Roche Holding AG ($ROG)

My name is Leonard and I'm the technical operator for today's call. [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, Leonard. And could I have the first slide, please? So welcome to our second IR went in 2026, focusing this time on the Phase III ALLEGORY results for Gazyva in SLE, which just got presented last Friday at SLEuro. Today's call is scheduled for 60 minutes, and let me quickly take you through today's agenda. Following my introduction, the first speaker for today will be Jay Garg, our Vice President and our Global Franchise Head of Nephrology. Jay will provide us an update on our pipeline in immune-mediated kidney and rheumatological diseases. This includes the Gazyva development program, but he will also quickly touch on other B-cell depleting agents currently in development. Our second speaker for today will be Dr. Richard A. Furie. Richard is an MD and the Chief of the Division of Rheumatology at Northwell Health. He's a Marilyn and Barry Rubenstein Chair in Rheumatology and the Professor of Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra in Northwell. He is the lead principal investigator of the ALLEGORY study and the lead author and he has also presented the results last Friday at SLEuro. Today, Dr. Richard Furie will take us again through the Phase III ALLEGORY results for Gazyva in SLE. After the presentations, we will have roughly 30 minutes of Q&A. In addition to our 2 speakers, we'll be joined for the Q&A by Stephen Wright, our Lifecycle leader for rheumatology and nephrology, which includes Gazyva and autoimmune diseases, but also sefaxersen in IgAN. Could I have the next slide, please? So before we get started, I just wanted to quickly summarize here, take the opportunity to summarize the opportunity for Roche in immune-mediated kidney and rheumatological diseases as we have previously communicated with you the Gazyva peak sales opportunity in immune-mediated diseases to be around EUR 2 billion. This includes SLE, LE, membranous nephropathy and INS. And as you can see here on the left side, the U.S. EU5 Japanese market for SLE, lupus nephritis, membranous nephropathy and IgAN is expected to more than double from 2050 to 2030 from USD 5 billion to around USD 11.4 billion, driven by the launch of various new and innovative medicines with different underlying MOAs. On the right side, I just wanted to provide a quick update on consensus expectations. You have seen this analysis back in September 2025 at Pharma Day. Since then a lot has happened and as we just got our latest consensus in last week, I wanted to provide here a quick update where we stand and what has been or has not been captured by the sell-side models. So let me start with Gazyva. Gazyva sales for 2030 are now forecasted to reach EUR 1.7 billion. That's EUR 0.7 billion more than 2025 and what you can see here is that the EUR 2 billion Gazyva immunology opportunity is still not really captured. Sefaxersen in IgAN, which is shown here in red on the right side and the potential upside has been, in the meantime, included in most analyst models with sales of EUR 400 million forecasted by 2030. Just to remind everyone, we have indicated here a peak sales potential in the range of EUR 1 billion to EUR 2 billion. And there are more NMEs I quickly need to cover here as they have become material to the Roche investment case. Sales expectations for giredestrant have now increased from EUR 0.9 billion in 2029 back in September to now EUR 3.2 billion in 2030. So the adjuvant and metastatic opportunities are starting to get captured. And finally, sales expectations for fenebrutinib in multiple sclerosis have hardly moved since last September despite positive Phase III readouts in RMS and PPMS with sales expectations only increasing from EUR 0.7 billion for 2029 back in September to now EUR 1.1 billion by 2030. So overall, we can see some initial adjustments to the peak sales consensus expectations. But clearly, there is additional upside once latest results will get presented at medical conferences. And as we are nearing the launch phases, but also as we will have additional data, for example, for giredestrant in first-line endocrine-resistant ER-positive breast cancer in 2027. So that's the pionERA study I'm referring to, where we have enriched for up to 40% in ESR1 muted patients. And where giredestrant is combined with the physician's choice of a CDK4/6 inhibitor. And with that, let me quickly move to Slide 7. This is just the latest immunology pipeline overview. Jay will touch here on many of these programs, including the Gazyva program, sefaxersen and also the various other B-cell depleting strategies, including various bispecifics and CAR Ts which we are pursuing in parallel to hopefully achieve B-cell research for various chronic autoimmune diseases. Maybe 1 other program here to quickly call out that's afimkibart, our TL1A antibody, where we expect Phase III readouts in UC and CD in 2027. We will be the second company coming here to market, with this novel MOA. And you also see that we test the afimkibart already in additional indications, including rheumatoid arthritis, atopic dermatitis and MASH and what you also see here that we have the first TL1A bispecific, the p40 x TL1A in Phase II development. And we just initiated another NME so far undisclosed NME and IBD last quarter, which is now in Phase I. Before I close, one other molecule here to be called out. This is our NLRP3i inhibitor in asthma. And as you know, we have broader development programs ongoing in the NLRP3 space with studies also ongoing in neurology with Parkinson's disease and also in CVRM so in -- for cardiovascular diseases. And with that, I will hand over to the next speaker. Jay, please, over to you.

