Roche Holding AG (ROG) Earnings Call Transcript & Summary

My name is Henrik, and I'm the technical operator for today's call. Kindly note that the webinar is being recorded. [Operator Instructions] One last remark. If you would like to follow the presented slides on your end as well, please feel free to go to roche.com/investors to download the presentation. At this time, it's my pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.

Thanks, Henrik. Could I have the first slide, please? Thank you. So welcome to our seventh IR event for this year, where we will focus on the latest clinical results from our ophthalmology portfolio, which got presented last week at ASOPRS and AAO. And let me quickly take you through today's agenda. The event will go for 60 minutes, I assume around 40 minutes for the presentation, and then we have 20 minutes for Q&A. If we go top down, then our first presentation will be given by Nilesh Mehta, our franchise head, ophthalmology and global product strategy. Nilesh will provide a quick introduction to our IL-6 development programs in ophthalmology. Thereafter, our second speaker then will be Dr. Nisha Acharya. Dr. Nisha Acharya is an Elizabeth C. Proctor Distinguished Professor of Ophthalmology, Epidemiology & Biostatistics at the University of California San Francisco and Director of the Uveitis and Ocular Inflammatory Disease Service at the Proctor Foundation. She's also Associate Director of the Proctor Foundation and Vice Chair for Faculty Development and Mentorship of the Department of Ophthalmology. She is a clinician scientist and an international leader in ocular inflammatory diseases for over 20 years. She has led an NIH funded research program conducting global clinical trials and outcomes research. Dr. Acharya will take us today through the Phase III SANDCAT/MEERKAT results for vamikibart [UME], which represented last Friday at AAO. And then our third speaker for today will be Cesar Briceno, who is an Assistant Professor for Ophthalmology, Dermatology and Surgery at the University of Pennsylvania and Chief of the Division of Oculoplastic Surgery. He's also the Co-Director of the thyroid eye disease program at the Scheie Eye Institute and was site principal investigator for the SatraGO-1 and 2 trials which we'll discuss today. In addition, he has served as Assistant Dean for Student Social and Professional Networks at the Paramount School of Medicine at the University of Pennsylvania. Dr. Briceno will take us today through the Phase III SatraGO-1 and 2 results for satralizumab and TED, which he presented at ASOPRS, I think last Thursday. In addition to our speakers, we will be joined then for the Q&A by Chris Brittain, our Senior Vice President and Global Head of Product Development and Ophthalmology, which many of you had the opportunity to meet at our Pharma Day in London last September. Could I have the next slide, please? Before we get started, just quickly, 2 slides from my side to update on the upcoming news flow for the remainder of the year, and then also providing an outlook into the news flow for '26. As you can see here on our updated 2025 key news flow slide, we have 3 more readouts to come. That's Gazyva in SLE, [indiscernible], the fenebrutinib data in PPMS. For several Phase II assets, we will have the data in-house. However, it has been decided in the meantime, primarily for competitive reasons, to share these results only at conferences in H1 '26. So these studies include the [emugrobart] data in SMA and FSDH and the CT-868 data in type 1 diabetes and the CT-996 data in type 2 diabetes. For a summary of the 2026 news flow, let's quickly have a look at the next slide. That's the updated '26 news flow. Overall, we expect now, 12 pivotal Phase III readouts in 2026 and several important Phase II readouts, which will inform the next development steps of our CVRM portfolio. The current planning is that most of these Phase II results in CVRM will get presented at ADA, which is in June next year. So with that, let me hand over then to Nilesh for a quick introduction to our 6 development approaches in ophthalmology. Nilesh, please.

