Roche Holding AG (ROG) Earnings Call Transcript & Summary

Ladies and gentlemen, welcome to the update following ASH 2020 webinar. My name is Henrik, and I'm the technical operator for today's call. Kindly note that the webinar is being recorded. [Operator Instructions] At this time, it's my pleasure to introduce you to Karl Mahler, Head of Investor Relations and Group Planning. Karl, the stage is yours.

Yes. Thanks a lot, Henrik. Warm welcome from my side, 2020 ASH audio webcast for Roche. I'm here with Tom Fuchs. Maybe you could kindly go to the agenda. Perfect. Thank you. I'm here with Tom Fuchs. He's the Vice President, GPS, Hematology. So basically, this is the commercial arm of Roche. And we have Ginna Laport. She's the VP for Development, Global Head of Hematology. Marion Ott, Global Franchise Head, AML, Multiple Myeloma, Pediatric. And after the presentation, there is a Q&A session. [Operator Instructions] Maybe you can go to the next slide here. I mean 2020 was maybe a bit different than that what we would have expected in January, February this year, I have to say. But I would say, at least as Roche, we can really close the year on a high note. In hematology, maybe we have the best pipeline in the industry, I dare to say, particularly what the diversity is concerned, what the maturity is concerned. So there is a broad set of technologies, as you can see here, with gene therapy, ADCs, bispecifics and so on. We are engaged in basically all -- most, I would say, markets in hematology, malignant and malignant hematology diseases. And importantly here, we are also engaged in markets we are not currently in yet. We have products already in the market with Gazyva, Rituxan, Venclexta and so on. We have 5 late-stage assets, bispecifics and aggressive and indolent Non-Hodgkin's lymphoma, multiple myeloma and others. So there is really, let's say, a very innovative pipeline which we have. My last remark, which I feel is important when we compare [ drives ] and we see that sometimes from some of the reports and sometimes you also do that here internally, we all wonder how the efficacy compares between the different assets which we have on the market from different competitors. And to put a bit more clarity on exactly that very question, we have put an analysis on Polivy, which was [ fun ] and it's in Ginna's part, where we looked at different stages of the disease, different patients per stage of the disease and so on. And it is very important to recognize the clinical outcome, and the trial outcome very much depends on the line of treatment, on the disease status, on -- if the patient is refractory or non-refractory, primary refractory and so on. And I mean just if you look at the slide, I mean, it's mind-blowing how different the data are. I mean if you -- for instance, for third-line, pure third-line patients for the same treatment, you have maybe 9.5 months survival benefit. If you have a second-line treatment, you have double, 18 months survival benefit. If you go refractory, 9 months. If you have non-refractory, the [ median ] is even not reached yet and so on. So there is a meaningful difference depending now on the patient differences. And so that we always have to keep in mind. And before -- I also thank, of course, the speakers. I also wanted to thank Loren Kalm from our department who took the lead on this event. And with this one, I wanted to hand over to Tom. Please, Tom.

