few years ago. And in 2021, when we set out on this program, there was already a pretty good basis of clinical rationale for JAK inhibitors in DM. Actually, over the last few years, that base -- that foundation of evidence has grown even more significantly. Today, we have 3 investigator-initiated trials that have read out and over 600 published cases around JAK inhibitors providing benefit to DM patients. And I would note that while some of the early data around JAKs on DM was focused mostly on skin disease, more recently, particularly in some of the more recent investigator-initiated trials, we've seen quite clear benefit, evidence of benefit on muscle disease along with skin disease. So that's quite encouraging to us as well. Next slide. And we're excited about brepocitinib in DM not just as a JAK inhibitor but as a JAK inhibitor, as a TYK2/JAK1 dual inhibitor, which we feel can provide a particular benefit to DM, consistent with what Matt walked through earlier. TYK2/JAK1 inhibition is uniquely optimized for type I interferon suppression. We hit the signaling pathway through both sides of the dimer. Type I interferon is a key pathogenic driver of DM disease activity. And in addition to that, we're able to suppress signaling through JAK1 of type II interferon and IL-6, and through TYK2 of IL-12 and IL-23. And as a result of this, we're able to address a broad array of different lymphocytic pathways, which are also overactivated in DM and contribute to disease burden in both the skin and muscle. And so really no other JAK inhibitor could achieve this and certainly a monoclonal antibody targeted at a single cytokine could not achieve it either. Next slide, please. And there's clinical evidence of really both of the JAK1 and TYK2 contributions to brepocitinib's potential efficacy. On the left here, you see the study of tofacitinib in DM investigator-initiated trial. Tofacitinib suppresses or inhibits JAK1 but not TYK2. And then on the right, you see results from a study of STELARA in Japan. This was a DM/DM study. What's shown here is only the DM patients. 15 patients per arm of DM patients so a small study. Did not achieve statistical significance, but you do see clear separation between the curves. And STELARA, of course, is an IL-12/23 inhibitor so really a proxy for one of the pieces of TYK2 inhibition, not present in JAK1, and we see some evidence of clinical benefit there. So very excited about brepocitinib's potential not just as a JAK inhibitor in DM but particularly as a TYK2/JAK1 inhibitor. Next slide, please. So that brings us to the VALOR study. As I mentioned before, this is a study that I think is really going to be a major event for the field if it reads out positively. Largest DM study ever conducted with 241 patients enrolled globally, including significant representation in the United States, 38%. Importantly, this is a DM-only study. So some myositis studies are pooled across DM and PM or DM and other myositis types. This is DM-only and so we think it's going to be really particularly meaningful and powerful results to patients and physicians when thinking about evaluating treatment options for this disease. Testing 2 doses of brepocitinib against placebo, randomized 1:1:1. 52-week double-blind treatment period, and then all patients are eligible for a 52-week open-label extension receiving 30 milligrams once daily. Next slide, please. So talking a bit about the inclusion criteria. First thing I would highlight is that the VALOR trial required both skin and muscle disease at baseline. This is important, both because we think it sets us up to be able to show maximum separation between drug and placebo, and then also gives us an opportunity clinically to show benefit on both of these symptom domains, which, as I talked about in the opening, are each very important to patients, so giving us multiple opportunities to show benefit to patients on clinically meaningful outcomes. Next slide, please. In terms of background therapies, patients were allowed to be on any combination of oral steroids up to 20 milligrams per day, antimalarials or nonsteroidal immunosuppressant therapies. They were not required to be on any of those therapies at baseline, although inadequate response to at least 1 current or prior therapy was required. IVIG, biologics and other JAK inhibitors were not allowed at baseline, but prior use with the washout was allowed. Importantly, I would just note that with IVIG, the reason that was not allowed was not medical in nature. Brepocitinib and IVIG could be used concomitantly, but rather, we felt that, including IVIG, created risk of contributing to placebo response, adding noise to the study, and we, therefore, excluded it. Next slide, please. So I'll talk a bit about the endpoints of the study and in particular, the primary endpoint, the total improvement score. This is an end point a lot of people may not be deeply familiar with. So I'll spend a bit of time going into it. As you can see here, this is a composite endpoint of 6 measurements of DM disease activity, 3 global activity measurements, 2 done by the physician, 1 done by the patient. And then 2 muscle-specific assessments and a patient questionnaire around activities of daily living. This is a registrational endpoint that was used as the foundation for the OCTAGAM IVIG approval. Next slide, please. As you can see here, this goes into more details on the exact scoring of the endpoint. I won't go through every detail of it, but I'll make 1 main key point, which is important for understanding at some point, which is that this is an improvement score, not a disease activity score. So there's no baseline and change from baseline. Rather, every patient starts at 0, and then consistent with the scoring you see here, they can either stay at 0 or increase across each of the 6 core set measures. The sum of any improvement has been added up on a range from 0 to 100, and that is the outcome of the TIS, the kind of continuous variable of the total improvement score. In addition, the TIS can be assessed as a responder endpoint, as you see in the bottom right here, with patients meeting certain response thresholds corresponding to minimal moderate or a major response. Next slide, please. So in terms of our study in particular, similar to many other studies, mean test is the primary endpoint in the study. So that's the difference in means between 30 milligrams and the placebo arm at 1 year on the continuous variable. As I mentioned before, the largest DM study ever conducted. The study is set up to detect with statistical significance even quite small differences between the means. And then in addition to this primary endpoint, we're going to be looking at secondary endpoints involving TIS 40 and TIS 60. So as I mentioned in the last slide, this corresponds to the percentage of patients receiving moderate or a major improvement, and we'll be looking at each of those on a placebo-adjusted basis as well. And then 2 other ways we'll be looking at the TIS. One is as a time to TIS response, and then also, given the steroid burden in this disease and the importance of eliminating that burden, looking at endpoints measuring the intersection of TIS response thresholds while also meeting certain steroid reduction benchmarks. Next slide, please. So one of the ways in which the fact that TIS only goes up, flows through to these DM studies is that we do see pretty consistently some real placebo response. There's obviously not a huge number of precedent DM studies, and there's been some variation around placebo, but this is certainly something to be very mindful of in running these myositis studies. There's a number of things that we've been focused on in terms of looking to manage that, including, as I mentioned before, including both skin and muscle disease, not allowing IVIG as baseline therapy. And then as I'll talk more a bit about later, the steroid taper that we have in our trial, which we think is an important way to hopefully address placebo as well. Next