Roche Holding AG (ROG) Earnings Call Transcript & Summary

[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 a pleasure to introduce you to Bruno Eschli, Head of Investors Relations. Bruno, the stage is yours.

Thanks Henrik. So welcome to our fourth IR call in 2024, this time focusing on our hematology franchise. And thanks also for your interest in Roche despite doing this call here on a Sunday. Could I have the first slide please? So let me -- I'm so sorry, please go back to the agenda part. Yes. So let me quickly take you through today's agenda. The event is scheduled for 1 hour. We will have probably around 40 minutes for the presentations and then followed by 20 minutes of Q&A. Following my quick introduction, we are very pleased to have today with us Dr. Jeremy Abramson. Dr. Abramson is the Director of the Lymphoma Program at the Jon and Jo Ann Hagler Chair in Lymphoma at the Massachusetts General Hospital Cancer Center, and he's also an Associate Professor of Medicine at Harvard Medical School. Dr. Abramson is the lead investigator for the Phase III STARGLO study and presented yesterday the results in the plenary session. He will take us today again through the data and will also join us for the Q&A session. The second presenter of the day then will be Bill Waas, our Lifecycle Leader for the NHL bispecific program. This includes Columvi and Lunsumio, who's also responsible for global product strategy. Bill will quickly summarize the NHL development program and providing us also an update on the next steps. And the last speaker of today then will be Daud Chaudry, our Lifecycle Leader for the hemophilia bispecifics program, and he is also responsible for global product strategy. Daud will talk about -- sum up our Hemlibra data and also give us some further details on next development steps for the program. For the Q&A, we will be joined by -- in addition by Charlie Fuchs, our Senior Vice President, Global Head of Oncology and Hematology, Product Development; by Peter Ahnesorg, our Franchise Head, Hematology Global Product Strategy; and Michelle Boyer, our Group Clinical Science Director for Hematology. Could I please have the next slide, please? This slide is just to summarize our current on-market hematology portfolio. In Q1, this hematology portfolio was growing by plus 12% and reached sales of CHF 1.8 billion. So growth remains driven by Hemlibra where we expect continued growth in coming years in actually all regions and by Polivy in first-line DLBCL. And then, of course, by our CD20, CD3 bispecifics, which just have launched in third line plus DLBCL and follicular lymphoma. And there is also growth coming from Venclexta, which is not shown here, as you know, as sales are recorded by our partner AbbVie. Have the next slide, please? This slide summarizes, I think, our broad hematology pipeline. Broad in terms, I would say, of drug modalities, but also the MoAs, which we target, which really sets up well to develop additional new drug combinations. And just to provide here a quick update on additional pivotal Phase III readouts for 2024, the Phase III STARGLO data is what we discuss today. There is a second DLBCL study in second line, which is called SUNMO which tests Polivy and Lunsumio. This readout has shifted from 2024 to '25 as this trial is event driven. And then last but not least, in 2024, we still expect Phase III data for Venclexta in first-line MDS, which could be an opportunity of up to CHF 1 billion. Can I have the next slide, please? I felt this slide might be helpful to quickly comment on our hematology franchise with regards to consensus expectations. So what you see here on the left side is that growth has accelerated as the Rituxan erosion is now more or less behind us, with growth really being driven, at that point in time, by Hemlibra and Polivy. And on the right side, you see the consensus expectations for '24 and up to '27. And let me make a few comments here. For Hemlibra, consensus expects peak sales of CHF 5.5 billion. I would say this is a number we feel pretty comfortable with. And we also expect that bispecifics as a class will keep growing beyond the 40% market share, which we have today achieved in the U.S. and in EU5. For Polivy, you see here, we indicated up to CHF 2 billion for the first-line DLBCL opportunity. I think this is what is more or less captured in the consensus. And then if we have a look at the bispecifics at 2027, we always mentioned the third line plus opportunities in NHL. They are together a couple of hundred million only. But of course, if we would move successfully into the second line, the bispecifics would have an opportunity of up to CHF 2 billion. And then, of course, if we would be able to move them into a first-line setting, the opportunity would even become significantly bigger. Can I have the next slide, please? Yes. We keep it short. Just the next IR events to come up. On July 23, we will have an IR call related to ASRS, where we will provide an update for -- we'll touch on Vabysmo data, longer-term follow-up in DME, but also provide you a bit of an update on the ophthalmology franchise. Then as you know, for end of September, we have scheduled the Pharma Day. I expect we will have additional events to come in the second half linked to data, which we will -- which we want to share at medical conferences. And we also are currently considering whether we would do again another digital day probably in November. And with that, let me hand over to Dr. Abramson to take us for the STARGLO data. Dr. Abramson, please.