Thank you, Karl, and welcome, everyone. Thanks for joining us at today's ASH review. We're really -- we had a really great meeting. We're excited about our burgeoning hematology portfolio and looking forward to going through some of the data and our strategies with you today. So we've been in this hematology space for more than 2 decades. And as such, we're really focused on innovation and how we can use that innovation to accelerate our portfolio in hematology. And a couple of examples we wanted to highlight before we get into the products, one example is the use of novel end points and prognostic factors such as MRD negativity. We have a Phase III trial going on with Venclexta and Gazyva in first-line fit CLL where we have the first study with minimal residual disease as the primary end point, as a surrogate end point for PFS and overall survival in first-line fit CLL. We're also developing ctDNA, or circulating tumor DNA, as a way to identify high-risk patients and poor prognostic -- patients with poor prognostic outcomes for diffuse large B-cell, and we're thinking about how to incorporate that into our development in first-line diffuse large B-cell. We're really working to bring medicines to market faster. We've got a couple of examples such as 2 RTOR approvals for Venclexta, one in first-line CLL and one very recently in first-line AML as well as using the accelerated approval pathway in the U.S. with Polivy for relapsed/refractory diffuse large B-cell. We continue to -- as you'll hear today, we continue to engage with health authorities on accelerated pathways for our early programs such as mosun-glofit, our 2 CD25 specifics; cevostamab, our bispecific for multiple myeloma; and crovalimab, our C5 inhibitor. And finally, we're working to reduce -- through our portfolio, reduce the cost to society. This is going to be important to also a competitive differentiator in the market for us, focusing on off-the-shelf medicines such as our bispecifics and our ADCs as well as fixed-duration treatments such as our G venetoclax in first-line CLL as well as the fixed duration that we have for our 2 CD20xCD3 bispecifics in relapsed diffuse large B-cell. So next slide, please. So just an update on Polivy. Polivy continues to perform well in the markets where we're approved and we have reimbursement, so the U.S., Germany and the U.K. in particular. We're looking forward to the readout of the POLARIX trial, which is testing Polivy plus R-CHP versus the standard of care R-CHOP in first-line diffuse large B-cell lymphoma, which we expect sometime around the middle of the mid -- of next year, 2021. With this regimen, we hope to change the standard of care for previously untreated diffuse large B-cell patients. But in the meantime, we continue to develop Polivy for relapsed/refractory diffuse large B-cell both with standard of care chemotherapy as well as our CD20 bispecifics, which you'll see in upcoming slides. So next slide, please. So as you're probably aware and as I referenced earlier, we have 2 CD20xCD3 bispecifics. The first is mosunetuzumab, which is our 1:1 format. This came from our Genentech Research and Early Development group. And the second is glofitamab, which is our 2:1 format, so 2 domains that hit CD20 and 1 for CD3. And both of these antibodies are incredibly effective therapies, but they are differentiated. So with mosun, we're seeing really high response rates, durable responses both as a single agent and in combination across NHL subtypes. And with glofitamab, we're seeing the potential for best-in-class efficacy with incredibly high CR rates in heavily pretreated relapsed/refractory diffuse large B-cell. From a safety standpoint with mosun, we're seeing no Grade 3 CRS and very low rates of Grade 2 CRS, mostly some Grade 1s. And as a result of this, mosun is the only CD20xCD3 bispecific in which hospitalization is not required. And we think that this is an incredibly important differentiator for those markets where many patients are treated in the community setting, such as in the U.S. and in Germany. And we're also developing a subcu formulation. You probably saw the data for that at this meeting, which has the potential to further improve the CRS profile as well as the convenience for patients. For glofit, we are developing -- we show data at this meeting where we're developing a new step-up dosing schedule, which allows us to target a higher dose of 30 milligrams and also with a manageable CRS profile, which is mainly Grade 1 and Grade 2. What's unique about glofitamab is that because of this 2:1 format, it does -- it can compete with circulating naked antibodies such as -- CD20 antibodies such as rituximab and Gazyva, so you could potentially use it in combination with one of these products or if given in a relapse setting for a patient who has recently progressed on therapy, you don't have to worry about circulating rituximab outcompeting your CD20. It can still be effective if given in the relapse setting. And in addition, we're developing a subcu formulation beginning early next year. So next slide, please. So as a result of these 2 agents, we really feel like we can tailor the development of these products to address diverse patient and customer needs. So mosunetuzumab, we think, is going to be, in particular, as I said, attractive for the outpatient setting and for settings where patients maybe are a little bit older or frail like -- such as the data that you saw in first-line unfit and frail diffuse large B-cell lymphoma. And then glofitamab is really, we think, with the best-in-class efficacy profile, with the potential to deliver off-the-shelf CAR-T-like efficacy, this is really going to be used for patients with the most aggressive disease. And we're thinking about how to segment and how to develop both of these products and bring them to market in a tailored way. Next slide, please. So all in all, we -- these 2 products are the leaders in this class of therapy, having treated over 1,000 patients, both as monotherapy and in combination with standards of care chemo as well as newer agents such as R-Polivy. We are pursuing accelerated approval with mosun in third-line plus diffuse large B-cell. We have Breakthrough Therapy Designation and we plan to file in the second half of 2021. And we're almost finished enrolling a third-line plus study for glofitamab in diffuse large B-cell, and we'll be talking with health authorities about this study as well. We have Phase III trials that are planned to start in early 2021 in second-line follicular lymphoma as well as -- with mosun and second-line diffuse large B-cell with glofit. And we have combination trials with both products with Polivy both in first-line fit DLBCL and first-line elderly and in the relapsed/refractory DLBCL. And as you saw at this meeting, we had the first-ever bispecific data in first-line diffuse large B-cell with mosun. So robust development plan and we are rapidly advancing both of these products to market. Next slide, please. So moving on to Venclexta. We continue to be pleased with the progress we're making here. So we have labels in relapsed and first-line CLL in combination with rituximab and with Gazyva in the first-line setting. And I referenced the ongoing study in first-line fit CLL. We recently got full approval in the U.S. for first-line unfit AML. And we have ongoing Phase III trials in AML as first-line maintenance and also post stem cell transplant. We have -- in multiple myeloma, we have trials ongoing in patients with the t(11;14) translocation, which constitutes about 20% of multiple myeloma. And we also just initiated a Phase III trial in the VERONA trial in first-line MDS following the really encouraging and exciting data that we generated in our Phase Ib for Venclexta in combination with azacitidine in high-risk MDS patients. Next slide, please. So moving on to Hemlibra. We also are pleased with our continued -- with the performance of Hemlibra. So far, we're -- up to 8,200 patients have received Hemlibra globally. And Hemlibra is now the most frequently prescribed prophylactic treatment in the U.S. for hemophilia A. We have a couple of studies ongoing: the HAVEN 6 trial in mild to moderate patients and HAVEN 7 is in pediatric and infant patients. So if you go to the next slide, at this meeting, we showed updated data with Hemlibra out to 3 years now. Our 0 bleed rate maintains in the low 80s and just shows the benefit that -- the sustained benefit of Hemlibra treatment for patients with hemophilia A. Next slide, please. And finally, the last product we'll cover is crovalimab. This is one that we haven't talked a lot about yet. This is our C5 inhibitor that -- this is a Chugai drug that we're developing first for PNH but we're also going to take more broadly. What's unique about this product is that this uses Chugai's recycling technology, which allows for really maximal inhibition of C5 as well as convenient Q4 weekly dosing, which we think is really important for these patients who take these products chronically. We've recently initiated 2 Phase III trials, COMMODORE 1 and 2 in PNH-naive and switch patients. And we have an additional study planned in China called COMMODORE 3. More broadly, I mean, this is our first foray -- this is our first area, but we're -- our plans are to develop this product broadly both for hematologic indications as well as to expand into CNS, autoimmune and renal indications. And with this best-in-class C5 inhibition and its very convenient, once-monthly subcu dosing, we feel like we're going to be really competitive in the market with this product. So with that, I will turn it over to Ginna Laport, who is our VP for -- in Product Development Group for Lymphoma and CLL, to go through our lymphoma data. Thank you.