Thank you, everybody. I hope you can hear me. It's a great pleasure to be with you all. And from my side, I'd like to just set a little bit of the context in which you can hear the other 2 data sets that will be presented by our experts today. So moving to the next slide. Just grounding us on some bigger picture and vision for ophthalmology, with the pun intended there. These data sets are relevant for our ambition. And on the left, you can see that we aim to establish ourselves in a leading part in ophthalmology by clearly building a beachhead in retina. And I think we've made significant progress there. To do that, we need a really differentiated pipeline of solutions for ones that are innovative enough to be transformational. And then we'd like to expand into areas where unmet need and science boundaries are intersecting. Today's focus, though, is on 2 areas in UME and thyroid eye disease, where we know there's a significant patient need, and you'll hear the experts share the data in depth. On the bottom of the slide, we talked a little bit about how we would approach that. And you see 2 elements in the middle there. Clearly, leveraging our commercial portfolio today, which includes Vabysmo and Susvimo, but then 2 areas where we want to go beyond VEGF and sustained outcomes in retinal vascular diseases, but also beyond complement and geographic atrophy in this next period. We'd like to pioneer innovation in vision restoration. And then obviously, underpinning a lot of that is build leading capabilities that sustain that innovation. On the next slide, a little bit conceptually what we're looking at. This ischemia shows how retinal conditions progress. On the left, we know there are a lot of anatomic changes that are suggestive of disease progression in early stages of disease. But many times, they're asymptomatic until they advance to a stage to edema, most normally and therefore, subsequent central vision defects. Today, that's typically where we -- where the current solutions where we intervene, we play a part in improving visual acuity, but we know patients still progress to permanent vision loss. And actually, we want to be able to address both directions here, going earlier to prevent disease and preserve vision for longer as well as being able to restore vision in later stages of disease. I showed on the next slide, a little bit of the pipeline that you're quite familiar with and that Roche has really built over the last few years. And of particular interest today are the Phase III data from uveitic macular edema with vamikibart and with satralizumab in thyroid eye disease. To note also, and I'll talk a little bit about this in a subsequent slide, is the VEGFxIL6 DutaFab which is a bispecific antibody that we declared recently. If we move to the next slide. IL-6 targeting vamikibart as a molecule targeting this pathway, which is significantly involved in inflammation. And we have data in-house in both Phase II in diabetic macular edema, both combined with VEGF as well as in monotherapy. And today, you'll hear a deeper dive into the Phase III data from uveitic macular edema, an indication which is strongly associated with inflammation. If we move to the next slide. As I mentioned, our next-generation bispecific antibody targeting both VEGF and IL-6 simultaneously, one injection as part of the DutaFab platform. This makes a potential option for also the Port Delivery system. We've seen encouraging data from the Phase II BARDENA study on functional improvements that go beyond VEGF alone. And that gives us a lot of conviction to progress this bispecific into diabetic macular edema. We have an already running Phase I study ongoing there. And finally, on the next slide, satralizumab. This is subcutaneous anti-IL-6. Again, we know inflammation is a hallmark of this disease, particularly suitable for [4W home] administration in an area of high unmet need. There's a wealth of evidence, both preclinically and as shown today, suggesting the role of IL-6 in the pathology of thyroid eye disease, and you learn more from the data from our other experts. So we're particularly encouraged as we build further innovation in the ophthalmology space. And with that, I'll hand over to Nisha.