Yes. Thanks, Bruno. So my name is Jay Garg. I lead the nephrology, rheumatology group here in the late-stage organization. Next slide. So as you know, immunology is one of our core therapeutic areas of interest at Roche, and immune-mediated kidney and rheumatologic diseases are a core part of that. So our ambition, our vision in this space is to introduce long-lasting remission in this area. And we did this in 3 ways: one, becoming a global leader in this space, really focusing on the highest unmet needs and transformational disease outcomes, delivering patient and health system value and then achieve this by using differentiated therapeutic approaches really with the goal of enabling long-lasting remission and freedom from toxic therapies. And this is really going to be led by our current portfolio in B-cell targeted therapies and complement inhibition. You can go to the next slide. So I just want to emphasize that this -- these areas are not new to Roche. So we've actually been in this space for a long time, getting back to the introduction or approval of CellCept in 1995 for the prevention of organ transplant rejection. This was followed by Rituxan approvals in RA as well as GPA, MPA, Mircera for the treatment of anemia due to chronic kidney disease; ACTEMRA for the treatment of RA giant cell arteritis as well as SSc-ILD and then most recently, Gazyva in lupus nephritis last year. You can go to the next slide. So in addition to Gazyva being approved in lupus nephritis, we actually had 3 additional positive Phase III studies. One in generalized lupus; one in membranous nephropathy; and one in childhood-onset nephrotic syndrome. In addition, we had a fourth positive Phase III readout with our anti-C5 monoclonal antibody crovalimab in atypical HUS. Next slide. And so I just want to call out that CKD is really a core interest of ours. It has a significant unmet need, both to the patients as well as to the health care system. So CKD is forecast to become the fifth leading cause of death globally by 2040, and you can see the numbers there. In addition, it is a significant impact to health care systems. It takes about 24% of the annual U.S. Medicare budget and really cost EUR 140 billion annually in Europe. Immune-mediated kidney diseases are really a significant contributor to CKD and actually on a per patient basis have one of the highest risk for progression to dialysis or need for transplant. Next slide. So lupus, which is what we're here today, it's really a chronic disease that affects nearly every organ system. So most patients will have mucocutaneous and musculoskeletal manifestations and renal involvement will actually develop in around 50% of patients. It's a disease of young women, mainly of color that causes irreversible damage due to really these chronic immune flares. And then the current treatment or the current aim is to really induce long-term remission with low-dose steroids. LN specifically can be considered the most severe organ manifestation of lupus. And it's not really that first episode of LN because that will cause damage to the kidney, but it's also subsequent flares. So the goal of treatment is not only to induce remission or response in those patients, but really to prevent subsequent flares. So up to 3.4 million people are affected by lupus worldwide, again, with about 50% having renal involvement. And then about 30% of patients will actually progress to CKD if they do not achieve a complete renal response. Next slide. And so when you look at the highest unmet need, so this is a survey done for KOLs. And so their thoughts are that what they need to see from a therapy, a really long-term efficacy and safety which is clear as well as steroid sparing. Now at the Euro lupus or at least the SLEuro conference this past weekend, there was a patient group that actually present their own survey and they actually queried care patients. And what they found was the biggest unmet need from a patient perspective was a treatment of fatigue, but also getting rid of steroids as background. So pretty significant for them and then comes efficacy, especially in the kidney realm as well. Now biologics are expected to rise in the future, at least the use of them, really, this is driven by guidelines. So the guidelines now are taking more of a treat-to-target approach, where you are trying to get to disease remission. In lupus nephritis specifically, the recommendation now is to start with triple therapy, which is really steroids, mycophenolate mofetil and then a biologic therapy, either BENLYSTA or advanced therapy, BENLYSTA, voclosporin and now obinutuzumab, has also been included in those guidelines. You can go to the next slide. So Gazyva. So the reason we believe Gazyva has been so successful in lupus and other autoimmune diseases is really because of its deep B-cell depletion that we've seen. So it's really the first glycoengineered anti-CD20 that's been evaluated in autoimmune disease. And what does this mean? It's a type 2 anti-CD20. So it binds differently than type 1 anti-CD20 antibodies like rituximab or ocrelizumab. So this leads to increased direct cell death, decreased complement-dependent cytotoxicity and reduced internalization. The Fc receptor has been glycoengineered. So it has greater affinity for effector cells, which then will lead to increased antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. There's actually good preclinical data in human data suggesting that this binding confirmation and the inhibition or the depletion of these B-cells is actually greater than therapies like Rituxan. You can go to the next slide. So in terms of LN, just as a reminder, our initial Phase II data were in a study called NOBILITY where we showed superiority to placebo on the background of MMF and steroids. And this was then confirmed in our Phase III REGENCY study, where we showed superiority and complete renal response at week 76. In addition, we showed a greater proportion of patients getting to CRR