Well, thank you very much. I'm really privileged to be able to share with you this important data that was presented at the plenary session yesterday at the European Hematology Association. These data are from the STARGLO trial, a randomized Phase III trial, evaluating the addition of glofitamab to gemcitabine and oxaliplatin for patients with relapsed/refractory diffuse large B-cell lymphoma. Next slide, please. These are my disclosures. Next slide. So as you all well know, glofitamab is a bispecific antibody targeting CD20 and CD3, designed to bind to malignant B-cells and directly engage a patient's T-cells to facilitate cell-mediated cytotoxicity. glofitamab was initially studied in a Phase I/II pivotal trial in patients with relapsed/refractory DLBCL after 2 or more prior lines of therapy and led to deep and durable rates of complete remission, which resulted in regulatory approval as a monotherapy in that population. Today, I'll share with you the STARGLO results evaluating glofitamab, gemcitabine-oxaliplatin versus rituximab, gemcitabine-oxaliplatin in patients with the relapsed/refractory DLBCL after one or more prior lines of therapy. Next slide. STARGLO is a global randomized Phase III trial conducted across 13 countries and 4 continents. Eligible patients had relapsed/refractory diffuse large B-cell lymphoma, not otherwise specified. After one or more prior lines of systemic therapy, patients who'd received just one prior line of therapy had to be considered transplant ineligible. 274 patients were randomized 2:1 to receive glofitamab, GemOx or R-GemOx. Randomization was stratified based on relapse versus refractory disease, and 1 or 2 or more prior lines of therapy. Glofitamab, GemOx and R-GemOx were each administered for 8 to 21-day cycles. On the glofitamab, GemOx arm, patients received 4 additional cycles of glofitamab monotherapy to complete 12 total cycles. Next slide. The primary endpoint was overall survival. Key secondary endpoints were progression-free survival, complete response rate and duration of complete response. The prespecified event-driven interim analysis was triggered at 11.3 months of median overall survival follow-up. By that time, however, not all patients had completed study therapy and so an updated analysis was performed with 10 additional months of median overall survival follow-up, at which time, all patients had completed study therapy. Next slide. Baseline characteristics were generally well balanced across both study arms. The median age was 68 years old. You can see here that 63% of patients had 1 prior line of therapy and 37% had received 2 or more prior lines of therapy. The majority of patients had primary refractory disease, and approximately 60% of both -- patients on both arms were refractory to their immediate prior line of therapy. Prior CAR T-cell therapy had been received in 9% and 7% of patients on R-GemOx and Glofit-GemOx, respectively. Next slide. Here, we see analysis for the primary endpoint showing a statistically significant overall survival benefit favoring glofitamab GemOx. At the primary analysis, the hazard ratio was 0.59, representing a 41% reduction in risk of death. At the updated analysis, with a median follow-up time of 21 months, the median overall survival was 12.9 months on R-GemOx and 25.5 months on glofitamab-GemOx. Next slide. Progression-free survival also favored glofitamab-GemOx with a hazard ratio of 0.37, correlating with a 63% reduction in risk of progression or death with glofitamab-GemOx with a highly statistically significant p-value. At a median follow-up of 16 months, the median progression-free survival was 3.6 months on R-GemOx and 13.8 months on glofitamab-GemOx. Next slide. Overall, complete response rates also favored glofitamab-GemOx. You see that the complete response rate was 58.5% on Glofit-GemOx compared to 25.3% on R-GemOx. Next slide. We did conduct an exploratory analysis of overall survival in prespecified subgroups. And this forest plot shows that results are directionally consistent in favor of glofitamab-GemOx in the majority of clinically relevant subgroups. That includes patients with 1 or 2 or more prior lines of therapy, patients with relapsed or refractory disease, IPI score and cell of origin. We did identify regional inconsistencies, particularly in the United States and Europe. However, interpretation of these subgroups is severely limited by very small patient numbers and extremely wide confidence intervals. Based on this observation, however, we did perform a multivariable analysis, including treatment arm, geographic region, as well as all clinically relevant covariants and found no association between region and overall survival. We did, however, on