slide, please. Also want to emphasize that TIS is not the only endpoint of relevance in our trial. As it relates to skin disease, in particular, really gold standard for measuring DM skin disease is the CDASI. This is a score that also ranges from 0 to 100, but is a more conventional score, whether it's a baseline and change from baseline. It's an activity score, not an improvement score. This is clinician-assessed measurements of disease activity across 15 different locations on the body, as you can see here. And this is an instrument where a 4-point change is the minimum clinically important difference and has historically been less susceptible to placebo response than TIS. Next slide, please. And then finally, there's a number of other endpoints we'll be looking at as well. One that I wanted to highlight here is the DMOMS, which is another composite endpoint like the TIS. But this one was developed more recently and was developed for dermatomyositis specifically, whereas the TIS is a general myositis endpoint. As you can see here, there is some features in common with the TIS but also incorporates the CDASI into the composite endpoint, which can therefore make it quite valuable to patients and physicians when thinking about the intersection of both skin and muscle disease. Next slide, please. So that brings us to the baseline data for the trial itself. I would say, broadly speaking, we're quite encouraged by what we've seen in the baseline data in terms of what the patient population we were hoping to enroll through our inclusion criteria flowing through to what you see in terms of the baseline disease activity. A few quick points I would highlight from this slide. The first is that the majority of patients in the trial have moderate to severe disease and actually meet the moderate to severe disease thresholds, both for muscle and skin disease. For muscle disease, any score below 136 is generally viewed as moderate disease. Anything below 125 is severe disease. And for the CDASI anything above 14, moderate to severe disease. And so you see us clearly with the majority of patients in that moderate-to-severe category on both skin and muscle disease, and that's reflected in the physician's global as well. Pretty similar baseline demographics to the ProDERM study. That was the IVIG approval study and the only successful Phase III study that we've seen to date in DM. Slightly more severe skin disease in the VALOR study, consistent with our IE criteria of requiring skin disease at baseline. Next slide, please. Now we look here at the background therapies at baseline. Again, a few points I would highlight on this slide. I think the most important one to me, particularly as we just think about our ability to show meaningful benefit to patients, as we think about the unmet need in dermatomyositis is just the end column here. As you'll recall from what I shared earlier, patients were eligible to be on the -- to enroll in the VALOR trial on none of these background therapies as long as they had tried and failed on one in the past. And yet you see these patients being heavily treated on these background therapies, 181 out of 241 on background steroids with mean dose of 12 milligrams per day. And that mean is in spite of the baseline being capped at 20 milligrams per day. And you see also a majority of patients on multiple background therapies. And they're on all these therapies in spite of the fact that they have moderate-to-severe disease. So this really, I think, reinforces what we saw in the claims data earlier in the actual enrollment of the patients we're seeing in our trial, that these are patients who are very sick, very heavily treated, on very high doses of steroids and need better therapies. And then very briefly, I will just talk about the right-hand side of the slide. What you see is that patients are on stable doses of these medications for significant periods of time. In the case of the immunosuppressive therapies, 80% at 6 months or longer prior to baseline, so again, as we think about placebo response risk in different ways to mitigate that, this was 1 factor that we were eyeing among many and some encouraging baseline data there. Next slide, please. Finally, to come to the steroid taper, this is really a very important part of our trial and I think it's important for 2 reasons. One is it's a way to control risk of placebo response, and 2 is as a way to show benefit to the patients who are on drug, given, as I mentioned, before how burdensome these steroids are, now taking patients off steroids carries with it its own health benefits. So there were 2 features of the steroid taper in the protocol. The first was a quite strict mandatory taper for any patient on more than 5 milligrams per day at baseline to 5 milligrams per day. The protocol language was quite strict around that, and we were very focused on adherence to that. As you can see on the table on the right, at the bottom, we had a 98% success rate, which is quite high. In addition to that, we also had an encouraged taper at investigator discretion off steroids altogether for all patients in the study on background steroids. So whether they started above or below 5 milligrams per day. And the investigators were very enthusiastic about partnering with us to really embrace this recommendation. And in combination with the mandatory taper, you can see here on the right that we've had a lot of success of bringing patients off steroids in this study. The mean dose has gone from 12 milligrams per day down to 2.5 milligrams per day. Bear in mind, all of this is blinded and pooled data. 85% of patients have reduced their dose from baseline by more than 50%. 60% of patients have reduced their dose from baseline by 3/4, and 40% of patients in the study blinded and pooled were able to come off steroids altogether. So this was an achievement that we feel very good about. Really, a lot of work from our team and from the investigators in embracing this as a key feature of the study and hopefully helps set us up for success, again, both in terms of managing risk of placebo response but also in terms of being able to deliver the most clinically meaningful and impactful data we can to physicians and patients. Next slide, please. So finally, I'll just offer a few concluding thoughts and then hand it back to Matt. I think we're looking at a lot of different endpoints. There's a lot. DM is a complicated disease, affects patients in a lot of different ways. And I think there's a lot of different ways one can show clinically meaningful benefit to patients that will matter in the real world, and we're evaluating a lot of different ones. But fundamentally, to come back to where I started, there are no modern approved therapies for this disease. These patients are suffering a lot. Any approved once-daily oral targeted therapy would represent a breakthrough for dermatomyositis. And so as we look ahead to the results, our focus is just a positive study, generating statistical significance on the primary endpoint. Again, bear in mind, this would be the first ever successful 52-week placebo-controlled readout in DM. So a major milestone if and when we're able to hopefully achieve that. Second concluding point I would make is just as you think about what an efficacious drug for dermatomyositis needs to do, I would think about the muscle disease and the skin disease both as important sources of patient burden and both as important sources of where patients need treatment. And then I would also think about the high-dose steroids being used by so many of these patients, the adverse health effects of that and the importance of bringing that down in an important way. And again, that's something that our study hopefully sets us up well around. And then finally, I would just note that we've had a productive engagement with the FDA consistently over the last few years. And if our study reads out positively, we would plan to follow that up with an NDA submission. So thanks so much, and I'll hand it back to Matt.