Thank you, Tom. So over the next several minutes, I will highlight the data presented at ASH from our NHL and CLL development franchise. Next slide. So here, we show the long-term follow-up data from MURANO and CLL14 that showed the benefit of Venclexta maintained over extended follow-up with fixed duration dosing. MURANO was our Phase III randomized trial that compared venetoclax-Rituxan with bendamustine-Rituxan in the relapsed/refractory CLL setting. This Kaplan-Meier curve now shows that with 5 years of follow-up, the median progression-free survival is 53 months versus 17 months in favor of the venetoclax arm. And looking at overall survival at the bottom, you can see the text that overall -- with regards to overall survival, this also favors the venetoclax arm with an 82% 5-year overall survival compared to 62% in the bendamustine-Rituxan arm. On the right side shows our CLL14 data. CLL14 was our Phase III randomized trial comparing venetoclax-Gazyva with chlorambucil-Gazyva in the first-line CLL setting. Now with a 4-year update, the median progression-free survival has not been reached in the venetoclax-Gazyva arm and is 36 months in the Gazyva-chlorambucil arm. This translated into a 4-year progression-free survival and shows sustained PFS with a 4-year PFS of 74% in the venetoclax-Gazyva arm, which is double the PFS seen in the Gazyva-chlorambucil arm of only 35%. Next slide. Now here, we show a longer-term follow-up of R-Polivy, bendamustine-Rituxan, a treatment arm in relapsed/refractory DLBCL. And here, we show that Polivy-BR has maintained longer remissions with longer follow-up and consistent across several high-risk cohorts. And just to remind everyone, Polivy-BR was -- this was based on a randomized Phase II trial of Polivy-BR versus BR. We obtained regulatory approvals globally in both the second-line and the third-line setting. This Phase II trial accrued 40 patients in each arm, BR versus Pola+BR, and now we show the 4-year follow-up. On the left side, the left Kaplan-Meier curve, with 4 years of follow-up, the median overall survival is still in favor of Pola+BR with a median overall survival of 1 year versus only 4 months in the BR arm. Now since we completed this randomized Phase II trial, we've accrued over 100 more patients, 106 patients to be exact, what -- we call this our extension cohort. This is a single-arm trial. And now we are showing follow-up on this extension cohort of 106 patients, and the median overall survival is consistent with what was seen in the Pola+BR arm from the randomized portion with a mean overall survival of 1 year. Next slide. Now continuing from this prior slide, notable responses were seen regardless of refractory status and prior lines of therapy, and strong efficacy was especially seen in the second-line and non-refractory patients. Patients in this Polivy-BR trial were highly pre-treated and highly refractory, which does limit the utility across trial comparisons. But I should mention, if you look at the profile, 72% of patients had greater than 2 lines of prior therapy, 75% were refractory to their last prior therapy and over half had primary refractory disease. And looking at best CR rates. The subgroup analysis there on the left side, that left table at the bottom, shows from pooled data that we have high CR rates, especially when you look at the second-line setting, a best CR rate of 74%. And looking at the non-refractory to last treatment and non-primary refractory, the CR rates increased to 92% and 87%. And looking at the bar graph, this shows again that patients derive benefit regardless of refractory status and primary -- and prior lines of therapy, and the bulk of responses were complete remissions. I should also mention why I'm talking about Polivy, remind everyone that next year sometime the second half most likely, we will have readout of POLARIX, our first-line study of POLARIX, of R-CHOP versus R-CHP+Pola in previously untreated DLBCL patients. Next slide. So now going on to our bispecific molecules. These are our CD20xCD3 bispecific molecules that Tom has already introduced. Here, we show the results of mosunetuzumab monotherapy and it shows durable responses in patients with relapsed/refractory follicular lymphoma. This is follow-up from our data that was introduced at ASH last year where mosun -- the data from mosun was featured in a plenary abstract. Here now we have follow-up -- longer follow-up, and on the swimmer lanes on the left side, this shows the duration of response of the patients who achieved a complete remission and the median duration in complete remission is 21 months. Looking at the bar graph, you can see the high response rates for all of the FL patients, the CR rates were 51%. But if you look at the different subsets of these FL patients, and these are the high-risk subsets, the CR rates are maintained and ranged from 47% to as high as 84%. We also -- as Tom also mentioned, we obtained Breakthrough Designation from the FDA earlier this year. Now based on these very promising results, I'll reinforce what Tom said as well, we are pursuing accelerated approval in the third-line follicular setting with mosun monotherapy, and we expect to submit our BLA in the second half of next year. The confirmatory trial for that planned approval will be a randomized Phase III trial planned in the second-line follicular setting, where we will compare mosunetuzumab-lenalidomide versus Rituxan-lenalidomide. Next slide. Now changing from follicular lymphoma to diffuse large cell lymphoma. Here we show the efficacy of mosun monotherapy in the elderly unfit population with previously untreated diffuse large B-cell lymphoma. Now we know that up to 30% of newly diagnosed DLBCL patients are not able to receive standard dose R-CHOP mainly because of poor performance status, frailty or higher age. Starting first with the bar graph on the right, you can see the overall response rates of mosun monotherapy in this previously untreated population is 63% with a CR rate of 45%. Now obviously, we know that this CR rate is inferior to R-CHOP, but remember, this is a patient population that was not eligible for R-CHOP. In these 22 patients that you see the data here, the median age was 82 years old with a range of 67 to 100 years old. And looking at the swim lanes, looking -- that show duration of response, I should mention that the top swim lane represents the first patient who was dosed on this trial. This was a 92-year-old patient who achieved a complete remission after 6 cycles of mosun monotherapy. I'm happy to say that this patient remains remission nearly 1 year after treatment completion. I should -- I would also like to point out that we treated a 100-year-old patient who tolerated the treatment well and also achieved a complete remission after 6 cycles of therapy. This was a well-tolerated regimen. All CRS events were Grade 1, except for one Grade 2. And as mentioned earlier, this regimen is completely given as an outpatient. Next -- what I'd also like to say -- I'm sorry, but I -- one thing I'd also like to point out that although this data is very promising, we think we can do better. So for our next trial in this elderly unfit population, we plan to add Polivy to mosunetuzumab to offer a chemo-light regimen to the elderly population in this setting. Next slide. Now I'd also like to show this data where we combine mosunetuzumab with CHOP. And this is the first-ever bispecific combination data in the previously untreated DLBCL setting. For first-line DLBCL, the overall response rate was 82% with a CR rate of 79%. And we know that this compares well to historical controls. And the data you see there on the right is actually CR rates and ORR rates from GOYA where the overall response rate in an R-CHOP control arm was 78%, so comparable to R ORR here with mosun and CHOP. The CR rate was 59% in GOYA, but here, we show a CR rate of 79%. So we feel that this data shows high potential to -- shows the highest potential to show high efficacy when mosun is combined with CHOP, and perhaps mosun will show higher activity over Rituxan. Based on this data, we are pursuing multiple combination regimens with both mosun and glofit in the first-line DLBCL setting currently in the Phase Ib setting and future trials coming over the next year. Next slide. So I also would like to spend a minute on the subcutaneous formulation. We showed preliminary data on the subcu formulation of mosunetuzumab. Now we chose to explore and develop subcu mosunetuzumab because preclinical data has shown that the slower absorption observed, the subcu formulation over IV formulation actually can help mitigate CRS. If we look at the efficacy data, it's comparable to the IV formulation. This was a heavily pretreated population across these 43 patients. The median number of prior regimens was 4. So the antitumor activity is comparable to the IV formulation. However, one thing that is different is that the safety profile is enhanced. We saw less Grade 1 and Grade 2 using the subcu formulation. We also showed a favorable PK profile. And like the IV formulation, we see high bioavailability but we show lower peak concentrations of IL-6, which we know is one of the main drivers of the CRS, cytokine release syndrome. So we are continuing to explore subcu step-up dosing to further optimize this profile with the hopes of decreasing the CRS rate even more. Next slide. Glofitamab, this is my last slide, and so glofitamab is our other CD20xCD3 antibody, and this is data from our step-up dosing that shows high CR rates in a heavily pretreated DLBCL population. This is an off-the-shelf option being a bispecific antibody, which we think has CR rates comparable to CAR-T therapy. And looking at the response rates on the left for these 52 patients, we had a CR rate of 53%. And when you split this population between the aggressive and the indolent histologies, the CR rates are maintained in the safety population. I would like to mention, if you restrict the analysis to the efficacy evaluable population, in the aggressive cohort, the CR rate increases to 58%; in the indolent cohort, the CR rate increases to 74%. Looking at duration of response in the swim lanes on the right, this is an early look. This follow-up is short, but we thought this was worth showing. We -- as Tom mentioned, we have nearly finished accrual of our pivotal arm of this population in third-line DLBCL and currently are engaging health authorities to pursue approval in the near future. We are planning a randomized Phase III trial in the second-line DLBCL setting comparing glofit-GemOx versus Rituxan-GemOx. So thank you for your attention. I would now like to introduce Marion Ott, my colleague, who is the global franchise of AML -- franchise head of the AML, multiple myeloma and the pediatric development setting. Marion?