Great. Good morning, everyone. It is my pleasure to be here and share with you the Phase III results of 2 trials for vamikibart with uveitic macular edema. As was mentioned, I am a uveitis specialist, so I'm an ophthalmologist who takes care of patients with uveitis and other ocular inflammatory disease conditions. I've been doing this for a while now, a couple of decades. And so I think I have a very -- I see these patients all the time, and I think I'm able to kind of put that into context when I see the results. We can go on to the next slide. All right. So as mentioned, there are 2 Phase III trials, MEERKAT and SANDCAT, and we'll be presenting the results of that. So just as a bit of background, uveitis is inflammation of the uveal tract of the eye, which is the pigmented vascular layer of the eye, the iris, the choroid, the ciliary body. It's the middle layer of the eye. And when that blood ocular barrier is lost, you basically have inflammation in the eye. Normally, the eye does not have its sort of an immune privilege site. But when you have uveitis, that immune tolerance or immune privilege is lost and there's inflammation in the eye and many different structures in the eye can get inflamed. So this is an immune-mediated process. Most cases are noninfectious. It's not known exactly what the causes are. It's probably just like any other immune-mediated disease, there's many different pathways, but it's autoimmune and pathogenesis. Unlike a lot of other conditions affecting the eye, uveitis affects patients of all age ranges and primarily the working age population, so -- and can be chronic and recurrent. And so there can be significant implications in terms of that population's trajectory and their life experience and their working ability. The prevalence of uveitis, there's different estimates, but the best we know from various studies is about 121 per 100,000 individuals, adults. We do think it accounts for about 10% to 20% of blindness in the U.S., that may be an underestimate and higher in the U.S. and in the European Union, but probably higher in the rest of the world. All the photos on the bottom are my patients. These are photos of their eye showing what we see in the eye when we have different types of uveitis. These are all non-infectious uveitis. You can see this inflammation from the front of the eye all the way to the back of the eye in the retina. And on the very far right, blood vessels and even macular edema, you can see on the fluorescent angiogram in the center there, there's leakage. We can go on to the next slide. Uveitic macular edema is the leading cause of vision loss in patients with uveitis. You see an OCT image there showing what macular edema looks like when we're able to get this noninvasive, basically cross-sectional really view of what's happening in the retina, you can see that the anatomy is really distorted there. So what happens in uveitic macular edema is you get thickening because of fluid accumulation in the macula, which is, of course, the center part of the retina where you have the highest density of photoreceptors responsible for your central vision. So very important part of the retina. We -- estimates are about 1/3 or maybe even a little bit higher percentage of uveitis patients will develop uveitic macular edema at some point in their uveitis course. Currently, corticosteroids or steroids of some form are the mainstay treatment for us to treat patients who have this. But unfortunately, steroids have very predictable and very common side effects, and those include cataract formation. And then also, I would say, even more worrisome is intraocular pressure elevation and glaucoma because that's not reversible when you have damage. So glaucoma is where you have high pressure in the eye, which steroids can cause and then it basically causes nerve fiber layer damage and optic nerve damage, permanent damage, which results in loss of the visual field and then eventually, it can result in full blindness. So uveitic macular edema is actually one of the more difficult situations that we face. It's common in uveitis, but it tends to be persistent or recurrent or chronic with our current therapies. And we've had multiple studies now, NIH-funded trials and other studies that have shown that when you're on systemic immunomodulatory or anti-inflammatory therapy, which is what we use to often control uveitis, that uveitic macular edema is often persistent in about 40% of eyes despite using other therapies for uveitis. We can go to the next slide. So currently, as far as treatments, I just -- as I said, it's steroid. It's steroid of some form. We do have steroid drops. They don't penetrate that well into the back of the eye, so limited efficacy there. Then, we have intravitreal steroid injections, implants and also steroid injections around the eye or in the suprachoroidal region of the eye. So these are just basically administering steroids to the eye. We don't have any FDA-approved non-steroid injections or implants. We do have -- there are anti-VEGF agents or injections, which have been used off-label for uveitic macular edema. We recently had an NIH-funded trial comparing steroids to anti-VEGF strategies and it had very limited efficacy. And the thought is that in uveitic macular edema, VEGF maybe plays a little bit role in permeability, but does not address the inflammatory basis of uveitic macular edema. So unfortunately, it's not been that helpful. So our current strategy is we do use steroids. Generally, it's going to be injections or implants. Those are usually relatively short acting. They do have a lot of side effects. And we do try to use other