Thank you, Ben. I appreciate that. And again, I'm super excited about this program. So great to hear Ben take us through both the details of the study as well as some of the baseline characteristics that make us feel good going into the end of the year. So on the next slide, I just wanted to wrap up with a couple of points that are important to me from an overall program perspective, from a Roivant perspective. Look, the first of these is it's funny. We've seen a lot of recent successful orphan immunology and orphan disease launches across different indications. And I feel like the ingredients for us here, again, assuming a successful study, feel great as we look across the competitive landscape. Look, I think there's a lot of recognition now of the commercial opportunity in DM. Obviously, there's a number of competitor programs in late-stage development. There's dazukibart at Pfizer. There's efgartigimod. There's anifrolumab in AZ. All of those are in late-stage studies, but all of those late-stage studies read out meaningfully later than the brepocitinib program. So that gives a nice head start. And then as a reminder, across all the late-stage programs, we are the only oral -- brepocitinib is the only oral in late-stage development. We think that just sets us up really nicely to define what this field could look like. And I think the relationships Ben and team have been able to build with the doc community are, in part, built on the commitment that we've made to get there and get there fast with a high-quality study for a good drug. There have been, since we began this program, a number of other Phase II programs begun across a variety of different mechanisms across a variety of different companies. And we think that's an acknowledgment of how much unmet need there is in dermatomyositis, how important this market could be and how important progress here will be to these patients who are, as Ben began with, quite sick. On the next slide, just to make 1 broader Roivant point, which is that brepocitinib is a perfect case study of what I think Roivant as a whole can be really good at. First of all, I think we have an ability to identify high-value programs with differentiated mechanisms of action. We brought the program into Roivant and created Priovant and put Ben in charge. It was late 2021. It was a time where JAK inhibition had been painted with a broad brush because of some of the data coming out of other programs. And we saw brepocitinib as a truly differentiated molecule, both with a ton of clinical data to back it up, but also with this unique dual TYK2/JAK1 mechanism that we thought was going to get to the best of what JAK inhibition has been able to do and with an opportunity to represent a next-generation treatment for hard-to-treat disease. So we like the mechanism a lot. The second thing here, and there's a lot of people who share credit for this, including many of the folks -- Ben and many of the folks on his team, I think we've been, in a way that I'm quite proud of, creative around our development plans for brepo, both in terms of indication selection and I think dermatomyositis is a great example. You saw in the previous slide how much attention it's garnered as an indication after we started our program. But I think we were pretty early here in identifying the opportunity, and I think we're bringing a great mechanism to the table. And then I think about things like non-infectious uveitis, like cutaneous sarcoidosis and like a few others that we have still under wraps that we're thinking pretty seriously about as opportunities to break new ground. And then look, obviously, a piece of that has been the sort of indication selection but also just the development plan, how we set up these programs, how we've been able to advance rapidly into pivotal studies and how we've designed those studies in steroid taper, things that are important, both we think to the success of the study and to the commercial opportunity of the drug. We think this is something that Roivant can be really good at. And then finally and here, there's a ton of credit that goes to Ben and the team, look, I think we've been really focused on execution and focused on driving sort of clinical progress. VALOR is the largest interventional DM trial ever conducted. And we think it's among the, if not the, fastest enrolling late-stage DM study and, frankly, has been meaningfully faster than some other late-stage studies we're aware of. And then I think we've been able to move really quickly beyond DM with VALOR into other indications, including a rapid transition from proof-of-concept data we generated last year to the pivotal program we began last year in NIU, again showcasing just really, really strong clinical execution by Ben and the team there. So I hope there's more to come that looks like this from across the Roivant family, obviously looking at doing similar things across other programs that we have now. But wanted both to express some pride over what I think we've achieved here and to thank Ben and the team for the work they've done to keep this moving forward at a good pace. And then finally, just to recap on the next slide here before we turn it over to Q&A. Look, I think this program has a lot going on. Starting now in the next coming months with the readout in DM, we have the opportunity for, assuming that data is successful, regulatory filing. We hope to get proof-of-concept data from the cutaneous sarcoid study in the first half of next year -- sorry, in the second half of next year. Then we begin with the commercial launches, first in DM, followed relatively shortly thereafter by top line data coming from our NIU study, which we're already happy with how it's enrolling at this point in time. And then finally, a regulatory filing in DM -- sorry, in NIU leading to potentially another launch. And then as I said before, we're working on a number of other indications that we're not talking about publicly yet that could add to this. And we feel like there's an opportunity to really stack commercial opportunities and to stack progress for patients on top of the backbone that is brepocitinib, which we just think is a really strong molecule on which to build the business and on top of the Priovant team that we have in place. So look, that's what we have prepared for today. We wanted to make sure we got everyone on the same baseline around the program, the endpoint, and a little bit of that baseline data that's got us excited coming into the second half of this year. So with that, I just want to thank everybody for listening today. And I want to turn it back over to the moderator to set us up for Q&A. So thank you, everybody, and moderator, over to you.