that analysis confirm the statistically significant overall survival benefit for Glofit-GemOx with a hazard ratio of 0.65. Next slide. Not unsurprisingly, with the addition of glofitamab, we did see an increase in serious adverse events. The excess serious adverse events on Glofit-GemOx largely reflected the expected toxicity profile of glofitamab, particularly cytokine release syndrome, cytopenias and infections. You will see here that there was a higher incidence of fatal adverse events on the Glofit-GemOx arm at 8.3% compared to 4.5% on R-GemOx, a difference largely driven by COVID-19. Next slide. Cytokine release syndrome occurred in 44% of patients on glofitamab-GemOx and was almost entirely low grade and occurred predominantly during the first cycle of step-up dosing. Among 76 patients who experienced cytokine release syndrome, tocilizumab and corticosteroids were employed in 37% and 51% of patients, respectively. Cytokine release syndrome was generally manageable and reversible. Next slide. Looking at other adverse events of special interest. We saw neurologic events common in both arms and slightly more common in Glofit-GemOx. Most common neurologic adverse event in both arms was peripheral sensory neuropathy related to oxaliplatin. Most of these events were low grade. We did see 4 cases of ICANS correlated to 2% on the Glofit-GemOx arm. Only 1 case was Grade 3 delirium. There were no grade 4 or 5 neurologic events and all ICANS events were completely reversible. We saw an increased rate of infections on Glofit-GemOx with severe infections 23% compared to 12.5%, respectively. Neutropenia was more common as well. But febrile neutropenia was rare in both arms at 1% and 3%, respectively. I will point out regarding adverse events in general, that there was a much higher exposure to study treatment on the Glofit-GemOx arm compared to R-GemOx. Specifically, patients on R-GemOx received a median of only 4 cycles of study therapy, and that was predominantly due to progression of disease on treatment, whereas Glofit-GemOx patients had a median of 11 cycles of study therapy. That much longer exposure to treatment, of course, means those patients are more susceptible to cumulative toxicities as well as immune suppression. Next slide. This study obviously was conducted amid the rapidly evolving landscape of the early COVID-19 pandemic. We did see an increased rate of COVID-related adverse events on the Glofit-GemOx arm at 18% compared to 9% on R-GemOx. Severe COVID-related AEs were 6% and 2%, respectively. We observed 7 cases of fatal COVID-19 related adverse events. All 7 cases were on the Glofit-GemOx arm. None of those 7 cases had received the antiviral therapy, PAXLOVID. Because of this finding of COVID-19 more common in the Glofit-GemOx arm, the study was modified during conduct of the treatment to require COVID-19 testing in all patients immediately prior to study enrollment. Furthermore, during the conduct of the study, any patients testing positive for COVID-19 would have to be immediately removed from study treatment. That requirement to discontinue study treatment for patients with any positive COVID test is reflected in the higher rate of treatment discontinuation due to adverse events on the Glofit-GemOx arm. Next slide. So I'll conclude presenting this exciting data to you today by saying that fixed duration, glofitamab added to GemOx demonstrated a significantly superior overall survival benefit in patients with relapsed/refractory DLBCL who are ineligible for autologous transplant. The median overall survival was 25.5 months for Glofit-GemOx compared to 12.9 months on R-GemOx. Glofit-GemOx also improved other secondary endpoints, including a more than tripling of median progression-free survival and a more than doubling of the rate of complete remission. Glofit-GemOx was tolerable. All adverse events were consistent with the known risks of the study drugs and were highly manageable. CRS in particular, occurred in a minority of treated patients, occurred primarily during cycle 1 and was mostly low grade. Glofitamab is therefore the first CD20, CD3 bispecific antibody to demonstrate an overall survival benefit in DLBCL in a randomized Phase III trial. We believe these results support the use of glofitamab-GemOx for the treatment of relapsed/refractory diffuse large B-cell lymphoma. Next slide. Of course, I most importantly, want to thank patients, their families, their loved ones. I am here representing all participating investigators as well as the hard-working study teams who do all the work at all participating centers across the globe. The sponsor, of course, Roche, and thank you, and I look forward to answering any questions in the Q&A session.