on low-dose steroids as well as showing in an exploratory analysis, a significantly reduced time to lupus nephritis flare, where we had a 56% reduction in the risk of lupus nephritis flare. As I mentioned, this has actually been included in guidelines so far. And the treatment regimen, just to remind you, is 2 doses at day 0 and week 2, repeat at week 24 and then week 26 and then it'll be 1 dose every 6 months thereafter. Importantly, we also got approval in both the U.S. as well as most recently, the EU for short duration infusion. And what this means is that after the first infusion if the patient has tolerated that well, they can then receive Gazyva and a 90-minute infusion as opposed to the typical 4-hour infusion, which we think will be a significant impact for both physicians and the health care system as well as the patient. You can go to the next slide. So Rich will talk about this in more detail, but since it's already been communicated both at SLEuro as well as in the New England Journal simultaneous publication. As you can see here, this is a trial design where we compared Gazyva in a similar dosing regimen as we did with lupus nephritis versus placebo on top of background immunosuppression in patients with moderate-to-severe disease activity. It achieved its primary endpoint of SRI-4, and you can see here was a 23.1% delta, which was highly significant. It hit off 5 key secondary endpoints, which Rich will go into in more detail. And I think importantly, it actually hit on some prespecified secondary endpoints around some higher bar endpoints like DORIS remission, which requires achieving a clinical SLEDAI of 0 on low-dose steroids 5 milligrams or less as well as LLDAS, lupus low disease activity. So the remission rate for Gazyva was 35% versus, I think, 14% for placebo. So kind of the highest we've seen so far in a global pivotal trial. You can go to the next slide. Most recently, we had a press release on the Phase III study, MAJESTY, which evaluated Gazyva versus tacrolimus as calcineurin inhibitor and primary membranous nephropathy, which is known to be an autoantibody-driven disease. This was a 2-year endpoint, looking at really a high bar response for a complete remission, which was achieving a UPCR of less than 0.3 with stable renal function. And these are patients that typically start around 6, 7, 8 grams of proteinuria. So pretty significant reduction. This is the most common cause of nephrotic syndrome in patients who are nondiabetic and about 1/3 of these patients will eventually progress to ESRD and require dialysis. Additionally, we reported last year in a press release around our Phase III study in childhood-onset nephrotic syndrome, where we met the primary endpoint. And again, the first global Phase III to study a targeted therapy in this disease. It actually received FDA breakthrough designation and has been accepted as a late-breaking oral presentation at the World Congress of Nephrology at the end of this month. You can go to the next slide. So we -- our thought is now, given what we've seen with both Rituxan and now with Gazyva and seeing the success of Gazyva where Rituxan wasn't as successful, especially in a disease like lupus that B-cell depletion truly could be a very effective approach in this disease. External data, again, just case reports, case series with both T cell engagers as well as CAR T suggest that if you can get greater B-cell depletion that actually might lead to even greater responses and potentially even remittance. We actually have a pretty strong pipeline in this area that will help us test the hypothesis. So we have a few T-cell engagers, T-cell bispecifics. We have Lunsumio, which is approved for follicular lymphoma already. This is a CD20, CD3 that can be given as an outpatient. The safety profile in follicular lymphoma seems to be appropriate such that we decide to take it into lupus and lupus nephritis. We've actually run a Phase Ib study, which we previously presented at EULAR last year, which showed an acceptable safety profile and did show B-cell depletion in this population. So we are now in a Phase II study with that molecule. In addition, our colleagues in pRED, our early development organization are evaluating an NME of a CD19, CD3, which is currently in Phase I in lupus as well. In addition to this, we have an allogeneic CAR T therapy targeting CD19, CD20 that we have initiated a Phase I study in both lupus and in MS. Next slide. And so I'm happy to announce that we also have announced positive results of our anti-C5 monoclonal antibody in atypical HUS. So this is a devastating disease in children that can definitely lead to high morbidity and mortality. And it showed positive results. We have not -- this will be presented, I believe, later this year at a medical conference. And you can see that we have data both in adults and in pediatrics. You can go to the next slide. And I think lastly, I just want to talk to you about our Phase III study in IgA nephropathy with our complement Factor B inhibitor. So sefaxersen is an antisense oligonucleotide that actually inhibits production of complement Factor B. So it inhibits it in the liver and actually had some local effects in the kidney as well based off of what we've seen in preclinical models. And our thought is that by actually inhibiting complement Factor B, we could have a greater effect in IgA nephropathy in terms of the complement-driven inflammation that this has. We actually have Phase II data that has been recently published in Kidney International reports where we showed that there was in a single-arm study reduction of 24-hour proteinuria. And then this led us to conduct the Phase III IMAGINATION trial where we're comparing sefaxersen, against a placebo in background on optimized background standard of care with a 9-month endpoint for proteinuria to hopefully lead to accelerated approval and then a 2-year endpoint on eGFR. You go to the next slide. And with that, I will turn it over to Rich.