Thank you. [Operator Instructions] Our first question is from Dennis Ding with Jefferies.

This presentation has been super helpful. So I had a question on TIS. I'm just curious what do you think the shape of the curve will look like for placebo with the steroid taper. I know you said TIS goes up into the right relative to baseline, but on a month-over-month basis, can TIS go down? And then number two, is there a predefined criteria for a doctor to add back steroids? And how would that patient be treated on TIS?

Thanks, Dennis. Thanks for listening, and those are both great questions, and I suspect on many people's minds. So Ben, why don't you take a look at both of those?

Yes. I think our view is on the first, that, generally speaking, the placebo group would probably go up in the first few months of the study and then flatten out. That's what we've seen most of the past placebo groups do, and I think our steroid taper would contribute further to that flattening out and quite important in a 52-week study in particular. On your second question, there are criteria around if a patient needs to be rescued in the trial, the ability to do that, and that's generally what would be involved if a patient is tapering and needs more steroids. As far as how exactly that will be handled in the primary analysis, we're not sharing that at this point, but I would say that we have put and are putting considerable thought into making sure what I think the FDA would want to see and what we want to see, which is that the way it's handled reflects the clinical reality of what's happening to patients because that's ultimately what we're solving for.

Thanks, Ben. Just 1 small quick note, which is you would also ask if TIS can go down on subsequent readings. The answer to that question is yes. TIS is measured relative to its initial baseline, and so it could, in theory, go up. And then, for example, if a patient flared after a steroid taper or something, could then go back down. Thanks, Dennis. Great questions.

Our next question is from Andy Chen with Wolfe.

So on Slide 12, you showed this standard of care based on your -- presumably, your claims analysis from 2020 to 2022. And this is shortly after the STIR study. But STIR study was 2021, right? So I'm just curious, like do you have more recent data from 2023 to 2025, basically showing that off-label JAK inhibitors are basically doing much better on this chart?

Thanks, Andy, for the question. Obviously, a good question and important for us to be on top of overall sort of concomitant users. Again, as a reminder, all JAK inhibitor use here is going to be classified as off-label. But Ben, why don't you go ahead and take the question?

Yes. So first, I would say that JAK inhibitors under the definitions on this chart are just viewed as part of biologics. So obviously, they're not biologic therapies but they are encompassed in that bucket. We've looked at a lot of different claims analysis. This is one cut. There's different claims data sources we've looked at as we look ahead to potential commercial launch. Obviously, we're looking at even more. I would say broadly speaking, that the use of JAK inhibitors is high from a perspective of an unapproved therapy in terms of generating clinical confidence of success for our trial. But as an absolute share of patients remains quite low, these are not approved drugs. I think a lot of physicians, even at centers of excellence, don't always like to prescribe off-label. And I think that speaks to the opportunity to generate or to deliver value with an approved JAK inhibitor and particularly with an approved TYK2/JAK1 inhibitor, which we think can be distinctive from the other JAK inhibitors.