agents. We use immunosuppressive therapy, both conventional and biologic therapy. But with this approach, the majority of patients still have recurrent or persistent macular edema and need additional local therapy. So there is a big unmet need for an effective and safe nonsteroid intravitreal therapy for uveitic macular edema. We can go on. We do know from multiple studies now in uveitis, multiple different labs, different studies that IL-6, interleukin-6 is very important in the pathogenesis of uveitic macular edema. It's a pro-inflammatory cytokine. And when it's dysregulated, there's a number of different downstream inflammatory pathways that are activated. You can see on the slide that this results in things like vascular leakage, chronic inflammation, autoimmunity because there's a -- the T cells are kind of targeting more towards Th17. And you also have just increased vascular permeability because of blood retinal barrier disruption and you have leukocyte infiltration in the eye. So a number of studies have shown that IL-6 is elevated in the aqueous humor of patients who have uveitic macular edema. And thus, there is strong scientific rationale to target IL-6. Go on to the next slide. So vamikibart is the first and only anti-IL-6 monoclonal antibody that's engineered for intravitreal therapy delivery. It's a recombinant humanized IgG2 monoclonal antibody. The Fc segment of the antibody has been modified. So there's very fast systemic clearance, which is good. And the half-life after intravitreal dosing is about 7.5 days. We do know from prior studies that with administration of vamikibart, there's a very rapid and sustained suppression of aqueous humor IL-6. You can see on the graph on the right, and this is from an earlier DOVETAIL study. So the Phase I and earlier studies that there's injections at the beginning here 0.4 in 8 weeks, and you have a very marked suppression of IL-6 that then looks to be sustained with 2 different doses that were used of vamikibart. Next slide. So MEERKAT and SANDCAT are 2 identical Phase III trials for uveitic macular edema. Patients had to be at least 18 years of age. They had to have non-infectious uveitis and uveitic macular edema. We define that with the central subfield thickness of 325 microns on an OCT scan, and they had to have vision about 19 to 73 letters. So not perfect vision and not vision that was already blind basically. This is a good range of about 20/40 to 20/200. And the trial was designed with 3 different treatment groups. You have the vamikibart higher dose, 1 milligram, vamikibart 0.25 milligram and then the sham treatment group. Patients got 4 injections 4 weeks apart. You can see there in the schematic. And then the primary endpoint was assessed at 16 weeks. And the primary endpoint was the proportion of patients who gained at least 15 letters, so 15 letters or more of best corrected visual acuity from their baseline vision. The trial does is continuing after that, and there's as-needed dosing of treatment and vamikibart after the primary endpoint. And so the end of the study is 52 weeks. Just other things to note is that rescue treatment was allowed from 4 weeks. And patients who have uveitis are often on systemic immunosuppressive therapy or they've had prior treatments. There were criteria to allow patients who've had these to be included in these trials with washout periods or -- and if they had stable immunosuppressive therapy, that was allowed as long as it was stable and then continued in the trial. We can go on to the next slide. Here are the baseline demographics for the treatment groups for the 2 Phase III trials. You can see that they are well balanced overall. The age was about -- it's in the 50s, maybe a little bit higher age in the SANDCAT trials, but in the 50s is the main age. The majority of patients were female. We tend to see that in uveitis in various immune-mediated conditions in the body, including uveitis. Patients were predominantly white and then also Asian. And then patients were enrolled in Asia, North America and the rest of the world. So a good generalizable population here. Go to the next slide. So these are ocular characteristics at baseline, and they were very balanced across treatment groups. Vision was about the same in all of the treatment groups. What I want to point out is that the central subfield thickness is very high here. It's in the 500, so 500/20s, 500/30s. That's -- we just remember that 325 was the necessary central subfield thickness, but keep this in mind when you look at the results. So this is very typical that patients have pretty substantial macular edema in uveitis. We did have about close to half, a little bit less were pseudophakic, meaning they've had cataract surgery. So it's very common in uveitis that 50-year-olds would have already had cataract surgery because of inflammation and all the prior treatments they've had. And about 20% to 30% had a problem with pressure in the past, too. Most patients had uveitis that was affecting the back of the eye and most patients had controlled uveitis. Remember, they could be on other therapy, but about 30% to 40% still had active inflammation and about 30% to 40% were on systemic immunosuppression. So here is the primary endpoint at 16 weeks for both trials, and we'll start with the MEERKAT trial. So here, you see the proportion of patients who gained at least 15 letters, 15 letters of best corrected vision. It's about 3 lines on an eye chart and between the different treatment groups. So 6.3% of the patients who were in the sham group achieved that versus 26.1% in the vamikibart 0.25 milligram group and 43% in the 1-milligram