Thank you so much, Ginna, for the introduction. Welcome, all of you, warm welcome, and I'm so pleased today. So the next slide, please. So I'm pleased today that I can share for the first time data for -- about cevostamab, where we had an oral presentation at ASH, a bispecific antibody, targeting FcRH5 and CD3 developed by Genentech. This is developed with the same technology like mosunetuzumab, what just Ginna described. So this bispecific antibody is a humanized IgG1-based T-cell engaging bispecific antibody. It targets the most membrane-proximal domain of FcRH5 on myeloma cells and on -- and the CD3 on T-cells and resulting in a T-cell activation and potent killing of myeloma cells. You see on the right the FcRH5 protein expression profile. So it's expressed in normal B-cells, normal plasma cells and with higher levels in myeloma cells. So FcRH5 is expressed exclusively in the B-cell lineage and with a near 100% prevalence in myeloma cells, which makes it really an attractive target for multiple myeloma. So with -- going please to the next slide. I want to show some of the key features of the ongoing Phase I study design. So we are in a dose escalation in relapsed/refractory multiple myeloma. And I have -- want to highlight here that patients were enrolled, which were heavily and highly pretreated and highly refractory. So please look now on the right table for the baseline characteristics. I'd like to highlight the median prior lines of therapy, around 6. I want to highlight that around 21% of the patients had a prior anti-BCMA therapy. And specifically, it's important also that 72%, the majority of the patients, were triple-class refractory, 45% penta-drug refractory and the majority of the patients had a high-risk cytogenetic profile. When you go to the left, I want to describe a little bit the Phase I dose escalation study design. So it's important here to mention that we did not achieve the current [ MTD ] and the recommended Phase II dose. We are still enrolling now in the higher dose cohorts for the target dose. And I want to highlight that cevostamab is given in a cycle of every 21 days. And first, we have determined the step-up dose. What we need -- what we used for -- in order to mitigate the CRS group. When you look on the left, so we started with 0.05 and escalated to 3.6 milligrams. And this is our current step-up dose, what we are administering in day 1 on cycle 1. So then we had to explore the target dose. So the target dose, when you look on the right, so we started with 0.015 (sic) [ 0.15 ] and escalated now, we are in the dose cohort of 160 milligrams where we're currently enrolling. So this target dose is used at day 8 in cycle 1 and on cycle 2 and cycle 3 and onwards, only on day 1. So when we go to the next slide, please. So here, I want to highlight, for cevostamab, the really exciting and promising monotherapy activity in heavily pretreated relapsed/refractory multiple myeloma patients. So on the left, you can see the response rates. And the response rates, specifically in the left column, are summarizing doses with a step-up dose of 3.6 milligram and target doses with at least 20 milligrams. It means -- various doses are here summarized. So we have -- we could achieve an overall response rate of 53% with a CR rate of 18% and a stringent CR of 12% and a VGPR of 32%. And when you look into more higher target doses, when you go on the very right, when target doses for 90 to 132 milligram, what we summarized here, we could achieve an overall response rate of 61%, with a stringent CR of 6%, CR 11%, VGPR 28% and PR 17%. So this is really -- what is really also important is the duration of response. So the data are currently immature and further evolving. But you see here, a graph which was presented at ASH. Here on the right, the 8 patients with the duration of response could achieve at least 6 months. When you go to the bottom, you see the cohort of 132 milligram and the majority of the patients in response are still ongoing. So it's important to highlight that we could achieve responses in penta-drug refractory patients with overall response of 41% in patients with a prior BCMA therapy of an overall response rate here in this group of 63%. We could achieve responses observed across all FcRH5 expression levels, which was presented in one of the posters at ASH. And interestingly, also is the MRD negativity. So we could achieve an MRD-negative status measured by NGS detected in 6 out of 7 patients. It was at least a VGPR. From the toxicity point of view, it was manageable, specifically the CRS with a step-up dosing. The -- mainly -- the CRS rates were mainly Grade 1 and Grade 2 and were occurring in the first cycle. We had 1 patient with a Grade 3 due to Grade 4 elevation of liver transaminases. This result and this patient could be later on retreated with cevostamab without experiencing any CRS events again. And we are currently planning to engage with half of our team for potential accelerated approval pathways, and we're also initiating trials in combinations with existing standard of care. So next slide, please. So now I want to change here to venetoclax for high-risk MDS. So we had here yesterday an oral presentation presented by Dr. Garcia presenting really encouraging response rate and overall survival rates for venetoclax and azacitidine, updated data from the Phase Ib dose escalation in front-line high-risk MDS. You see here on the left the overall response rate from 78 patients. The overall response rate is 79% with a CR of 39.7% and a marrow CR of 39.7%. And I have to highlight that this is -- this is a group where various doses were included. So at the recommended Phase II dose, which was selected at 400 milligram, we could achieve an overall response rate of 84% and with a CR rate of 35%. And it's highlighted here also the historical control for azacitidine alone is 38%. And I want to highlight also the majority of the patients were getting transfusion independent and really impressive results. And it's a Phase Ib single-arm trial. We don't have randomized data yet, but it's really very impressing what we're seeing here. It's where we look at the mutual -- currently, the patients on study, median time of study, 16.4 months. And when you look at all patients in various dose cohorts for ven and azacitidine, the current median overall survival is 27.5 months with a landmark OS of 12 months of 77%, 24 months of 60%. And with the current recommended Phase II dose of 400 milligram in these 51 patients, the median OS is not reached yet. And the historical azacitidine control here for median OS is estimated around 15 months. And this is here the basis and so -- and this data are so exciting that let us to initiating a Phase III VERONA trial, what Tom mentioned. It's currently enrolling the first patient in -- was in October, and it's enrolling in frontline high-risk MDS patients. Thank you for your attention.