And I'll just add 1 thing, which is look, I think, first of all, we've seen -- you can see on the -- I think there's another slide in here we talked about how the amount of data has increased over time. Obviously, that's good evidence, the number of case reports, et cetera, and the docs continue to be excited. We also just hear it, right? We're out talking to docs. Ben and team were out talking to docs. There's a lot of physician enthusiasm for JAK inhibitors. But obviously, all of that is tempered by the fact that JAK inhibitors are expensive therapies. On market right now, access for off-label use of JAK inhibitors, even for DM patients is challenging. And so I think there's a lot of enthusiasm for an approved JAK inhibitor in DM. And then also, look, there is no opportunity to use on or off-label. A dual inhibitor of JAK1 and TYK2 because there are no dual inhibitors of JAK1 and TYK2 out there. And us reiterate, we do think TYK2 is an important component as well as of what we're going to be able to deliver. Thanks, Andy. Great question.

Our next question is from David Risinger with Leerink Partners.

Thanks, Ben, and Matt, for hosting this session. It's quite informative and helpful. So following brepo's historical trial success in HS and NIU at 45 milligrams and Crohn's disease at 60 milligrams, why did you decide to study brepo in DM at 15 and 30 milligrams? And I have a follow-up, but I'll get back in the queue.

Thank you, Dave, for respecting our back in the queue wishes as well. So Ben, please take both. Both great questions that are important to people.

Yes. Yes, I mean, 30 milligrams has delivered efficacy in quite a number of Phase II studies. If you look at the, yes, that's very helpful. If you look at the Pfizer program, you see across a wide array of Phase II programs, 30 milligrams delivering excellent data in the NIU program. Among other reasons, we went with 45 to ensure adequate penetration into the eye, but we feel good about 30 milligrams delivering high efficacy in this trial. And then 15 is also a therapeutically relevant dose, and we did want to explore multiple doses in the trial to support the approvability of the indication as the first indication for brepocitinib. But ultimately, we think 30 is likely to be what delivers the most efficacious and the best outcome for patients for DM.

Thanks, Dave, for the great question.

Our next question is from Prakhar Agrawal with Cantor Fitzgerald.

So maybe on the 25% of the patients who are not on steroids at baseline, how does the severity and disease course of these patients vary? I'm guessing these are milder patients and maybe more skin-dominant disease, but wanted to get your perspective. And just maybe a quick follow-up. What was the rationale for choosing 36 weeks as the starting point of the steroid taper protocol? And what's the tapering based on? Is it just based on physician assessment or certain endpoints that's being followed across different trial sites?

Thanks, Prakhar. Obviously, the steroid taper is an important part of the protocol. So Ben, why don't you take both those questions?

Yes. So I'll start with the second one, and just to clarify, the steroid taper goes -- it starts at week 12 and goes to week 36. So throughout this study, the reason it starts at week 12 is to -- for the patients who are on drug just to ensure appropriate time for the drug to take effect, although we do think for many patients, that may be even before 12 weeks. As far as the patients not on steroids at baseline, I would not assume that those patients are less severe. They might have been on -- or almost all of them were on ISTs like azathioprine, mycophenolate methotrexate, somewhere on ISTs and also on anti-malarials. We did have a number of patients who washed out of IVIG, so some of them may have been on IVIG and then washed out to participate in the study. So I would not necessarily assume that those patients are less severe. And then also just to come back to your first -- to the other question and to be very precise, for the mandatory taper here, all patients, there was no investigator discretion if the patient started on more than 5 milligrams per day of steroids, independent of what was happening in this study. There was a requirement to taper them. Now if the patient needed to be rescued, that was different, and then they get classified as rescue and are subject to that set of considerations. But absent rescuing therapy, there was no ability for the patients on more than 5 milligrams per day not to taper per the protocol. And as you can see with the 98% success rates, the investigators really rallied behind that. That protocol requirement incorporated their input, and we had a lot of success with that.

Thanks for the great question.

Next question is from Brian Cheng with JPMorgan.

The trials evaluating brepo out to week 52, when you look at program, the IVIG trial and tofa Phase II, the efficacy kind of plateaus much early on. When we think through your efficacy, can you talk about the magnitude of improvement that you expect at a later time point beyond week 32 to week 52. And 1 more question is that when you think about the trial powering, are you expected to capture the difference on the 15-mg arm versus placebo? I think on the slide, you only mentioned the 30 mg versus the placebo.

Thanks, Brian. Thanks for listening, and thanks for the great questions as well. Ben, you want to take the first shot there?

Yes. So as far as the efficacy plateauing, I mean, these were shorter trials so I think it's hard to know what would have happened to the efficacy over a longer period. I would say that 1 thing that KOLs and other physicians have consistently expressed to me is a view that muscle disease takes longer to improve than skin disease. And even once you get the inflammation under control, it can take time to rebuild muscle strength. And so I think on that dimension, having the 52-week trial could serve to our benefit. I also think it's very meaningful to patients and physicians to be able to show benefit sustained out to 52 weeks. That's something that patients and physicians care a lot about. And then certainly, ultimately, it's something FDA has expressed to us as being important. And I think you've seen that for other Phase III trials as well, selecting a 52-week endpoint. As far as the trial powering, like I said, I think it was focused around the primary endpoint between 30 milligrams and placebo, and we'll have to see what happens with the 15 milligrams. Again, I think ultimately, it's a very large, large robust study. And so we feel good about it from that perspective.