group. And then statistically, when you look at the difference compared to sham, each of those was highly statistically significant. When you look at the treatment difference, it was about 20% and about 37% difference. Those are very statistically significant differences. In the SANDCAT trial, 13 patients or 13.3% of patients did gain at least 15 letters. In the 0.25 milligram group, about 34 -- or exactly 34% of patients achieved that endpoint. And in the 1-milligram group, 24.2% of patients achieved that endpoint. So when you look at the treatment differences versus sham, this results in about a 20.7% treatment difference when you compare the low-dose group compared to sham and about 10.9% when you compare the 1-milligram group to sham. So the p-values here, it was highly -- so the way the trial was designed was that the primary analysis was prespecified to be the 1 milligram against sham. You can see the p-value here was 0.069. And so that did not reach statistical significance over sham. And so because of that, you can't really have a definitive call on the lower dose, but you can say that there's a nominal significant p-value of 0.0019 when you look at the 0.25 milligram group compared to sham. We can go on to the next group or the next slide, okay. So this is showing the actual change in visual acuity, best corrected visual acuity from baseline for all 3 treatment groups in both trials. And for both trials, there was a very comparable, very robust improvement in visual acuity. In the MEERKAT trial, sham was 3.5 letters and then both treatment groups, you have 9.6 letters in the lower dose and 12.8 letters in the higher dose. In the SANDCAT trial, they sort of reversed a little bit, but these are very -- pretty similar when it comes to letters, 9 and almost 12 letter gain compared to 5 letters in the sham group. So pretty consistent results across trials in terms of vision. Can go on to the next slide. Here, we see the reduction in central subfield thickness, that's CST measured in the -- by OCT. And this is really a marker of anatomical of what's happening to the anatomy of what's actually happening to the macular edema. Remember that we started very high in the 500 range. And you can see for both trials, sham was in the 40 -- well, for MEERKAT, there was a reduction of 58 microns. And by the way, about 50 microns is within the range of 25 to 50. So really not much reduction there with sham. But in both treatment groups, very similar and pretty rapid and comparable reductions close to 200 microns, so about 190 to 196 micron reduction, and each of those was statistically significant compared to sham. And in SANDCAT, very similarly, the reductions are about 200 micron reduction in each of the different drug doses. And then we come to safety. Overall, there was a very low incidence of treatment-related ocular adverse events through week 16 in both trials. So the numbers are quite low actually in terms of what it is. You can just recall that these patients have uveitis, and so they already have inflammation. And so it's natural in the course of uveitis that you may sometimes see a little bit of inflammation happen and investigators could report that as an AE. But there was very low numbers of AEs leading to treatment discontinuation across all treatment groups and very, very low SAEs as well. We can go on. And more I think this is probably of most interest in terms of significant adverse events that we really do care about are intraocular inflammation, which, again, is what uveitis is, but really the more devastating complication can be retinal occlusive vasculitis, which is where the blood vessels in the retina become inflamed and you can have ischemia and infarction of the retina that can really have a risk of vision loss. So these patients have uveitis, so it's natural that the uveitis can go up and down a little bit. Even with that, there's very low levels of intraocular inflammation, just a few patients in each of these treatment groups. So overall, that's pretty low, and that's expected. But there were 0 cases of retinal occlusive vasculitis across the entire study in both Phase III trials. No endophthalmitis and it's a 16-week study. So it's a short time point, but very low rates of cataract and pressure. Again, these things can happen in patients with uveitis, but they were very low across all study arms. We can go on. So in summary, vamikibart offers -- this is the first non-steroid intravitreal therapy that is an option for patients with uveitic macular edema. In terms of efficacy, it really -- it did lead to rapid improvements in vision and macular edema. We did show that there was that -- that the primary endpoint of vision did meet or did miss the primary endpoint in the high-dose group in the SANDCAT trial, but the results are very consistent really across both studies in terms of vision, anatomical outcomes in terms of reduction of central subfield thickness. So from my standpoint, I'm seeing that there's a clear signal that this anti-IL-6 strategy is leading to improvement. And in terms of safety, overall, very well tolerated and really the key no events of retinal occlusive vasculitis. Given that we currently really struggle to take care of patients with this and that all we have are steroid injections, which have very known side effects, that are pretty -- that are very significant. There is a huge unmet need to have other therapies available. This could be a very novel nonsteroid option that could, I think, change the treatment paradigm for patients with uveitic macular edema. I think -- and that's what we have for now, and I look forward to the discussion. Thank you.