Great. Thank you, Dr. Abramson for the excellent presentation. I'm Bill Waas, Lifecycle leader for the CD20, CD3 bispecific subprogram of Roche, and I'm pleased to provide an update on the Roche lymphoma program. Next slide, please. As you're aware, Roche has a long-standing legacy of innovation in the field of lymphoma spanning over 25 years. During this time, significant progress has been made. And today, the majority of patients with diseases by DLBCL and FL benefit from Roche's early innovation in products. We remain highly committed to further advancing the standard of care, with core ambitions in the space that include increasing cure rates in DLBCL and delivering long-term remissions in follicular lymphoma. Recognizing the significant heterogeneity of lymphomas and the unique clinical situations faced by patients, our vision is centered around providing flexible solutions tailored to their specific needs. And this is why we continue to invest in the development of novel approaches and modalities across the lymphoma space. Next slide, please. Amongst Roche's newest innovations are the CD20, CD3 bispecifics, Lunsumio and Columvi, which are now approved in over 50 countries worldwide. Both are enjoying strong uptake in their respective late-line indications, achieving double-digit patient share in key markets. Looking beyond these initial indications, we have a broad and industry-leading clinical development program, which we expect to deliver continued patient impact and growth for years to come. Lunsumio's clinical development is currently targeted to indolent forms of NHL and populations that may not be suitable for traditional chemotherapy. This includes ongoing studies in a variety of FL population, but also extends to CLL and selected relapsed/refractory studies DLBCL segments. We're supporting 3 ongoing Phase III studies with Lunsumio, including SUNMO in relapsed/refractory DLBCL, CELESTIMO in second line FL and Morning light (sic) [ MorningSun ], a frontline FL study in collaboration with the Lifestar Group. Columvi clinical development is targeted to aggressive lymphoma, and this includes different lines of DLBCL and relapsed/refractory mantle cell lymphoma, where we just received breakthrough designation for monotherapy. So our program includes a broad set of studies, but they all share a common feature, which is fixed treatment duration. Long-term follow-up data from our early pivotal studies continue to show that long-lasting remissions can be achieved with finite treatment. And we believe that this will translate into extended treatment-free intervals for patients, reduced burden to the health care system and differentiation from in-class competition. Next slide. Now shifting our focus to relapsed refractory DLBCL, you've had the opportunity to see the STARGLO study. And this is the first positive randomized Phase III study for this class, which has shown a compelling overall survival benefit in transplant noneligible patients, which represents up to 50% of second-line patients. It's important to note that this is an area of high unmet need where the disease progresses rapidly and there are a few treatment options. As an off-the-shelf therapy designed to deliver best-in-class efficacy, Columvi in combination with GemOx has much to offer in this setting. We're quite excited about the regimen and the external feedback coming out of EHA and are actively engaging health authorities with the aim of making it available to patients as soon as possible. Next slide, please. In addition to STARGLO, we have SUNMO, a Phase III study of subcutaneous Lunsumio and Polivy, which is also being developed in transplant noneligible DLBCL. The SUNMO regimen is clearly differentiated from that of STARGLO as a subcutaneous chemo-free option that has been exclusively studied in the outpatient setting. We expect these features to be attractive to patients that cannot tolerate or do not want traditional chemotherapy, as well as community-based practices, which treat a large proportion of DLBCL in key markets like the U.S. We do expect some overlap between the STARGLO and SUNMO-eligible populations [Audio Gap] complimentary local rules and potentially [indiscernible]. Based on our current event projections, SUNMO of will read out in 2025. In the meantime, we remain encouraged [indiscernible] ASCO and EHA meetings. Next slide, please. Moving on to our frontline program. It's important to highlight that our ultimate ambition is to cure more patients in this setting. As you're aware, our latest approval stems from POLARIX, our broad frontline study which showcases significant improvement in progression-free survival for Pola-R-CHP or Pola-R-CHOP. The data and subsequent approval marked the first major advancement in frontline in decades and the POLARIX regimen has seen consistent uptake since launch with patient shares of nearly 25% in the U.S. and more than 45% in Japan. It's now become part of the global guidelines of 18 countries and continues to change the standard of care in many other regions. Looking ahead, we aim to share a comprehensive 5-year follow-up analysis later this year, which will provide further insights into the long-term efficacy and impact of this treatment. Next slide. While we're excited about the progress achieved through POLARIX, we firmly believe that there's still more work to do in frontline. To this end, we've invested in the Phase III SKYGLO study combining Columvi with the POLARIX backbone. Our early clinical data with this combination have been very encouraging with complete response rates exceeding 90%. And notably, this was achieved with a relatively low incidence of cytokine release syndrome due to our frontline protocol at about 11% with no Grade 3 or greater. This has allowed out-patient administration in the Phase III study and could potentially support a full outpatient label in the future. The SKYGLO study is currently underway and enrollment is progressing really well, thanks to the availability of the Pola-R-CHP background in both study arms. We eagerly anticipate the outcomes of the study, but we'll need to wait a few years for the primary endpoints to mature. So that concludes my update and I hope this was helpful for [indiscernible] NHL program ambitions. With that, I'll turn it over to Daud Chaudry, Lifecycle Leader for hemophilia to share an update on Hemlibra program.