All right. Thanks, Jay. I'm Rich Furie, I'm the Head of Rheumatology at Northwell, which is a 30-hospital health system based in New York. My passion is to take care of lupus patients and in the early '90s got involved in couple of lupus trials because that's all we had back in the '90s. And now we have a huge number of studies. All right. I have 6 minutes to present this, but I understand today, I can take a little bit longer, and I started out just to try to break the ice talking about ALLEGORY being a misnomer because remember, go back to your high school English days and ALLEGORY was a fictional piece of work. It was a fictional story with a lot of symbolism. And this is the polar opposite of that, pure facts. All right. Next slide. Disclosures, yes -- so just a little bit of background. And Jay went into this. I mean I could spend an hour on this because it's such an interesting story. If you go back to our early efforts to deplete B-cells and see how patients with lupus and lupus nephritis did. What we learned is that we weren't depleting enough. More is better. And so obinutuzumab, and I'll go over this again, is a far more potent B-cell depleting antibody than our predecessors. Next slide. And I really like this slide. It's so simple. If you look at the left, you'll see the modifications made to the molecule. So it is glycoengineered and so what does that mean? It means it was defucosylated, so these fucose groups were removed. And the end result there is that there's less steric hindrance and greater enhancement of binding of the Fc to an Fc receptor. But there are also modifications done to the front end of the molecule, a so-called type 2 binding confirmation. And then if you shift over to the right side of the slide, you'll see the results. We have greater antibody-dependent cellular phagocytosis. And at the bottom, antibody-dependent cellular cytotoxicity is increased as well. Because of the type 2 binding configuration, there's greater direct cell death and less dependence on complement-dependent cytotoxicity. This all adds up to just greater B-cell depletion. Next slide. Here's the design of ALLEGORY similar to other studies done in lupus. So remember, when we study lupus, we usually have a split between SLE and lupus nephritis. So different treatment algorithms and somewhat different treatment designs. So in ALLEGORY, there were 303 patients who were randomized 1:1 to either receive obinutuzumab or placebo. On top of their standard of care therapies, and we'll go into the standard of care in a little bit. There were a total of 4 infusions over the 52 weeks. The first 2 infusions constituted 1 course and that was done at baseline, and then there was second course, it was done at 6 months. With each infusion, whether a patient got obinutuzumab or placebo, they received a methylprednisolone intravenously 80 milligrams to prevent any kind of infusion reaction. The primary endpoint was the SRI-4 at 1 year. And we could go into that maybe afterwards if you're not familiar with the SRI-4. The SRI-4 made its debut, I actually presented, as I recall at EULAR, some almost 20 years ago, but it's been along with BICLA as an endpoint, the regulatory endpoints for our SLE trials. There are a lot of key secondaries. I'm not going to go through them right now. I'll show you on the next slide when I show you results, but we're not ready for the next slide. I'm sorry. I just want to point out a few more things. So prednisone. Prednisone has been a confounder for our studies. And we know in clinical practice, it's so important to taper prednisone. So we do that as part of our trials and patients who are on prednisone, which is a good chunk of these patients were required to try to taper to 5 milligrams or less by week 24, but then from the -- from week 40 till the end of the study, so the last 12 weeks of the study, they cannot change their prednisone dose. And probably one of the most important features of this particular slide is on the bottom right. This study enrolled very high disease activity patients. So what is a high disease activity patient? We required a SLEDAI of 8 or greater. Almost all other studies, the bar was at 6. We required a BILAG A or 2Bs. So just another measure of disease activity. So the patients had to achieve -- had to have both and then, of course, a Physician Global Assessment of 1 or greater. But in addition, they had to be autoantibody positive. So that meant an ANA or an anti-DNA antibody or yet another antibody called Smith. And what was very unique to this study was the requirement for a low complement level, a low C3 or low C4 or low CH50. So these requirements added up to a very active group of patients. Next slide. Baseline characteristics. I'll just go through a few of the points here. If you look at what's bold, mean SLEDAI score of a little over 13%. That's a very active population. Most of our SLE trials, the average SLEDAI score has been around 10, maybe up around 11. And then what's a little different from other studies also bold, background therapies, background immunosuppressives, about 70%, usually in our studies about 50%. And in fact, I think, the percentage using hydroxychloroquine was a little bit higher. In most of our studies, it's around 2/3 to maybe 70%. This was a little higher. Next slide. All right. So the primary endpoint, the SRI, and it is defined on the left-hand side. So if I have some time, I will go through this. The SRI in order to be a responder, and it is a dichotomous endpoint. One has to have a 4-point or greater reduction in the SLEDAI score. And they can't acquire new activity in the form of a BILAG A, which is the most active domain score that one can achieve and/or they can have more than BILAG B. There can't be deterioration in baseline Physician's Global Assessment and obviously, no occurrence of any kind of intercurrent events like changes in medicines and so forth. So is that a rigorous endpoint? It really is. When we first developed this, no one really understood what an SRI was, but it turns out it's a very rigorous, hard to achieve endpoint. But if you look at the right-hand side, you see that 76.7% of patients on obinutuzumab achieved this endpoint whereas in the placebo group, a little over 53% achieved this endpoint, accounting for a treatment difference of 23 percentage points. How does 76.7% compare to other studies? It's the highest we've ever seen. And I must say I can editorialize now when I saw those numbers, my first word was wow. Next slide. Let's go through the secondary endpoints. There were 5 key secondary endpoints that are listed on the left. The short of it is that every single endpoint and we've never seen this. Every single key secondary endpoint hit statistical significance with treatment differences