Hi, everyone. This is Cesar Briceno from University of Pennsylvania, and I'll be sharing with you the results of the Phase III SatraGo-1 and SatraGo-2 satralizumab trials in thyroid eye disease. Next slide, please. So thyroid eye disease is a complex inflammatory autoimmune disease that at this point has limited durable treatment options. Currently, there are treatment options targeting the IGF-1 pathway, namely trontinemab, and that can be associated with some serious adverse events as well as a not infrequent relapse of disease activity. As a result, there is an unmet need for other targeted therapies that modify disease progression and that minimize long-term complications and have more favorable side effect profiles. IL-6, as has been previously discussed, is known to drive inflammation and that has been shown in thyroid eye disease as well. Basically, in steroid-resistant patients, it's been studied as a modality of treatment by way of tocilizumab and shown to reduce clinical activity score in a significant way versus placebo. Next slide, please. The SatraGo-1 and SatraGo-2 trials were identically designed in Phase III randomized, placebo-controlled studies. And in this cartoon, we can see the crossover design. So patients were randomized 1:1 to receive satralizumab every 4 weeks versus placebo every 4 weeks. And after 24 weeks, based on their proptosis response, then they were rerandomized to receive either placebo or satralizumab for an additional 24 weeks. This particular presentation is of the 24-week data where the primary endpoint was the proportion of active participants with thyroid eye disease achieving a greater than 2-millimeter reduction in proptosis from baseline at week 24. I should note that these trials also included inactive participants in order to look at how this molecule behaved in inactive thyroid eye disease in addition to active thyroid eye disease. Next slide, please. The baseline demographics were largely unremarkable and similar between the groups with 2 notable exceptions. First, there was a slight preponderance of female participants in the satralizumab arms. And in SatraGo-2, there was a slightly higher proportion of Asian patients. Next slide. Looking now at the efficacy, the proptosis response was observed in a higher proportion of participants receiving satralizumab. On the left side of the slide, you can see the active thyroid eye disease primary endpoint. In SatraGo-1, there was a 49% response rate versus 31% for placebo. And in SatraGo-2, there was a 53% versus 23% with a larger treatment effect. As a result, SatraGo-2 was able to reach statistical significance here where SatraGo-1 was not. If you note, the primary difference is in the rate of efficacy in placebo rather than the rate of efficacy in the active arm. On the right side, we have inclusion of the inactive patients in addition to the active patients. The inactive arms were capped at 25% of enrollment. And in these, the primary endpoint was met in both SatraGo-1 as well as SatraGo-2. Next slide, please. Here, we look at this in a little more detail. We can see the proptosis response over time over the 24 weeks in SatraGo-1 on the left and in SatraGo-2 on the right, and this was for the active TED population. As you can see, there's a steady increase in dark blue in the proptosis response for the treatment arm. The placebo arm in SatraGo-1 was quite variable. In SatraGo-2, you can see a similar pattern with a slight increase over time in the proptosis response, but the placebo arm was more steady in SatraGo-2. Next slide, please. Here, we have similar histograms looking at the results when we include the inactive patients in addition to the active patients, and they're rather similar. In SatraGo-1, you have a steady increase in proptosis response over the 24-week period versus some variability in the placebo. And in SatraGo-2, steady increase over the 24-week period with a more relatively steady placebo arm. Next slide, please. We also looked at diplopia and how that was reduced by treatment with satralizumab. In the active TED population, the diplopia reduction scores were 44 versus 34%, which did not reach statistical significance. And in SatraGo-2, it was 61% versus 26%, which did reach statistical significance. This was, by the way, measured as a reduction of 1 point by Gorman score. On the right side, we have the active plus inactive TED population. And here, again, in SatraGo-1 at 47% versus 28% did not reach statistical significant. But in SatraGo-2, it was 59% versus 28%, which did reach statistical significance. Next slide, please. We also looked at clinical activity score reduction as one of the secondary endpoints in this trial. Here, we're looking at a greater than 2-point reduction in clinical activity score. On the left side of histogram, we see that there was a significant reduction in CAS in both SatraGo-1 and SatraGo-2. And the achievement of a clinical activity score of 0 or 1 at week 24 was also assessed, and this turned out to be significant in both SatraGo-1 and SatraGo-2. Next slide, please. We also looked at overall response rate, which was defined as a greater than 2-point reduction in clinical activity score and a greater than 2-point reduction in proptosis. When looking at our active TED population in SatraGo-1, this was achieved in 44% versus 18% of patients, which was statistically significant and in SatraGo-2, in 50% versus 20%, which was also statistically significant. Next slide, please. One of the things that's most impressive about this trial is the low incidence of adverse events and treatment discontinuations with satralizumab. There were no serious infections noted. And as you can see, the adverse events in the treatment versus placebo arms were essentially equal between -- in both SatraGo-1 as well as SatraGo-2. Next slide, please. Most of the common adverse events were also listed here. You can notice a similar pattern. There were very, very few in the way of adverse events in the treatment arm, and they were equal statistically to what was observed in the placebo arm. And this included measurements such as neutropenia and also things like nasopharyngitis. And there's a notable absence of the typical adverse events that we worry about with IGF-1R blockade, such as hearing loss, spikes in diabetic sugar measurements as well as exacerbations of irritable bowel syndrome and muscle spasms. Next slide, please. So in summary, satralizumab was efficacious and extremely well tolerated in participants with TED. We looked at the pooled data between SatraGo-1 and SatraGo-2 since these were 2 identical Phase III trials. And when pooling the data, looking at satralizumab versus placebo, statistical significance was reached across all the endpoints that are listed in this slide, including the proptosis response, CAS reduction, achieving CAS-01, overall response and diplopia reduction. Next slide, please. So in summary, satralizumab showed clinically meaningful improvements across key efficacy endpoints, including those that we listed in the prior slide, proptosis, diplopia and CAS in those patients with active thyroid eye disease. The safety profile is consistent with what we've seen with satralizumab in NMO spectrum disorders, which is to say that it is highly favorable with no reports of the adverse events commonly associated with other treatments for TED. Satralizumab, thus, is the first IL-6R inhibitor, combining both a positive benefit to risk profile for active and inactive TED with a convenient subcutaneous dosing and a wonderful adverse effect profile. And it could, as a result, represent a new treatment paradigm and certainly a new very useful option for our patients with TED. Next slide. I think we're done.