Great. Thanks, Ben, and thanks again for the great questions.

The next question is from Yatin Suneja with Guggenheim Partners.

Maybe if we can just talk a little bit about what you know or what our experience has been with off-label JAK use in myositis and what the experience has been? And then maybe if you can also then touch on some of the NTA FcRn data that is emerging. I mean, obviously, you also have a very good offering in immuno and in IMVT-1402. How are you thinking about that?

Yes, great. Thanks, Yatin, and obviously, particularly interested in the competitive landscape, given our overall setup here. Look, I'll take the FcRn question first and then maybe hand to Ben for his other thoughts. Look, obviously, we're excited about what NDFs antibodies can do across a variety of indications. We had Immunovant at the time that we initiated the study with brepocitinib, and I think there's a reason we focused first on JAK inhibition in DM. And I think that actually gets a little bit, to your off-label use question bluntly, which is that it is obvious from talking to physicians who treat DM, that there is a lot of enthusiasm for a potent anti-inflammatory mechanism like this to benefit these patients. And so I think, look, the data from efgartigimod was encouraging. It was encouraging on the well-behaved endpoints. It was encouraging on the overall efficacy, which I'm sure could be helpful across myositis. But for DM specifically, I think we're really excited about what we're going to be able to deliver in an oral format. Ben, anything you'd add on that or anything you want to talk about in terms of other off-label JAK use?

Yes. I'll just make the points on the off-label JAK use. As we noted in the slides, there's now 600 cases that have been published, that's quite extensive. And I think just speaking anecdotally to dozens, if not hundreds of physicians who have tried this, there's, generally speaking, quite a bit of enthusiasm on it. And then I would just highlight on the VYVGART trial, that was a cool data across multiple myositis types and the VALOR trial obviously is focused just on DM. So I think that's just 1 difference in what the data is measuring and reflecting ultimately as we think about that.

Our next question is from Yaron Werber with TD Cowen.

This is Sara Kai on for Yaron. Thanks, Ben and Matt so much for a really helpful presentation and congrats on all the progress. I have 2 quick questions, if you don't mind. So first, the physicians that we've spoken with are really excited about this data, too, and they've mentioned that they want to see TIS kind of 40 range. That's kind of the bar for efficacy. Do you agree that, that would be a bar for the delta versus placebo? And then secondly, how sensitive is the TIS scale to evaluating skin in particular? Because we're curious maybe what -- out of all the factors that you've mentioned on TIS, what is going to drive that endpoint out of the different parameters on that score.

Yes. Thank you for your questions. Look, I think to restate something Ben has already said but just to say it again, I think our pretty strongly held view is that there is no sort of "magic bar" for efficacy on TIS. TIS is sort of an artifice, right? It exists only in the context of a clinical trial that measures only sort of "performance" from a baseline point in time. And to our view, after a lot of conversations with physicians and so on, is that on TIS, it really just -- it's a means to an end, that we're looking for a statistically significant performance so that we can get the drug approved. And then I think the ultimate use of the drug will hinge on other endpoints and overall back experience. But Ben, anything you'd add on that and also, obviously, if you want to talk about how sensitive TIS is to skin?

Yes. I would just add on the first one, as we think about TIS 40, kind of how I think most of the field would think about that is less in terms of the continuous variable of mean tests and more on the responder endpoint of just the threshold of TIS 40. So again, bear in mind, TIS is an improvement score, not a disease activity score. Just how many patients hit that moderate improvement from baseline threshold and comparing across how many patients hit that in the drug arm to the placebo arm. I think that's really the way I think most people would be looking to see that TIS 40 endpoint measured and reflected. I think as far as how sensitive is it to skin, somewhat is the answer I would give. The 3 global assessments comprise 50% of the score, and skin disease matters a lot to patients and physicians. So we expect that skin disease to factor into all 3 of those scores and obviously, particularly the extramuscular physician's global assessment, which accounts for 20 points, muscle disease would play zero role on that. So we would expect skin disease to feature prominently there. That said, it's a very good question. And TIS, I think, measures muscle disease more than skin disease, and that's why we're also looking at other endpoints in this study that incorporates skin disease more like the CDASI and the DMOMS, which I mentioned in the presentation.

Thanks, Ben. Yes, just as a reminder here, look, I think skin is really important as a part of the symptomology disease. And as you talk to docs, and I think this has actually been in part like a patient-led phenomenon, affecting skin disease really matters to these patients and it can be super debilitating. And so I think in addition to its measurement and inclusion and measurement in TIS, treating the skin effectively is a super important part of treating these patients.

Next question is from Allison Bratzel with Piper Sandler.