ranging from about 22 percentage points up to about 30 percentage points. But let me just run through them since I do have some time to explain them. BICLA is our other regulatory endpoint and you can see about a 22 percentage treatment difference there. Glucocorticoid reduction to 7.5 milligrams or less that was sustained for the last 12 weeks of the study. I emphasize the importance of steroid reduction, also significant. The SRI-4 at week 40 sustained, so that not only speaks to efficacy, it speaks to durability. Now you might counter or people counter, but we know anti-CD20s can improve complement, they can improve DNA antibodies. And if you normalize both of those, you lose 4 points off your SLEDAI. So was it just about complement and anti-DNA antibody? No, because if you look at the next 1 down, SRI-6 requires a 6-point reduction. So now you have to introduce clinical improvement as well. And then the last one, time to first BILAG flare. I mean the name of the game in lupus is to prevent damage. And where does damage arise? The damage arises from flares, from activity. So it's very important for a drug to be able to reduce flare rates. And there's a whole slide dedicated to that, that I'll show you. And we talked a little bit about additional secondary endpoints. These are not in the testing hierarchy, but I have a slide, and we'll go through DORIS and LLDAS in just a couple of slides. So next slide. Time to first BILAG flare and that BILAG flare is defined as Ia or IIb that arises. And this, again, is very important. And you can see a hazard ratio of 0.58, which translates into 42% risk reduction of flare. And again, I can't tell you how important flares are because that's how patients accrue damage. And for each 1 point, we're not going to go through the SDI damage index, but for each 1 point increase in damage, there's about a 30% increase in mortality risk. So damage is very important. Next slide. SLEDAI scores over time. So the main driver of SRI response is a reduction in SLEDAI. SRI-4 means a 4-point reduction. And this just gives you an idea of the kinetics of response. Sustained reduction in SLEDAI occurred about week 24, but you see there are certainly some separation even before week 24. Next slide. All right. DORIS and LLDAS. So what are they other than cute names? Well, when patients not even that long ago, 6 or 7 years ago, asked me, "Doctor, am I in remission?" I said, we don't really use that word in lupus. We talk about maybe control of disease. But now we use that word. And so DORIS remission has a definition. It's pretty stringent. And you can see that about 35% of the patients who received obinutuzumab achieved DORIS remission by week -- or at week 52 compared to about 14% on placebo. That's -- I can tell you that, that's a very high number, 35%. It's a very stringent definition. LLDAS, lupus low disease activity state, achieved by a little over 57% in the obinutuzumab group versus 25% in the placebo group. LLDAS is not as stringent as DORIS And it may be worthwhile just taking a couple of moments to talk about, well, how is DORIS and LLDAS. How are they different than SRI or BICLA? So SRI is improvement in activity by, as I mentioned, 4 points, whereas DORIS and LLDAS are absolute, you have to hit a particular state. And the state that of relative well-being is associated with a lot of benefits. Reduction in mortality, a reduction in damage accrual, less health care utilization and the list goes on and on. So to clinicians, DORIS and LLDAS are far more important in practice than say to SRI and BICLA. I mean, they're all important, but DORIS and LLDAS really do stand out. Next slide. B-cell depletion in peripheral blood. An interesting slide that compares the degree of B-cell depletion in this particular study to what we've seen in the EXPLORER study, EXPLORER, we did many years ago. It was a comparison of rituximab to placebo on background therapy. In this particular slide, dark blue are the obinutuzumab-treated patients and gray represents the rituximab-treated patients. And every single pair shows that more patients are achieving a threshold of B-cell depletion, which was 10 cells per microliter with obinutuzumab than with rituximab. So not only a greater percentage depletion across those patients, but it would seem to be more sustained. But this doesn't tell the whole story. We need to know what's going on in the tissues and now that wasn't evaluated in this particular study, it was evaluated in the lupus nephritis regency trial and the data were quite impressive that we were achieving deep B-cell depletion in the tissue of kidneys from patients with lupus nephritis. All right, next slide. What about safety? So there were a total of 4 deaths during the first 52 weeks, one in the obinutuzumab group, 3 in the placebo group. And I could spend a lot of time going through this, but let me just kind of shorten it, and we'll go through some of the bold items. Infections were, in fact, more common in the obinutuzumab group than in the placebo group. So we've kind of seen mixed results across the 3 studies. If you go back to the NOBILITY lupus nephritis trial, there are actually more infections in the placebo arm. The REGENCY was the opposite and here we did, in fact, see more manageable infections like urinary tract infections, respiratory infections, pneumonia. So more common, but very manageable. We can jump down to infusion-related reactions, more common with obinutuzumab, but these are like nausea and headache and lastly, drug-related neutropenia. What we've been finding with basically, any strategy to deplete B-cells is that patients, and we don't quite understand why can't become neutropenic, there were slightly more patients in the OB group that developed neutropenia than in the placebo arm. And let's go to the next slide, which is the last slide. I'm not going to belabor all these conclusions because I just went through them. But the most important one is at the bottom. This was a very active cohort of patients. So to be able to achieve a relatively high rate of DORIS remission to show that the drug is steroid sparing and that it reduces flares. This is what is so important to the clinicians and also to the patients. Next slide. So I did want to thank all the study participants, not only in this study, but this has been a journey that started about 20 years ago with the rituximab studies, the ocrelizumab studies in lupus, and we really do owe it to the study participants to their families and the study investigators get a little credit and their staff. And this was -- simultaneously appeared online at 1:45 Lisbon time on what was it, Friday, so you can look at the article. It has a little more information than what I just went through. And that's it for me.