Okay. I think with that, we can start the Q&A session. I'm currently having a technical issue here. Let me maybe quickly jump to a couple of the questions we had coming in, in the Q&A section, do them first. So there were a couple of questions from [Gena Wang] from Barclays. For the SANDCAT and MEERKAT studies, what was the reason to use the percent of patients to achieve a 15-plus letter gain as a primary endpoint? And is there any drawback compared to single BCVA changes versus the control arm?

Maybe I'll take that to start with. Essentially, the 15-letter primary endpoint is a regulatory required primary endpoint because that's recognized by the FDA as the letters required to demonstrate a clinically meaningful improvement or lack of deterioration in visual acuity. So that's why we use 15 letters. However, I think as you see, as Nisha shared very nicely, the drawback is that -- because it's a dichotomous endpoint, you either hit 15 letters or you don't, there's increased risk of not kind of capturing the full benefit of the visual acuity gains, which we see. And that's why the data which showed the improvements in visual acuity on average, the mean average changes from 9 to 12 or 13 letters with the 2 different doses are very, very robust gains. But Nisha, anything to add from you?

Yes. I mean I will tell you that we actually -- in the clinical world, we actually consider even a line gain. This is a very hard condition to treat. And we did recently completed a lot of NIH trials for uveitic macular edema. And even with steroids with patients who had uveitic macular edema, we were seeing -- we were seeing 5, 6 letters, and we were happy about that, right? And so 15 letter is a high bar. I understand that, that's been the norm in other kind of retina trials. But uveitis can also damage vision, and it can be difficult to always have vision correlate with the benefit of a drug, right, because you have uveitis and you also have macular edema. So I would say that clinically, seeing the net change in vision is very important for us and seeing gains of 10 to 12, 13 letters is really, really very meaningful.

Okay. That's very good. Then we take the first questions here from the queue. It's Michael Leuchten from Jefferies.

Maybe just going back to that exact question on the spot estimates versus percentage of change. Just wondering about the regulatory discussions around filing. Can you pull the data or do the studies have to be submitted independently, MEERKAT and SANDCAT, that is? And then a question on CST versus the visual acuity. In terms of dose response, it seems to be very little between the 0.25 and 1 milligram on CST. Does that matter in the way 1 thinks about the dosing and the patient response?

Sure. Maybe I'll take a stab to start with. In terms of the regulatory pathway, so we -- as you've seen on the press release, we are discussing with the regulators the path forward. Obviously, it was unfortunate that the 1 milligram failed the primary endpoint. And because we have hierarchical testing, the 1 milligram went first and the 0.25 milligram went second. So therefore, the 0.25 milligram p-value becomes nominally significant rather -- and that's why the study is regarded as technically a failed study. Nonetheless, we are -- as I say, we will be discussing with the regulators, and we'll be looking forward to kind of sharing next steps as soon as we're able to on that side. In terms of the dose response, I think Nisha shared quite nicely the -- as a reminder, the fact that the vamikibart at both doses suppresses intravitreal IL-6 all the way out to the 16-week time point. And therefore, it was no major surprise that there was no dose response bearing in mind that we were dosing these both doses at every month. But maybe, I mean, in terms of kind of the clinical difference on those 2, Nisha, any comments on CST.

In terms of the -- do you mean in terms of the CST, in terms of both treatment groups, they're both very robust and looks very comparable. So I think that really fits. We've seen that IL-6 was suppressed in both groups. From prior trials, we know that there's rapid IL-6. So it could be that you're getting an effective and sufficient suppression, right, to be able to get your maximal benefit from this with both doses. So I think that actually explains that in my opinion.

Michael, all questions have been answered?

Yes.

Then, the next one would be Peter Verdult from BNP Paribas.

Yes. Thanks, Bruno. Peter Verdult here from BNP. And thanks to the doctors for their time. Just a couple of questions, please. On vamikibart, you talked about steroids being the current plan of care. Just to help us understand the pace of adoption should vamikibart get approved? And also, could you just parse out the competitive landscape? I apologize, I'm not -- I'm all over this disease area. So if you could just put it into context. What else is out there that's sort of grabbing your attention? And then on Satra, forgive me for calling a spade to spade, you've got 1 failed study, 1 positive. If you were a half, you'd say the absolute level of efficacy versus TEPEZZA is much lower. I take your point on placebo effect, but when you do it on efficacy, it's lower. They are going to have subcuts so the convenience at home goes out of the window. So what is the proposition here? Is it about safety? Or where does this really fit in the treatment paradigm? And to you, Chris, is there any scope to pull the data? Or is there a risk here that the FDA will say we want 2 positive studies before considering approving the drug? Sorry, a lot of questions there, but over to you.