Yes. Thanks a lot to all of you, Ginna, Marion, Tom. And we are ready for questions now. Maybe, Henrik, if you could kindly repeat on how the investors and analysts can have their questions answered by us, and then we will start with the Q&A.[

[Operator Instructions]

Okay. So I'll just start with basically 2 questions here which I got via the chat so that it is done. Tim Anderson from Wolfe Research was wondering about mosunetuzumab and glofitamab; Glofitamab, CD20xCD3 -- CD3xCD20. Roche routinely reports on CRS, but how about the neurotoxicity of the 2, maybe on its own also as compared to other bispecifics. Ginna, maybe one for you.

Yes. I'm happy to answer that. We don't report on any neurotoxicity because we don't have any to report. And we feel like this is a key differentiator from the CAR-T cell. The ICANS or neurotoxicity is not an issue with our bispecifics.

Yes. That's a short answer to the question, which is good. Thank you. The next one is from Luisa Hector. She asks, "Could you comment on the durability of response of mosun and glofitamab relative to CAR T's durability? So how do the 2 different classes of treatment compare?" She says it is maybe easier to use the bispecifics in the CAR-Ts. How is -- about the durability question of the 2?

That's a little bit difficult to answer because we don't have as long -- the long-term follow-up that some of the CAR-T cell products have. So I think only time will tell, but we think our response rates are comparable. But with longer follow-up, we hope to confirm longer duration. I'd like to mention though, we're already -- with the mosun, mosunetuzumab, again, in the third-line follicular setting, we see a response duration already of 21 months of response in CR.