This is Ashleigh Acker on for Allison Bratzel. This might be looking a little bit ahead in the future but we just had a positioning question. So from where you guys are sitting, how are you thinking about the product positioning once this is potentially approved? Would brepo fit -- where would it fit relative to IVIG? And just considering JAK inhibitors are efficacious in DM and an oral option, would you expect brepo to potentially be used ahead of IVIG? Just any color there as we look to the future would be really helpful.

Yes, thanks. Great question. And look, I think the truth is it's a large patient population with a lot of unmet need, and we don't "need to outrun the bear", so to speak. We just need to find our home. That said, look, this is a -- it's a great opportunity to introduce an oral therapy, and I think there are a lot of patients here who are going to be excited about an oral option. So I think there's a real chance of being used in early-line therapy. And I don't know that we're thinking about it as like a refractory to any specific other therapy or whatever. I think we have a shot here at standard of care. Ben, anything you'd say about this?

No, I would just echo that point. We really think about the entire market basically as being the pool of eligible patients and appropriate patients being an oral once-daily therapy is going to matter a lot to patients, as we've seen the vast majority of patients are already coming in treated with some combination of steroids or ISTs. And so I think ultimately, it will be a patient- and physician-specific determination for any given drug for any given patient, but we think by and large, brepo is going to be a very attractive option to a large number of these patients pretty early on.

Remember, IVIG is neither a panacea. And in fact, there have been failed IVIG studies, nor is it a joke to use. The infusions are long and there's meaningful through safety and tolerability associated with it. So look, I think overall, we have a pretty attractive profile.

Our next question is from David Risinger with Leerink Partners.

So just to follow up on that question. Could you just paint a little bit of a picture of IVIG's efficacy on the primary endpoint that you're using and also other key endpoints? Just so we have a sense. I mean, obviously, brepocitinib would be dramatically more convenient for patients. But I think it would be helpful for you to just frame out how you see the efficacy bar that IVIG has set since it is approved.

Yes. Thanks, Dave. Ben, do you want to take that one?

Yes, yes. First of all, I would say IVIG has been used in DM for many decades. I would -- although there has been a recent approval trial, which I think is very informative for clinical research and for companies like ours when we were designing subsequent trials, I don't think that was -- that's kind of a known fact in the field. If you look at use of IVIG in DM today, OCTAGAM is not used more frequently than other forms of IVIG. It's just a function of what a particular infusion center has. So this is a drug that's been used for a long time, and I think patients and physicians are really eager to have something better and more modern. Just to be even more specific about Matt's point before for the DM dose, patients have to go in generally 3 infusion days in a row 1 week per month for several hours per day. So this is an extremely burdensome infusion regimen, has a lot of safety risks associated with IVIG. A lot of doctors aren't comfortable with it. So I think that any kind of new modern therapy, not just brepocitinib, any new modern therapy, I think is somewhere just acting on a different plane than IVIG is. That said, the IVIG data did show strong data on TIS. It was only at 16 weeks. There's a -- that was the OCTAGAM study, there was HIZENTRA subcutaneous study, which failed. So there's variable data around IVIG or immunoglobulin in general. And then I would also note that they really did not demonstrate clear efficacy benefit on skin disease. That was not a focus of their reported data and so -- or it was not a prespecified endpoint in the study at least. And so I think there's a lot of ways for the profile to be different in terms of the data, but I think the real differentiation is just between a modern oral once-daily therapy and kind of drug that has been used only due to a lack of alternatives.

Great. Thank you. All good there. Thank you very much for a good question. Steph, over to you.

Our next question is from Doug Tsao from H.C. Wainwright.

One of the questions I had was there is a lot of interest at UR and recently in terms of cell therapy for treating DM and we saw some data sets there. And I'm just curious how you view -- I think you sort of referenced sort of some of the FcRns and other modalities that are being explored. And when you think about cell therapy that offers potentially some very comprehensive sort of significant responses, which we've seen from some of the companies, right? And obviously, very small end in terms of cell therapy. But how does that sort of make you think about brepo's positioning in this market?

Yes. Thanks, Doug. It's a great question. It's one that we now see pop up across a variety of autoimmune indications. Look, I think the sort of obvious fact is it's just a completely different ball game, right? The level of infrastructure required to administer it, the care required for patients receiving it, some of the safety issues. Obviously, we also need to see things like long-term durability data, which we don't have yet. But even if all of that pans out, this is a major intervention. And my view is compared with something that people do every day, taking a once-daily pill, this is the kind of thing that will fall later in line for the most severe patients would be my view on that. Ben, anything you'd add?

No, I would just add that you think about CAR T therapy involving chemotherapy, lengthy hospital stays, the burden of proof, I think, for patients to use this in the real world is going to need to be extraordinarily high. And I think even then, they would try any oral or biologic therapy, for that matter, first. And what we have so far today is single-digit numbers of patients, most of whom there's 8 to 12 weeks of data. So I think just a lot to be seen there. And as we think about it in the real world, I think that whether it's brepocitinib or a biologic, I just think there's a lot of different options that patients would look towards first before going through with that.

Our next question is from Jason Gerberry from Bank of America.