Thank you, Bill, and thank you, everyone, for tuning in. My name is Daud Chaudry. I'm the Lifecycle Leader for the hemophilia bispecifics program. And I'm really pleased to be able to give you an update on the Hemlibra program overall as well as share a little bit of what is to come. So welcome today. And if we want to move to the first slide, we can jump into the conversation. So to start, let's have a quick look at Hemlibra's market position and future growth opportunity. With about 40% patient share in the U.S. and EU5 and over 25,000 patients treated globally, Hemlibra is clearly the standard of care in hemophilia A. If you look at the map to the left here, this demonstrates that enabling broad access to Hemlibra is one of our key missions. We're actively working on adding more green countries to this map so they can have sustainable access for all people with hemophilia A, where clinically appropriate. Uptake additionally continues to be strong in both the non-inhibitor and the inhibitor populations, with upwards of 70% market share in the severe population in many countries. And in fact, there's some very recent wonderful stories, including New Zealand, where we saw just post launch, a very rapid uptake to over 90% of the population on Hemlibra. So clearly, still much upside potential in many markets. And penetration among the moderate and severe patients continues -- who are uncontrolled in factor VIII is further increasing. We're going to share some more details on Hemlibra's strong profile in the coming slides. But we continue to be happy to see that greater than 2/3 of the patients are choosing monthly or Q2 week, the subcu administration of Hemlibra. And that Hemlibra continues not to induce factor VIII inhibitors because of its novel mechanism of action. So why are we confident in further growth outlook for Hemlibra? Well, there's 3 key pillars that enable this: First, as I mentioned before, we are really focused on geographic expansion, especially for the non-inhibitor population for moderate and severe in many countries; we continue to produce data to address special populations, including the pediatric population and others, where unmet need is remaining high; and lastly, and we'll talk a little bit about the towards the end of the presentation, we want to simplify the treatment and care experience, and we are committed to doing so and creating a strong patient experience. So we can move to the next slide, please. So we are also very proud, we're also very proud of our extensive clinical development program in hemophilia A. This is a clear demonstration of our commitment to making sure Hemlibra is available to as many patients as possible and addresses the unmet needs in various hem A subgroups. Hemlibra's demonstrated significant and clinically meaningful impact for patients with and without inhibitors, from pediatrics all the way through adults and in multiple approved dosing regimens including Q week, Q2 week and Q4 week. On top of that, the clinical efficacy and safety profile was confirmed in real-world data by over 100 publications. And we have studied in our clinical program over 1,000 patients for over 10 years, including the follow-up. So we are very proud of this. We know this is a high bar and sets us apart in many different ways and it creates a bar for new therapies as well too, to try and meet this level of data. If we can move to the next slide, please. So HAVEN 1-4 were some of our key studies from our clinical program that I just presented that helped support the initial approval of Hemlibra in hemophilia A. We pooled the data from those 4 studies and looked at almost 400 patients to eliminate the efficacy and safety profile in Hemlibra across multiple populations, including inhibitor and non-inhibitor and all age ranges. And what we saw was about 80% of patients experienced 0 treated bleeds with the vast majority of the remaining patients experiencing between 1 and 3 bleeds. Combine that with a median ABR of 0 and a model-based ABR of 1.4 and we think this really demonstrates the highly efficacious bleed protection that Hemlibra can offer. Furthermore, Hemlibra treatment resulted in a resolution of 95% of target joints out of the greater than 500 joints identified in study participants. Now these bleed rates were maintained across the broad population regardless of age, inhibitor status, or dosing regimen. And all of this combines to highlight the strong bleed protection offered from Hemlibra. From a safety perspective, the most common adverse event was injection site reactions. Almost 94% of those were mild and occurred within the first 24 weeks and that declined to less than 1% over time. Also importantly, there were no discontinuations due to the injection site reactions. And of course, because of its mechanism of action, Hemlibra does not induce factor VIII inhibitors. So this was a nice summary and preview of our clinical data. And as I said before, importantly, we didn't just stop there. We've also looked at Hemlibra extensively in the real-world setting as well. And in the next slide, I can share some of the data and details from that real-world data. So really, what we see is that the safety and efficacy results coming from the real-world data really does support our clinical program as well. It was very extensive, greater than 100 publications with greater than 10,000 patients studied in a real-world analysis. And first and foremost, I mean, we do see that this sets us apart, both the clinical program as well as the extensive real-world program from other therapies and programs and sets, as I said, a high bar for new therapies entering the marketplace. This is the demand from the hemophilia community to really have well-studied safe drugs and effective drugs. And we have been committed to do so from a Hemlibra perspective since the beginning. So the real-world study showed Hemlibra benefits in numerous ways. First, we see a median and mean ABR that is very similar to the clinical trial data, respectively. Again, we see about 80% of patients with 0 treated bleeds and this underscores the underlying strength of Hemlibra. And when we look at joint bleeds, which, of course, can be very debilitating, we saw an 88% reduction in joint ABR regardless of inhibitor status. So again, very good confirmatory efficacy data similar to our clinical trials. And from a safety perspective, our EUHASS registry looked at about 1,000 patients across EU countries. And the study confirmed again the strong safety profile. In fact, we saw that injection site reaction was again the most common adverse event. And it was even a little bit lower in the real-world studies than what we saw in the clinical development program. So another further sign of Hemlibra's strong efficacy and safety profile. But we also know, if you want to move to the next slide, that as a lifelong condition, treatment burden and matching a patient's lifestyle is key in hemophilia A. Hemlibra reduces treatment burden versus standard and extended half-life replacement therapies considerably. In fact, you may need up to 208 IV infusions per year on some of those therapies and as few as 13 Hemlibra injections. So this is very important. We know as for many physicians, actually about 90%, they said the reduced treatment burden was a key factor in deciding to put patients on Hemlibra. So you can have that reduced treatment burden and sustained bleed protection without the peaks and troughs that are associated with other products. And we think this is a very strong benefit that has made Hemlibra very attractive for many, many people. And as you know, of course, we offer the 3 dosing regimens. So the Q week, Q2 week and Q4 week. And we see greater than 2/3 of the population choosing Q2 week and Q4 week, with the majority on Q2 week. But of course, we do offer Q week for those who choose to do so based on their lifestyle. And I think this is, again, one of the benefits of Hemlibra is being able to have that flexibility. And lastly, but certainly not least, I do want to cover patient satisfaction. This is an extremely important thing to us. I mean, one thing we are dedicated to doing is continually listening to the community. We connect with providers and patients. We do market research. We hear from them what they want, what they expect and what they want in the future. And we have continued to try to meet and exceed those requests and those goals from a community perspective. But first, what I do want to say, Hemlibra has extremely high patient satisfaction overall. If you look on the left, I mean patients definitely prefer Hemlibra over their previous treatments. They miss fewer work and school days, and have to take less pain medication and are engaging in physical activity. As we outlined here in the previous slide, administration convenience is very important and we have launched a couple of new vial configurations, one to help with administration, but also two, to help reduce wastage, which was very important to the community as well. Later on this year and early next year, we will be launching a new administration kit that simplifies the transfer from the vial with a vial adapter versus a transfer needle. And we think this is a great improvement. Again, the community communicated to us that this is what they wanted and we're excited to be able to provide it. Also, we will be bringing in a smaller needle as well too. So from a 13-millimeter to a 9-millimeter needle. We think this is very important for the community. And last and most importantly, I am very excited to be able to let you know today that we will be developing an autoinjector for Hemlibra as well. Of course, as you can imagine, it's very early on in the process and the competitive space. So we are keeping many details sort of close to the vest right now. But we are happy to share with you early on that we have heard from the community that this is important to them. We've listened to them extensively about what they want, and we have a device that we think can meet those needs and has the potential for helping save time with administration, the potential for improved comfort and, of course, we've made the choice to use a nonvisible needle, which we heard was very important, again, in market research. So as more details are available and we get closer to launch timing, we will be sharing more with you as it's available, but wanted to give you a preview of what's to come and our excitement about the future for Hemlibra. So with that, I'll say thank you, and I'll turn it back over to Bruno.