Okay, thank you. We do have about, just for your background information, about 230 people, which is a lot for such a specialized call. So thanks for your interest in Roche. And with this one, I wanted to go over to the telephone, in line questions. So Wimal, perhaps you would be the first one. I open your line and allow you to talk, please.

Wimal Kapadia from Bernstein. So could I just ask a little bit more about duration for the CD3xCD20? So just curious to hear your thoughts on the fixed dosing period versus treating to progression. Now how do Roche think about the idea of maintenance treatment for these products? And does that vary between mosun and glofitamab? And then just sticking with the CD3xCD20, clearly, the mosun data in first-line unfit patients was very interesting. So I'm just curious if you plan to run any head-to-head trials versus mini R-CHOP, given the unmet need for a cleaner treatment here could be well received. And then just tied to that, you highlight a plan for mosun plus Polivy in first-line unfit DLBCL. Just curious how Roche think about the tolerability profile of that combination? And will it be a head-to-head versus mini R-CHOP?

Ginna, it's your day, please. Ginna, you're on mute.

Hello, can you hear me?

Yes. Now, we can hear you. Yes.

Okay. Yes, sorry. So let me start. There's a few questions in that one. Let me start with maybe the last one. As far as mosun and Pola, we're excited about that regimen because again, that is a chemo-light regimen. It's not chemo-free, it's chemo-light, so it offers an option for patients who don't have -- who can't tolerate chemotherapy. And we think again, this will possibly show higher efficacy compared to mosun monotherapy. With regards to the mini CHOP regimen, we are actively are considering a mini CHOP regimen with mosun and most likely, we'll think of the Phase III trial that we will launch in the next -- within the next year or 2, exploring mosun mini CHOP to offer that as another regimen for patients in this specific population. Regarding maintenance therapy, yes, I agree that compared to some of our competitors, we believe in fixed duration. We think fixed duration obviously has a few benefits: one, you don't have the long-term side effects from long-term use; two, it's much more convenient for the patients and don't forget about their caregivers who have to take off time to take care of these patients; and three, it's less of a cost burden on the health care system. We don't currently have plans on maintenance therapy, but it's something we continue to explore.

All addressed, hopefully, Wimal. Then I would invite Richard Vosser from JPMorgan. Richard, over to you.

Maybe on glofit and mosun, perhaps you could -- there's early data out there from the Genmab product, which is subcutaneous and maybe at higher dosing that they've been able to achieve. So maybe you could talk about how you see your products relative to that one? I know it's early days. But also how you would think about whether the higher doses that you can get with subcutaneous, you could enhance your efficacy as we see going forward. Second question, just -- mosun seems, as we can see, much more tolerable. So should we think about that having greater commercial potential and combinability in the early stages of both DLBCL and NHL? So just some idea of how you see the relative commercial potential of the 2, glofit and mosun. And then finally, just on Polivy, the launch in the U.S. has gone pretty flat. Could you just talk about the penetration in that third-line segment of DLBCL and how you're seeing the receptivity in this COVID environment to Polivy?

So I think there's 3 questions here, and I'll split this between answering besides -- between myself and Tom. So I'll answer the part about Genmab. So how do we compare to Genmab? So mosunetuzumab, as I mentioned, is all outpatient and we are exploring a subcu option. We are also exploring a subcu option in glofitamab, but that patient won't be dosed with glofit subcu until sometime next year. We have quite a bit of data in mosun subcu with a greater enhanced safety profile, comparable efficacy to the IV formulation. And again, mosun is all outpatient. I believe Genmab does require hospitalization on the first dose. And I'll let Tom answer the question about the commercial issues on mosun and Polivy.

Yes. Thanks for the question. I mean we think that the commercial potential for both products is high. Different patient segments and different physician segments have different needs, right? So outpatient setting, like we think that mosun is a really attractive agent. But for more -- for patients who have really serious diffuse large B-cell where they need really high efficacy, we think that glofit's going to be really attractive. And we're also excited about our combination strategies, which -- it's a work in progress, and we'll see data in the summer meetings and at ASH next year. So we're really quite excited about the potential for both. As it relates to Polivy, I mean, we're -- we continue to be encouraged by the utilization. I mean, I think that COVID has -- it's fair to say COVID has affected a lot of products. But I mean, obviously, the unmet need in relapsed DLBCL remains high. And -- but the reception that we're getting is good. And so it's not -- obviously, we're not -- it's not going to take over the entire market. It's a very heterogeneous market. And at this point, we just have third-line label. We are looking to expand that into the second line in the U.S., and that would obviously create -- generate a new growth opportunity for Polivy.

Yes. Thank you, Tom. And as I mentioned before on the comparability of data, sometimes, it's really tricky to compare data if you are not 100% sure always of the refractory status, line of treatment and so on, severity of the disease. Good. With this, Richard, I hope we could address all your questions.

Yes. Thank you.

Yes. Thank you, Richard. Next one will be Michael Leuchten from UBS. Michael, you just disappeared somehow. Good. Then we go for -- Michael, you're on again.

Okay. I'll try again.

Okay. Now we can hear you. Yes, please. Yes.

Yes. Sorry about that. Just going back to the first-line DLBCL setting, just taking what you said. The trial that is yet to start, the glofit plus Polivy plus R-CHP, without an O, trial, what's the aim of that? Is that trying to get a higher dose of the bispecific in because Polivy's better tolerated? I'm just trying to figure out what that combination would give you in first-line DLBCL that you wouldn't be able to achieve with the other combination, including mosun.