[Operator Instructions] The first questions go to Simon Baker from Redburn.

A couple of questions. Firstly, Dr. Furie, looking at the subgroup analysis by SRI-4 scores, it looks like a very consistent result across the piece. So 2 questions. Firstly, are there patients where you would not consider using this. And secondly, the one area where there seemed to be an enhanced performance was in people of Hispanic or Latino ethnicity. I just wondered if you had any thoughts on why that was? And then probably a question for Jay. On cell therapy, there's been a lot of activity in the broader autoimmune CAR T space. Just intrigued to see why you're going straight for allogeneic rather than autologous. Is that -- any specific reasons? Or is this really about scalability of the opportunity that allogeneic gives you? Any thoughts? Much appreciated.

All right. So first question, who would I not use it on? Well, there's still a lot of data that we need to see. I mean lupus is not 1 disease. Lupus is about 1,000 diseases. And we treat by interviewing the patient, I mean, we're so old fashioned in rheumatology. So we interview, we examine and we look at labs. And some of the major manifestations of SLE are skin rash and arthritis. I haven't seen the domain-specific data for OB just yet, nor the kinetics of domain-specific responses. But I must say Anifrolumab works very well for skin. It works very quickly. So in all honesty, I think it's going to be hard to compete with Anifrolumab in patients with very active skin disease. But again, that's without seeing the OB data. Other than that, patients who are serologically active with arthritis, patients who have a little bit of nephritis and patients who have a lot of nephritis, they'll get obinutuzumab. So I can't really think of contraindications to giving someone obinutuzumab. Plus it's very convenient to infusions, and we have a problem with noncompliance and nonadherence. Patients don't take their pills. And so to be able to have them come in for an infusion and the infusion duration will be decreasing and then just have them come back 6 months later. Now it's hard to beat that. You asked about ethnicity. Well, you asked about subgroup analyses. So I have such mixed feelings about subgroup analyses because they're hypothesis generating. And if you took them at face value, you probably won't use a lot of these drugs, belimumab, Anifrolumab or obinutuzumab in certain groups. So I can't really explain why the differences. It certainly would be interesting to find out. But again, I think, we just have to think about mechanisms, but not take them at face value.

I'll answer the question, maybe Bruno, you can chime in as well. So it's a good question around allogeneic versus autologous. And if you remember the first slide of what we're trying to achieve for both patients and the health care system. An allogeneic off-the-shelf therapy if we can -- if it does demonstrate the efficacy, we are expected to see with autologous or what we have seen that would be just from a convenience or accessibility, more so a factor that it would seem like it would trump the autologous. So that's our main goal. And the data that we've seen with the allogeneic suggests that this is something that we might be able to achieve.

Next question would go to Luisa Hector from Berenberg. Luisa dropped off for some reason. Let's quickly then continue with Graham Parry.

So two on Gazyva, and then I've got 2 on persevERA that we just been it would be good to address. So on Gazyva, just thoughts on commercialization with an IV administration only given there is a subcut BENLYSTA. I think it's about half of patients actually get that. And AstraZeneca has obviously refiled now its subcut formulation there. So is there an advantage to subcutaneous administration? And perhaps Dr. Furie can actually chime in on that one as well. And then secondly, do you expect to see the remission data on label, the DORIS remission data on label, given again, Dr. Furie indicating the importance of that? And then just the 2 on persevERA, the question we've been getting all day was just was that missed due to powering. So did you beat the target 0.85 hazard ratio just missed on [indiscernible]. So trial -- powering the trial was fine? Or do you just see a smaller effect size with a 0.85 hazard ratio? And do you have a sense of whether that fail was due to not enough naive patients in the study that were endocrine sensitive? Or does this validate the theory that CDK4/6s negate the advantage of an oral [indiscernible] in combination?

Okay. Maybe I'll do this in between oncology question first, Graham. It's the big topic of the day. So yes, what we've seen -- we had powered when we were looking for getting a hazard ratio of 0.85 and the effect size was below. We have indicated in the press release, there was a numerical benefit. There is, I think, no more I can say right now at this point, but I think let me also remind you that there was a limited number of ESR1-mutated patients in this study, so around 5%. So as said, there was a bit of a benefit seen. Does it -- what does it mean in terms of CDK4/6 combination development? I think we have indicated in the press release that we believe that there still is a viable path forward in the adjuvant setting. And we -- I would not agree -- what you have asked me basically, does this mean that there is no additional benefit to be gained in combining giredestrant with CDK4/6? Is no, I would not draw this conclusion from the data we have seen. And did I miss anything on your -- what else, Graham?

No, I think you covered there. Thanks, Bruno.

Okay. Then let's go back to Gazyva.

I've forgotten the questions. I guess the first one was subcu versus IV. Is that right?

Yes, exactly. So it's just the importance of -- potential importance of having a subcu just given I think it's about half of the BENLYSTA patients subcu and AstraZeneca filed for an indication because it has only got IV. And so if you could just talk through the dynamics of that would be great.

Yes. So I'm spoiled. We have an infusion unit. It's about 50 feet from where I'm sitting right now. So we can offer it either. And it's kind of open discussion, shared decision-making as they say. But IV every 6 months, I think, is pretty easy, and it guarantees that the patient gets the drug. I don't know about adherence and compliance to subcu. But I could say advantages to -- I mean I can argue both sides for this. So I don't really have a definitive answer for you. It's more about how effective the drug is and what the -- I mean that's -- and then we have other variables. We had to deal with insurance companies and what they're telling us, how to give it and then resources as well.

And maybe I can take the remission question because this is something we'll discuss, right, with health authorities. I do think just based off of what Rich was saying, the importance of remission to physicians and to patients and in the guidelines seem to be something that should be shared, right, in the label. So -- but that's a discussion we'll have health authorities. So it is not Type 1 error control. So it wasn't of the key endpoints, but it is -- it was prespecified.

Yes, I was just thinking of one question, which came here in the chat from Michael Leuchten from Jefferies, maybe also to access and the question is about would you expect that there would be a step through, BENLYSTA first and then Gazyva. Or how would you expect this to develop?

Well, we can distinguish a lupus nephritis from SLE. I'll start with lupus nephritis. No, I don't see any step through at all there. And for SLE, I don't see that either unless it's dictated to us by insurance companies. But clinicians will want to use obinutuzumab upfront without having to fail other drugs.