Thanks a lot, Daud. With that, we will open the Q&A session. And the first questions would come from Richard Parkes from Exane BNP.

So I've got two questions. Firstly, for Dr. Abramson, just in terms of the geographic differences in overall survival, there's a possibility that could be caused by improved availability of second-line therapies like CAR T -- third-line therapies like CAR T and bispecifics. So it's likely to -- could lead to a debate over whether it's better to use this treatment or kind of later lines. So could you give us any thoughts on that? Is there any data on post-progression treatment? And maybe you could -- you mentioned your covariant analysis. Could you just explain in layman's terms why that makes you comfortable that there isn't another explanation for that difference other than just a small [ n ]? So that was my first question. So maybe we'll start there.

Okay, sure. No, that's an important question. We've obviously thought a lot about these regional inconsistencies that were observed. The most important thing is that the number of patients treated in North America and Europe was a small number. And that is largely related to the fact that this was during the COVID-19 pandemic, where we had really inability to conduct clinical research at most centers in the United States and Europe for an extended period of time. So when we look at this, we looked at a few things. One is we looked at the drug itself. Is there a possibility that glofitamab is differentially effective by race or region? And the answer is no. The pharmacokinetics are no different across race or region. And monotherapy clinical efficacy is also no different across race and region. So we then looked, of course, within these subgroups. And what's important to recognize and what we identified is that minor variations across baseline characteristics become massively magnified within a subgroup of small patient numbers. So getting to your point regarding next line of lymphoma therapy, within the European cohort on the R-GemOx arm, there was a higher use of the most active medications, including CAR T-cells and bispecific antibodies. So that's clearly going to affect the behavior and overall survival of the control arm. Furthermore, in the European cohort, the 7 deaths related to COVID, I mentioned, 5 of them were the Glofit-GemOx arm of the European cohort, and that's going to massively impact a study of that size within that cohort in terms of progression-free and overall survival. In the North American cohort, which I should note was only 25 patients, we saw also some variations in baseline characteristics, particularly on the Glofit-GemOx arm, which were enriched for high-risk features, including the presence of primary refractory or early relapsed disease, which is a dominant risk factor in second-line therapy for large B-cell lymphoma, as well as high tumor volume was increased in the Glofit-GemOx arm. So ultimately, these are minor variations that become exaggerated in small patient numbers, which is why we really can't draw firm conclusions. What I can say is that these small variations don't make an impact in the overall findings of the study. And that's why randomized clinical trials like this and others are designed to be interpreted based on the intent-to-treat population as opposed to small underpowered univariable analyses. Regarding the other part of your question, which was the multivariable analysis. So because these are univariable analysis, meaning you look at whether a patient had relapsed or refractory disease, independent exclusively, you look at these other factors, short of a multivariable analysis, it's very difficult to draw conclusions about the independent predictive power of a single variable, because patients, it turns out, are all multivariable. There's no such thing as a univariable patient. Patients come from a region. Patients have relapsed or refractory disease. Patients have received one or more prior lines of therapy. You have to view them all together. And what we find is that you have to adjust for risk factors in aggregate. And when we do that multivariable analysis, which is a highly refined statistical tool that's, of course, completely standard in these analyses, we find no impact whatsoever of geographic region at overall survival.

Dr. Abramson, maybe if I may interject. Part of Richard's question, I think was also about the sequencing of therapies. Maybe you could address that question specifically because I think it's of broader interest.

Sure. I think in diffuse large B-cell lymphoma, as with other diseases, one thing has been consistently true since the beginning of development of therapies for lymphoma, which is the best treatments work best the earlier you use them. And we know that with CAR T-cells to be sure that second line is better than third line or later in those studies that have been done. And we have a hint that that's true here as well. And while we don't have formal studies say of glofitamab monotherapy in the second line, what I can say is that the glofitamab-GemOx regimen produced significantly deeper rates of complete remission and a longer progression-free survival than was observed in the monotherapy study, suggesting that earlier use of this regimen is inducing deeper and more durable responses.

Perfect. And then my second question, hopefully a bit shorter for Daud, just on the Hemlibra auto-injector. I just wondered if you were able to comment on potential time lines. I'm just wondering if you're optimistic this could be available by the time Novo Nordisk, by May, launches? And what technical risk is remaining? I'm just wondering if you've done kind of initial formulation work. So is the execution -- technical execution risk relatively low?

Yes. Thank you for the question. So obviously, we're still in the development side of things. So there's some variability around time line, et cetera, but we are working on an expedited time line. And we are pretty confident with our program moving forward. And I would say you would look to expect something in the next few years. And we think, again, we'll be working on a very expedited time line with a good potential.

Richard, did we answer all your questions?

Yes. That's great.

Then let's move on. Next one in the row would be Emmanuel Papadakis from Deutsche Bank.

Hopefully, you can hear me okay. Maybe a follow-up question on the safety and the imbalance of events in U.S. and Europe. I think you gave us some helpful numbers there for the portion of the European deaths due to COVID. Perhaps you can give us the same on the U.S. To what extent was the imbalance in overall survival in terms of absolute events in the U.S. driven by COVID versus other drivers of disease progression or death? And then...

Sure.

Sorry, go ahead.

Yes. The numbers were much smaller in the United States cohort. So I wouldn't say that COVID was a dominant driver in the U.S. In the U.S. cohort, it did appear to be more in balance of high-risk features in the Glofit-GemOx arm. I will also note that the U.S. cohort was 25 patients which meant that in a 2:1 randomization, there were only 10 patients on the R-GemOx arm and 15 on the Glofit-GemOx arm. Any single event is going to massively sway the numbers within a population of that small size.

Understood. And then, Dr. Abramson, perhaps you could just help us think through the implications of this for your clinical practice. We heard that there's around 1/2 of second-line patients typically considered transplant ineligible. Is that consistent with your current experience? And what percentage of those would you then deem typically fit enough to receive this glofitamab regimen?