Should I take the first question was about where this will fall clinically, right? And how would the uptake be and all of that? Yes, I mean, we have a lot of patients with macular edema because we said that it's 30% to 40% of patients have macular edema at some point in their uveitis life, right? So we see a lot of patients with this. We have to treat it. I mean it's not an option not to treat it, and we only have steroid injections. We have a lot of them, not a lot. We have a handful of different versions of steroid injection and implant. But the bottom line is they're all steroids. You can't -- we have to treat because you lose vision. And the problem with macular edema is once you lose the photoreceptors or you have damage, even if you then treat late, you may not regain your vision. And so we have to treat. So we basically just are forced to kind of use what we have and we deal with the side effects. And we just -- patients are suffering from kind of having repeated injection of steroid and they have cataracts and they have high pressure. So I would say that if we have something come out that is -- that's shown to be effective and safe in Phase III trials, there would be very -- there is very strong interest in the uveitis community for that. There's been -- we haven't had that, and we need it. And it would be almost, I think, an immediate uptake. It's an injection. It's a simple injection to give, so everyone is comfortable with it. Retina doctors also can give this. It's not something that's hard to administer, right? It's just an intravitreal injection. So I think in terms of uptake, I think there would be a very quick uptake to try substituting this instead of steroids. There's lots of patients where steroids are a big problem because they have glaucoma, there's other issues where they have like very -- you don't want to give steroids. But even in all patients, there's risk with steroids. And so I really see this as being applied as really as an alternative to steroid, which is preferable. I don't think we mentioned this in the talk, but if you look at the CST reductions, which is what we presented here and you look at what they were in recent trials of like the OZURDEX implant, which is the go-to steroid injection implant for macular edema, they were really comparable. We saw in this -- in MEERKAT/SANDCAT, it was like 38% or so -- it was a 38% combined CST reduction, right? That's almost 40% reduction. If you look at the dexamethasone in OZURDEX implant in the MERIT trials that were done, it was 35%. So you're seeing really comparable kind of efficacy without the side effects. So I see it as being a replacement for steroids.

Yes. And I think we can move on to the Satra question. And Cesar, if you want to comment.

I'd be happy to. Yes. So I think your questions are spot on. I mean 1 of the key differences between satralizumab and the known data on IGF-1R blockade is that the efficacy is lower. I think there's no secret about that. I mean the efficacy, if you look at the Phase II and III trials for teprotumumab was in the 80s. If you look and include the Phase IV data, it drops a bit to maybe around 70 or so, and we're talking about around 50 for this trial. I think that the primary value proposition is surrounding safety. There are 2 groups of people that primarily get thyroid eye disease. It's a bimodal distribution. And the first group is a young and relatively healthy group of people. The second bump is an older and relatively less healthy group of people. And in that second bump, which is a lot of what I see at the university, there are a lot of both relative as well as near absolute contraindications for treatment with teprotumumab. None of them are absolute. But in my mind, I wouldn't give it to certain patients. Those are brittle diabetics. Those are people who already have sensor renewal hearing loss, and there are people who have trouble with IBS or some sort of other GI inflammatory issue. Given that we live in the U.S., this is not a small number of people. And then on the flip side, there's also the people who recur after treatment with teprotumumab. Even if the efficacy is quite remarkable, within 6 months, we see about 1/4 of those people then really have a reintroduction of their proptosis close to levels that they were before treatment or even sometimes beyond or to the same level. And so there is an unmet need for another class of drug that has a label for thyroid eye disease. So as a clinician, I hunger for this, and I know that a lot of my colleagues do as well for treatment of those 2 specific groups that I just described, the ones in whom we're too hesitant to give the IGF-1R blockade because the side effect profiles are unacceptable. And then the second group of people who recur and then you need to have some sort of other option in order to treat them because, otherwise, you're right back to where you started before you expose them to 6 months of another biologic. And so there is a need because there's only one FDA-approved drug for this out there for class variability so that we can have a better opportunity to treat our patients in a more tailored way. So it's not just hammer and nail. It really becomes more tailored and more thoughtful as far as how we treat our patients.

And next question goes to James Quigley from Goldman Sachs.

Hopefully, you can hear me. I've got, well, 1.5 on the SANDCAT and MEERKAT trials, and then maybe another 1 on satralizumab. So within MEERKAT, MEERKAT looks like exactly what you'd expect from the distribution, but is there anything that you still noticed about SANDCAT as to why the higher dose led to a lower response? Is there anything in sort of how the trial was conducted. Anything in baseline characteristics that might give you clues as to what happened there? And the half question for SANDCAT is between weeks 12 and 16, there's almost doubling in the placebo response. So sort of what happened there? It seems unfortunate that's when you measure the primary endpoint that something happened in placebo for the BCVA to almost double. So any sort of color you can give there would be brilliant. And then similarly on the SatraGo-1 trial, any thoughts on why the placebo group was so volatile relative to what we saw in SatraGo-2?

Do you want to try to take that, Chris? I mean -- or you can comment first. I don't know.

Maybe I'll comment first and you chip in a little, then do the same for Satra. Essentially, really great questions. And we've only just recently gotten the data in-house, and we're still exploring. I think that's the basics. The fact is that uveitis is a very complex condition, whereby patients' disease can rebound at any given time, and there are lots of confounders, including systemic medications. So the simple answer is we're still actively looking through the data, but we've not found anything. But maybe, Nisha, do you want to comment on that.