So you're asking specifically about the Phase Ib trial that was mentioned of glofit-Polivy-R-CHP?

Yes.

Okay. So we are running multiple Phase Ib trials. Obviously, we don't know what the readout will be of POLARIX, so we're covering all bases. So if POLARIX is positive and R-CHP+Pola becomes a standard of care, we'd -- perhaps the glofit-Pola-R-CHP, we think glofit could probably add more efficacy and perhaps we could explore that in a higher risk subset. The POLARIX trial is focused where the IPI 2 to 5 is very broad -- the broadest population of first-line DLBCL. So perhaps with higher efficacy, we would focus on a subset of that first-line population.

Thank you. Next one would be James Quigley. I opened your line. James?

Hello. Can you hear me? Can you hear me, Karl?

Yes, we can hear you now. Yes, please.

Awesome. So James Quigley from Morgan Stanley. So the data from mosunetuzumab and CHOP in the first line were -- looked pretty good but quite a few Grade 4 neutropenia events. So how are these treated and was it fairly straightforward? Is it resolving naturally? I can't remember what the data were in the relapsed/refractory setting, but how concerned or not are you with this finding? Then in the second-line for glofitamab, why did you decide to go for a chemo combination versus Rituxan and chemo? Curiously, this could have been an opportunity for a chemo-free regimen? And AbbVie and Genmab have gone down the route of a similar trial with the chemo-free regimen. And then if I can squeeze in a third. You mentioned filing for mosunetuzumab in the second half of 2021. You've had good data across indications at ASH pretty much for 3 years in a row now. What else do you need to see before getting that file in? Are you waiting for additional data for the subcu? Or is there anything else that we're missing?

Okay. I think there's 3 questions there. I'll start with the most recent question. On the mosun second-line filing, that is really based on just time to event and duration. So with mosun filing, we completed accrual last patient in about 3 or 4 months ago. So we're just waiting for the data to mature, and that's really what the holdup is there. So it's done and we're just waiting for the readout sometime next year. As far as our combination of glofit with chemotherapy, I mentioned we are -- we have the Phase III trial of glofit-GemOx versus R-GemOx. We also are exploring other options of glofit with Polivy. So we are combining Polivy with glofit and mosunetuzumab in various indication settings. So it's not a chemo-free regimen but again, a chemo-light regimen because Polivy does have that chemo payload. As far as the question with mosun, CHOP and the neutropenia incidents, yes, the neutropenia incidents was, I believe, in Grade 3 or 4, it's about 60%. This -- we did recommend primary prophylaxis. This is something we are watching and we still need to -- we need to look at the compliance, make sure NEUPOGEN is used across all patients, but it is something that we definitely will monitor.

Yes. Thank you. James, I hope we could address all your questions. So we have one here from the Q&A from Steve Scala. He was asking about the bispecifics versus CAR-T. It's a bit along the same line what we had before. Ginna, does Roche think that bispecific safety will allow outperform CAR-Ts? Or will the 2 look similar as CAR-T transition in the familiarity with the treatment [ in group ]. So what is your best guess here?

Yes. We get that question a lot, how does bispecific compare to CAR-T. Remember, we feel the advantages of bispecific. It's off the shelf. We don't see the neurotoxicity with the CAR-T. And also remember, with the patients who go to CAR-Ts, it's a selected population. There's -- 6 to 8 weeks of manufacturing is required. I know that duration is getting shorter. For our patients, they don't need bridging therapy as opposed to the CAR-T. So we feel like we have a higher-risk population and we're reaching efficacy rates that are comparable to CAR-T.

Okay. So hopeful. That's good. Next one would be Emmanuel Papadakis. So I guess, Emmanuel, this is your first question on the call in your new capacity for a bank where you just landed. So the line is yours and it's open here. Welcome back to the market now. Looking forward to your question, Emmanuel.

Almost back. Emmanuel Papadakis at Deutsche Bank. Maybe I'll take a couple -- a quick follow-up on the CD20s. I mean, I think the original plan was to clearly segment the 2 assets by indication, and that seems to have blurred somewhat, i.e., simtuzumab in FL and glofit in DLBCL. So other than performance status, disease burden, et cetera, are there any plans to develop a biomarker or a more comprehensive diagnostic approach to segment populations to help physicians make a decision about which treatment might be most appropriate? Second question on the FcRH5, pretty impressive data. There was a lot of mild grade CRS neurotoxicity. What does that imply for your clinical development plans, particularly in combination? And how soon might you progress that into pivotal studies?

I'll answer the first question and give the second one to Marion. So yes, about how are we segmenting the market, we are taking both bispecifics in DLBCL in the refractory setting, and we feel like there's a place also in the first-line setting. As I mentioned, mosun monotherapy with Pola, we're looking at in first-line elderly unfit. And we have plans for glofit in the first-line setting, using biomarkers that's still under exploration, which I'm not comfortable revealing yet, but we are definitely using biomarkers and personalized health care tools to help us define those populations. And Marion?

Yes, thank you. So in terms about the question around the CRS rate for FcRH5, what I was hearing. So in overall, the CRS rate was around 70%, mainly Grade 1 and Grade 2, what I have to highlight here. And it was resolved and all the CRS was resolved with and were treated with standard of care but mainly resolved within 2 days. And we also counted -- we had quite conservative criteria. We took all the lead criteria and we also counted in the CRS also the pyrexia. So this is also what is important to highlight. We don't see here any obstacles to enter and combine here with standard of care and also potentially also with other compounds. And we have to first determine the recommended Phase II dose, what is important and what we are aiming for. And we are planning to approach the FDA in Q1 next year and discuss here what the recommended Phase II dose. We are quite advanced in the current dose escalation, [ in the current and] the clinical trial preparation for a combinational trial with [ Combex ].