So when we think about the VALOR study results, I'm wondering if you would caution us from drawing distinction on the subdomains of muscle versus impact on skin components. And when you look at the data from STELARA or the JAK single agent, if you have an expectation that the clinical benefit might be derived in 1 domain versus the other.

Yes. Thanks, Jason. And look, I think we've gotten sort of versions of that question embedded in different places here. It's a great question. It's obviously on people's mind. I think the evidence at this point from the bulk of the -- and Ben has talked a little bit about this earlier, from the bulk of the JAK inhibitor studies that we have suggests that JAK inhibitors can work in a variety of different ways, that they provide meaningful improvement across skin and muscle. And so I guess my hope and expectation is that we will see both of those things. Obviously, they both matter to patients. Skin disease is a major part of the experience of being a DM patient. And what matters most is that the patients feel better overall. I think as far as like TIS is concerned specifically, we keep saying we're focused on just getting a static result because I think it's just not a particularly fine-grained measure of the patient experience. But regardless, I think the short answer to this question is we expect to see benefit on both. We hope to see benefit on both, I should say. And I wouldn't spend too much time sort of piecing it apart as far as TIS is concerned. Ben, anything you'd add to that?

No, that covers it. Yes.

Our next question is from the audience. It's a 3-part question. I'll read it here. One, can you give a good comp for how to think about pricing, given you're looking at multiple indications? Two, given the MMT baseline information you provided, what does that tell you about the chances of showing a benefit? It looks like the patients are not too severe and not too mild. General thoughts on improvement in muscle symptoms. And three, as it -- is encourage taper expected to be uneven across arms? Does it affect placebo rate?

Great. Thank you. And yes, I think that's a compilation of a couple of different questions we got from the broader audience. Look, on pricing, the obvious statement is we don't even have a positive study yet, let alone an approved product so it's hard to talk too much about pricing. The only comment we've made in other places is it's a disease with very significant unmet need. The other classes of therapies in late-stage development, and obviously, you got approved IVIGs, which are probably north of $200,000 price drugs. And then you've got FcRns, which are a multiple of that. And so I think like the band of pricing set by other mechanisms is wide and affords us some real flexibility. And look, I think we're excited for that opportunity, but obviously, it will depend on our data on getting the drug to market. On muscle, I feel like we've probably talked a bit about this, but I think we feel good again about our ability to treat muscle symptoms, given the JAK data that we have. And we think it will be helpful and will matter overall that we're able to deliver on that, but I think we're optimistic, given the data available. And then on taper being uneven across arms, obviously hard to say at this point. But the fact that 98% of patients adhered to the taper means that the mandatory taper at least must be distributed across the arms properly. And I'd say given that the mean steroid dose at the end of 2.5 milligrams, I'm not sure it's going to have a huge impact in the end. But Ben, anything you'd say on any of those 3 points?

Yes. Just taking the last 2, I would say I agree with the question in terms of kind of where we netted out with the baseline MMTA data, where we found that quite encouraging really is at that kind of right threshold with patients centered in the low- to mid-120s of patients who really have bad muscle disease and an opportunity to show significant improvement on that and have that move the TIS but while also avoiding those really kind of end-stage patients where the level of fibrosis or scarring is so great that an anti-inflammatory drug may not be able to address that. So that's really kind of what we were targeting when we set the inclusion criteria as we saw in terms of the baseline data in the ProDERM trial. And so we do feel encouraged by what we see in the baseline data there. And then as far as your question on tapering, to Matt's point, especially with the mandatory taper, we were very strict about it with the 98% success rate. If you go back to that slide, or I don't even have to go back to it, but I think over 80% of patients reduce their dose from baseline by over 50%. So clearly, just given this is blinded and pooled data, patients in the placebo group will be reducing their steroids as well. And then finally, I would just briefly in the presentation, but I think the success with the steroid taper lets us look at some interesting endpoints, too, that are the nexus of steroid tapering and benefit. For instance, something like the patient -- the percentage of patients who are able to achieve a TIS 40 response while also having a steroid dose of no greater than X milligrams per day, endpoints like that, I think the success with the taper we've had, I think, can be really clinically meaningful to patients that sort of framework of thinking is something we've developed with a lot of input from KOLs and site investigators and other myositis physicians. And I think things like that are a nice way, even if the tapering was a little bit greater in the treatment arms, a way to kind of, well, that's a good thing. It speaks to the fact that the drug is steroid sparing and a way to kind of illustrate that benefit through different evaluations of the data.

Great. Thank you.

There are no more questions. I will hand it back to you, Matt.

Thank you very much. Well, thank you, everybody, for listening this afternoon. Thank you to Ben and the Priovant team for all their hard work on this program and for joining us today and to the Roivant team for getting it teed up as well. And then a huge thank you to the patients and investigators in the VALOR study and across the brepocitinib program without whom, obviously, there'd be no trial at all. So I just want to say thank you for that. Thank you for listening. We are super excited about this data coming in the second half and looking forward to getting back on the phone with all of you when it's available to go through the results. So thank you, Ben. Thank you, everybody, and we'll talk soon.

Thanks.