Next one is James Quigley from Goldman Sachs.

My question, I've got 2, please. So firstly, maybe for Dr. Furie. So as you think about your typical lupus population given the inclusion criteria and activity levels, what proportion of your SLE population would this trial represent? And similarly, when you think back to other studies, many of which have failed in the past. Did you see any differential benefits between the higher risk groups in the SLEDAI versus the lower risk group. It doesn't seem to be the case here, but the cutoff used in the subgroup analysis in the New England Journal was greater than or less than 12. So interested to see if you see any differences there with other trials, which maybe had lower activity, including criteria? And secondly, for Roche on the bispecifics, you've got one targeting Lunsumio, CD20, you also got CD19. So what are your expectations here for differential B-cell depletion and then also the -- why you got different approaches for each of those assets? And what are your expectations of differentiation between Gazyva, Lunsumio and then your CD19, CD3?

Okay. Let me see if I remember the question. So the first question was what percentage of, say, my cohort here in practice? Has that kind of SLEDAI, you mean a SLEDAI of 13?

Yes, yes.

Very few unless they have lupus nephritis. But that's one of the problems with SLEDAI. It doesn't tell the whole story. You could have someone with terrible, terrible arthritis or terrible, terrible rash. So the arthritis patient picks up 4 points and the rash patient picks up 2 points. You might want to use this drug in those patients, even though they don't have the entry criteria that ALLEGORY had. So sometimes they're held to this by insurance companies, for example, with belimumab. They go, well, the patient -- in order for you to get belimumab approved, the patient has to have a SLEDAI of 6. And then we argue back, that was for the studies. We're talking about practice. So not everybody that we see has low complement. That was part of the criteria to get a high disease activity group. Anyway, so there's discordance between what we actually can see in practice and call severe versus what is severe in a study. I hope that kind of gets to your question. Then you had one about studies with lower disease activity.

Yes. So did you see differential efficacy between the lower disease activity groups and the higher disease activity groups in other trials or maybe the entry criteria was for lower disease activity. Did you see the -- do you see benefits in the higher disease subgroup of those trials?

Well, this trial, as I recall, I mean, you can look at the subgroup analysis in the New England Journal, but as I recall SLEDAI. So the partitioning threshold was -- for entry was a SLEDAI of 12. And as I recall, those above 12 and those less than 12, performed about the same. I mean I have to go back and look at the paper, but that's how I recall it. For other trials, with average SLEDAI, I say, 10 to 11, I have a lot of data swirling in my head. I'd have to go back and look. But so look at the subgroup analysis for this study, I think your question will get answered. Jay, help me out.

No, you're right about our data. I don't know the other data as well. So just a question on our T-cell bispecifics. So it's a good question. So we don't know what the best target antigen is in all honesty. So we know that targeting CD20 works as we've demonstrated with Gazyva. Are the hypothesis we're testing with Lunsumio is whether greater B-cell depletion targeting CD20 will get you great efficacy? So we have preclinical data head-to-head showing that a CD20-CD3 is superior to a monoclonal antibody targeting CD20 in terms of tissue B-cell depletion. So that's the question here that we're trying to answer with Lunsumio. Again, it's approved. We know what the safety profile is. We have some initial data on lupus. So we feel interested in understanding what it can do. But the question around CD19, CD3 is a different target antigen that has a broader B-cell expression profile So this was the data that Georg Schett has presented with this CAR T CD19. It does hit some plasma cells that a CD20 might not hit. So that's a question of what can that do? Can it actually induce some more remission-like profile than what you could get with CD20, CD3. So we're testing kind of 2 separate hypotheses there and understanding what each of these can do. I hope that answers your question.

Next one is Luisa Hector from Berenberg.

I'd love to hear from Dr. Furie. Just thoughts on why the patients are still flaring, what is the biology and how we might eventually get better control on that. Does it link to simply the B-cell suppression or that alone is not enough? And in the New England paper, there was some commentary around the response rate to some extent being attributed to modern refinements in trial design. So I'm curious to know what that is. And does that mean the older drugs run with the same refinements would also look better perhaps?

You all ask difficult questions. So for the flare, I don't have an answer for you, but that's something that will be analyzed. I mean -- you have to -- you could look at the definitions in BILAG. You can go through what Ia means and b means. But I don't have an answer for you for these data, but hopefully, we will soon. All right. The modern refinements is actually very interesting. I mean lupus is one of the hardest diseases to study. I mean, we go back to the belimumab Phase II, that's where we learned our lesson. Not all the patients were serologically active. So each study thereafter, patients had to be serologically active. And then we learned something more than that in the next study and the next study. So we have made major refinements that I think allow us to say that our patients who were enrolled in the study probably truly do have lupus and that the their activity indices are not overinflated. And then there are some other things that we've added like steroid taper and so forth. So it's a very interesting question. I mean, if we were -- if we went back and studied rituximab again, would we see better results? I don't have an answer, and we're not going to do it.

So Rich, I just want to chime in because the argument I would make because one, you participated in EXPLORER. So you know that was unfortunately, pretty negative, where we missed all primary and secondary endpoints. I think the question here, especially with the low complement population where Rituxan actually depends on more complement-dependent cytotoxicity. We have this type 2 confirmation, which deals with -- or depends less on complement-dependent cytotoxicity. I think in this particular population, it might be hard to say. You may have seen something in some patients with Rituxan. The question is, would you have seen what we're seeing with Gazyva? I don't know. But it seems less likely.