Yes. So actually, 50% is really far lower than patients who are truly considered transplant ineligible. Remember, the median age of this disease is 67. And so the much higher proportion, probably it's estimated about 2/3 of patients are considered transplant ineligible in the upfront therapy. There's some regional variation across the globe. In Europe, auto transplants are rarely done in patients over the age of 65. In the U.S., they've been often done up to the age of 70. But with the availability of more highly active, far less toxic regimens, more and more patients are being considered transplant ineligible due to the excess toxicities conferred by high-dose chemotherapy. The other thing I'll point out about transplant ineligibility is the biggest reason patients don't go to transplant is because they don't have chemotherapy-sensitive disease at the time of relapse, which is a necessary requisite to proceeding to high-dose chemotherapy and auto transplant. And so clearly, an active immunotherapy is far more appealing. So in my practice, this becomes an appealing option for second-line and later patients. I think it's safe to say that the vast, vast majority of patients who are considered transplant ineligible are fully eligible to receive glofitamab-GemOx. There's no upper age limit. For glofitamab-GemOx, it's generally well tolerated as far as organ function and hematologically. It can be easily supported with growth factor. So the vast majority of patients are going to be eligible. I think in my practice, which is not representative of the practice where patients are treated most in the world, it really comes down for me of a CAR T-cell in the second-line setting versus glofitamab-GemOx. CAR T-cell, of course, approved in the United States as a second-line therapy with liso-cel based on a single arm, not on a randomized Phase III trial. And we have several years of follow-up for CAR T-cells. We don't yet have several years of follow-up for glofitamab-GemOx. And that is something I really want to see. If I have both options available, right now, I would probably would give a CAR T-cell for patients who are candidates for CAR T-cells until such time as we see, which I'm optimistic that we will, at the rates of durable disease control and curative potential are seen with additional follow-up of glofitamab-GemOx. I will note that many patients in my practice, however, are not good candidates for CAR T-cell therapy. They have to travel multiple hours. They don't want to relocate. Their performance status is iffy. And there are a lot of patient and disease-specific reasons, why patients might not be considered a CAR T-cell candidate, particularly for a treatment that requires 3 to 4 week of manufacturing. And disease kinetics often preclude the ability to take them to CAR T-cells, whereas glofitamab-GemOx, of course, is an off-the-shelf regimen. The other thing I'll point out is that CAR T-cells are not available and accessible to most patients in the United States or worldwide. They're currently only done at large major academic centers, in large urban centers, and that isn't where most patients live across the globe. And so the real merit of glofitamab-GemOx is that a time-limited therapy can be given second line off-the-shelf to really patients anywhere across the world who has this treatment in their pharmacy.

That's extremely helpful.

Emmanuel, any additional questions?

No, that's great.

Okay. Then the next one would be James Quigley from Goldman Sachs.

Just want to follow up, Dr. Abramson, on your points there on CAR T. So what proportion of your patients would not be eligible for CAR T based on the reasons that you said? Second question for you as well, is there anything at STARGLO that gives you additional incremental confidence in the first-line combination with Polivy and R-CHP?

Sorry, repeat -- I didn't quite hear the latter, the second question.

So the second question, was there anything in STARGLO that would make -- give you greater confidence for the use of Glofit in combination with Polivy in the first-line study?

Got it. Yes. The first question, I'd estimate about 1/3 of patients are not candidates for CAR T-cell therapy in my practice. We're also a very large CAR T-cell center. And I'd say it's probably a higher proportion in many other centers that maybe have a lower CAR T-cell volume. And obviously, that only applies to patients who are targeted for CAR T-cell therapy and many never -- most patients are never even referred for consideration of CAR T-cell therapy because they don't want to travel. As far as your second question, whenever you have a great treatment in third line, which is, of course, what glofitamab is, and until we apply the STARGLO results, glofitamab is my go-to third-line option. I give patients Pola-R-CHP or R-CHOP frontline. I give them CAR T-cells in second line and I give them glofitamab in third line. That's in general. Obviously, there's variation, but that's a general approach. So whenever something works well in third line, you move it second line, right? Your best treatments, you want to move earlier. So that's what STARGLO shows, and I think that that's practice changing. And when something works well in second line. Obviously, the goal is to cure more patients upfront. Pola-R-CHP is our best upfront regimen. Glofitamab, I think is our best bispecific antibody. And unlike other immunotherapies like CAR T-cells, it's easily combined with chemo immunotherapy as you've heard. And so actually, I'm very excited about the SKYGLO study and the potential impact for glofitamab, pola-R-CHP to be a new standard of care in the future because I actually believe that the ultimate future for glofitamab belongs in curing more patients upfront.

Great. And I've got a couple of questions for Roche as well if that's okay. So in terms of the epidemiology data on treatment in second-line DLBCL in academic versus the community setting, do you have any data there to show you what that split is or what the proportions could be? Again, that seems relevant given what Dr. Abramson said about the CAR T specialist centers. Maybe one on Hemlibra as well, the market research. On the research you had conducted, what proportion of patients would look to switch to an autoinjector with a less visible needle, et cetera, if it were available?

Peter and Daud?

Yes. I mean, maybe I can start on the demographics. So I don't have concrete numbers for you, James. I guess we could follow up. I mean that should exist, right? But I mean, the gist is obviously that large cell lymphoma, particularly in the United States, is treated in the community and those patients, right, particularly because of the geography of the country, as you can imagine, have real difficulties accessing CAR T, just for practical reasons, as Dr. Abramson pointed out. So there is a significant population that is not treated by CAR T and we don't see that changing. I think if I recall correctly, the current number, CAR Ts roughly of 20% share overall currently in the second-line setting in the United States. And I'll pass it to Daud for the Hemlibra question.

Yes. Thank you, Peter. Certainly, in the aspirational statements about the autoinject we've made, we're looking at the current Hemlibra administration and improving upon that. And so we're really comparing our current options for administration, which already have a very high satisfaction rate and trying to further improve upon those with the autoinjector. But certainly, in research, we did hear a lot of interest from patients around the autoinjector. And what we find is that the vast majority would indicate that they would certainly consider the autoinjector once it's launched.