But it is very possible that we had successful drugs or "successful drugs" in the past, but the study design didn't allow us to see that.

Could I just ask then, so I get more excited to see drugs with even deeper B-cell depletion or perhaps new mechanisms or combinations, like combinations for the patients might get more -- or raise the efficacy bar more than the B-cell depletion?

Well, that's a good question. So yes, if you go back to the EXPLORER and the LUNAR trials, the message there seemed to be more B-cell depletion is needed. So that came from some observational studies up in Leeds by Ed Vital in lupus and in RA and then post hoc analysis of the LUNAR trial, anyway, there was a lot of evidence accumulating that more is better. So how do you achieve that? Well, there were a series of studies done with sequential belimumab and rituximab. And there were 2 strategies behind them. When we did the Phase I study with belimumab and by gosh, we're going back over 20 years. What we saw was actually an increase in memory B-cells after the delivery of belimumab. And so some of those combination sequential studies were based upon giving belimumab first to mobilize these B-cells come in with rituximab to get better B-cell depletion. There was yet another strategy that was employed to justify the sequential belimumab-rituximab studies. And that was when you wipe out B-cells, and it doesn't matter how you do it, rituximab, obinutuzumab, cyclophosphamide, you still have a lot of BLyS or BAFF being made, but it has nowhere to bind. But as the B-cells return, it's now a high BAFF environment, which may lead to a lot of autoreactive B-cells. But those studies were done. And they were done in SLE. They were done in lupus nephritis and nothing sort of very major. I mean there's a little bit of pharmacodynamic benefit. I think the last one, I forgot what it was called BLyS, B lupus or something...

Believe or...

No, it's less believe, but the one after that done by the fellows in London, I think that was -- had a lower -- saw a lower flare rate. So when I lecture about this, I do talk about those 4 studies, but then I say I introduced obinutuzumab. And you have B-cell depletion data. You have at least 2 studies that I know about. There was one that the folks at Genentech conducted in patients undergoing kidney transplant who had received obinutuzumab because they had been previously sensitized. Not lupus nephritis just -- and as I recall like some 20-some-odd patients, only 2 patients had -- or 2 to 3 patients had B-cells in their lymph nodes that they harvested at the time of kidney transplant. And then you have the 64 patients in the REGENCY lupus nephritis trial who underwent second biopsies. And they are very impressive data, and you really should take a look. They were presented at ACR, ASN and then again in Lisbon last week.

And we got the final person in the queue, this is Steve Scala from Cowen.

Three short questions. First, doctor, given the strength of these data, will you switch your BENLYSTA patients to Gazyva. Secondly, should the oral products be successful in Phase III, such as RINVOQ and Sotyktu. How will they fit into the treatment scheme? And then lastly, for Bruno, could you tell us if the persevERA trial showed an OS trend?

Tough, very unanswerable questions. Will I switch a beilimumab patient who is doing well? No. Will I switch a beilimumab patient who is not doing well? Absolutely. You asked about how will the orals affect. I mean it's a problem. We're sort of entering the same kind of dilemma that rheumatoid arthritis group has had. We were yearning for all these new drugs, and now we have them, we need to know which drug, which patients. So it's going to be dictated by -- I don't think it's going to be dictated by comparing SRI and BICLA responses. I think we'll want to see domain responses. We'll think about safety. We need some kind of way to predict who's going to respond to what? And then on top of that, we have insurance companies who are going to tell us what the high -- at least in the United States, what the hierarchy will be. So I really don't have an answer for you. And then we have the patients who are prescribed pills and don't take them. That's a big problem. So with hydroxychloroquine, we've had available hydroxychloroquine blood levels in the United States for a lot of years. I can't tell you how many patients. It's like Nathalie Costedoat told us years ago. Patients don't take their hydroxychloroquine. So if they're not taking their hydroxychloroquine, they're probably not taking all their mycophenolate or their deucravacitinib or their upadacitinib and you can go down the list. So there's something to be said for a parenterally-administered drug.

Doctor, in response to your answer, could you tell us what percent of your BENLYSTA patients are not doing well. And Bruno, if you could answer the persevERA question, that would be helpful.

Unfortunately, I have to tell you, I also have no answer for you, Steve. So you're going to have to wait for the data presentation that we plan to have the data at ASCO.

I don't have data for you. I would say maybe 30%, 40%. I mean, with BENLYSTA, you have to be very patient and tell the patient that as well. So I won't declare someone a failure until they've been on at least 6 months and up to 12 months. But yes, I should probably take a look at our switch numbers.

Very good. I think with that, we are at the end of today's event. I would like to thank again all of our speakers for their time and also their efforts in exploring here new treatment options for patients with severe autoimmune diseases. Let me also thank the IR team members who prepared today's event after call out here, Julia Brauer and Sabine Borngraber and also Melanie Wolf for event organization. I hope the event was helpful to provide a timely update here on our immunology franchise. The next event, which we plan now will be for fenebrutinib, the FENhance 1 and 2 data in RMS, which will be presented at AAN mid of April. We'll send out the invite as soon as we have a date fixed. And with that, I think, if there are any remaining questions, then please reach out to the IR team. We are always happy to assist you and follow up.