And just maybe adding to Daud here, very clearly, the question we've asked is, you are very satisfied with Hemlibra; would you be interested if we would offer you to have Hemlibra with an autoinjector? Right? Because overall, we are hearing from patients that they are not interested to change given their current satisfaction with Hemlibra.

Thanks, Peter. I think it was an important point to be made. James, any additional questions from your side?

No, that's it.

Then we move on, and the next one would be Peter Welford -- Welford from Jefferies.

So I've got a question for Dr. Abramson and then a question for Roche and Hemlibra. So let me start with the first one. Just with regards to coming back to the sort of third line setting as it is at the moment in your choice. You made the comment that the glofitamab at the moment is your go to. I guess there is an alternative CD25 specific that's available for this setting. I guess curious your views on the pros and con and why glofitamab is your preferred go to? And I guess related to that, if glofitamab and the bispecifics like that move into the second line, would you consider treating a patient then in the third line with an alternative CD20 bispecific? Or would you prefer, once you've used that type of mechanism once, to then move in the third line post this, to move to a different type of mechanism? Then perhaps I'll come back on Hemlibra.

I mean maybe I can jump in here. I'm not sure that it's fair to ask Dr. Abramson on a Roche call to talk about his preferences in third line. I mean I can talk maybe more generally what we're hearing from providers. And then maybe if Dr. Abramson has sort of a clinical comment based on my statement, then he's obviously very welcome to add on top of that. But I mean, we are seeing very strong uptake of Columvi-glofitamab, particularly in the United States. We're very happy with the share. I would also like to remind you, right, we're seeing sometimes in your reports that you're looking at revenue numbers. You need to pay close attention to the pricing of the products. Glofitamab is significantly cheaper, so just comparing price -- particularly in the first year. So just comparing price gives you a wrong picture of the share distribution in the market. And the reasons we hear why physicians like glofitamab is the fixed duration cost of therapy. Half the number of visits to providers to be treated, right? Which again comes back to the geography component in the United States that is huge. So reducing the numbers you have to visit your treatment center makes a big difference. The far preferable steroid regimen that we used to manage CRS. So those are all factors that play together. And then obviously, now we believe with the STARGLO results, we have really underscored that glofitamab is an extremely potent treatment option for patients. And we're seeing very durable responses in the third line setting. Dr. Abramson, sorry, I didn't mean to interject, but I also didn't want to put you on the spot there with the question. Anything you would have to offer from a clinical perspective?

No, I think that's accurate. I think that there are 2 big issues: One is it's time-limited therapy, that means a lot; and the other is it's a once every 3 week schedule, which is a far easier schedule than weekly for 3 months, every other week for another 6 months and then every month ad infinitum. So it really is easier for patients and, of course, highly effective. As far as your next question, with glofitamab, if glofitamab -- if and when glofitamab moves. Second line based on these data, what do you do in third line? This is always personalized to the patient. What I would say is using a bispecific antibody doesn't -- in second line doesn't negate using it in a third or later line. That's not true for CAR T-cell therapy by the way. We're in large cell lymphoma. We just don't see responses after that. But I think a bispecific antibody is likely very different. And obviously, we'll be gathering data in real time. But we use rituximab first line, second line, third line, fourth line, right? We use rituximab always, right? And of course, this regimen, the control arm was R-GemOx and all of these patients got rituximab-based chemoimmunotherapy front line. So we're just really using a better antibody technique here, and I see no reason why it wouldn't be similarly effective in second -- in third or later lines. Obviously, you have to consider when a patient progressed. So if a patient is truly refractory to upfront chemo -- to second-line therapy, you mean they're progressing within months or have -- or don't respond at all. I wouldn't be enthusiastic about a bispecific antibody. If they relapse a year later, 2 years later, 3 years later, I'd be very happy to retreat that patient with a glofitamab-based regimen. And I would see no reason why I would change bispecific antibody. It's not really -- to me, it's not a function of one drug versus another drug. It's a question of whether the patient was refractory to the class and if they weren't, I'd be very happy to retreat with a bispecific like glofitamab.

That's great. And then just on Hemlibra, I'm curious just with regards to the smaller needle, the 13 millimeters to 9 millimeters. Is that purely a sort of psychological benefit? Or have you done any testing with regards -- well, what is the benefit for the patient potentially with regards to the injection itself? Or is it just seeing the needle size? And on the autoinjector could I ask. Given the dosing is -- to some extent, it varies, the volume varies by patient, is the autoinjector, is it going to be -- is the idea of range of pens? Or is the idea a dialable autoinjector pen just to understand how that would work?

Yes. So thank you for the questions, and happy to answer. From the 13 millimeter to the 9 millimeter, this is really based on patient preference. So this is something we heard from the community that they wanted a smaller needle for various reasons. And so we're happy to be able to accommodate that for patients. As far as the autoinjector, right now, we're not sharing that level of detail and hopefully, we'll be more in the future. But from a competitive perspective, there are details we're keeping relatively close today, and we'll share a little bit more in the future.

Thanks, Daud. Peter, did we answer all your questions?

Yes. That's great.

Okay. Very good. If there are no more questions, then I think we would close the call. Let me thank again Dr. Abramson and all the other speakers for their time and commitment here. And also from the IR team, let me thank [ Rachel and Sally ] for the overall lead for the event and slide preparation. The same is true for [ Yan Philip Schwartzans ] and then also Melanie Wolf, who was responsible for event organization. So I hope the event was helpful and it was a helpful update on our hem franchise. If you have any remaining questions, then please reach out to the IR team. We are happy to assist. And with that, I wish you a good weekend, and talk to you soon. Bye.