Now that is really an interesting and exciting new asset, which we have in the pipeline, I have to say, the only one of its kind now at this stage. I wanted to continue with the questions via the phone. Now I have a challenge because there is no name behind it, but it's a U.K. number. It's 207-774-100. So I open the line and please, the floor is yours, whoever that is. Again, it's a U.K. number. It's 207 -- hello?

It's Keyur Parekh from Goldman Sachs. Hopefully, you can hear me okay. Two questions, please. One on crovalimab. Just wondering if you guys can help us understand how you're thinking about the commercial positioning for this versus Ultomiris and kind of especially, given the 8-week dosing for Ultomiris and the lead that it has from a time-to-market perspective. And then 2 just quick clarification questions. When did you guys suggest you could potentially file glofitamab? And then separately, I think there was some comments made about next steps for the multiple myeloma assets. Just wondering kind of when we might have an update on that from a regulatory perspective or a filing time line perspective.

I'll take the question on glofitamab. So for glofitamab, we -- as was mentioned earlier, we have nearly completed accrual of the pivotal cohort of glofitamab in the third-line DLBCL setting. We're currently engaging with health authorities so we hope to pursue approval in the near future. And so Tom, can you answer the question on crovalimab?

Sure. Yes. I mean, I guess I would say that we think that the Q4 at home -- Q4 week at-home subcu administration is even another -- an improvement over -- in the treatment for PNH and other complement mediated diseases. So we think that, that's going to be -- because of that recycling technology, the convenience that, that offers as well as the data, I mean, we're really optimistic that it's noninferiority trials that we're running, but we really do think that the maximal C5 inhibition, the sort of ability to prevent breakthroughs, it's going to be attractive to treaters and to patients, and we're cautiously optimistic about the potential for this product.

Yes. And for potential filing time lines for cevostamab, so what I mentioned before, it's quite early to say. So we first need to determine the recommended Phase II dose. We want to go to the FDA in Q1, ideally depends, of course, on the dose escalation and clinical parameters here. And I hope we can share that next year here more. It would be too early to say right now.

Okay. Thank you. So with that, Keyur, once we have -- we are a step close with the whole thing and the discussions with the FDA are more advanced or where we can share something with you. Next one would be Peter -- Nick -- sorry, Nick Nieland, allow you to talk, please?

It's -- I think it's Andrew Berens from Morgan Stanley.

Okay, interesting. But the indication here says Nick, but never mind. Please, Andrew, go ahead.

I'm masquerading. It was one of my team members.

No worries.

So a couple of questions, please. There's been some recent papers on the importance of TIGIT as a resistance mechanism in -- for BCMA failures. I'm interested in your plans given tiragolumab in terms of exploring that opportunity. And then second, perhaps you could give us time lines on the Chugai GPRC5D given the possibility of combination strategies with your other bispecific?

Thank you, Andrew.

That's an interesting -- very interesting comment on the TIGIT. This is actually what we really evaluating currently and potential combination with our internal anti-TIGIT antibody. And for the interest of -- the Chugai one is there for pRED, the TCB, GPRC5D. It is a 2:1 format like the glofit, what Ginna presented. We just achieved here first patient in right now, so it's quite in the early days of dose escalation.

Thank you. We are already coming close to an end, but we also have one more questions over the phone, Peter Welford. Please, over to you.

I've got just 2 quick ones, if I can, please. Firstly, just going back to the fixed-dosing duration of treatment that you're doing with the CD20 bispecifics. I'm curious there, I think if you achieved a CR in only 3 cycles, would you have any data in terms of whether those patients potentially relapsed and whether or not there would have been any benefit, I guess, to treat even longer and whether or not there's any work undergoing to potentially look at biomarkers or that potentially predict whether or not some of those patients should actually have benefited from more cycles? And then secondly, just on cevostamab. I guess, clearly, very impressive efficacy in some high refractory patients. Is there an opportunity here to further enroll, what I guess you could call, I don't know, it's hexa-refractory or whatever you want to call BCMA. I guess, penta-plus BCMA refractory patients, I mean, clearly, that's a new unmet need that's starting here. Is that a population you could consider? Or realistically, should we be considering this as the usual triple and penta groups?

So I can answer the question about the fixed duration in our bispecifics. So in our bispecific trials, they are all a fixed duration. None of them are continuous dosing. I should say, for mosunetuzumab, when we presented this at ASH last year and this year, we do have retreatment data. So patients who are -- who obtain a complete remission and relapse, they do respond again to retreatment. So that is also an option for patients -- for these patients because they're not receiving maintenance therapy. As far as biomarkers, yes, we are exploring many biomarkers. They're highly exploratory, but we are looking for signals or biomarkers that can help us determine who would be at higher risk of relapse. I think the next question is for Marion.

Yes. Very interesting question. And yes, we have impressive data on prior treated with anti-BCMA patients, around 62%. And this is definitely one of our strategic pillars here to develop cevostamab, also for potential here to focus on this patient population. It's not the only strategic focus, but it's a very important one, specifically with this extremely high unmet need.

Many thanks. Many thanks for your interest in Roche. Many thanks for your attention here. Also Ginna, Marion, Tom and Loren for preparing the event, helping out. Wish you a good year-end, a safe one, a healthy one and looking forward to seeing you in person hopefully somewhere and next year at one of the events, and enjoy the time with your family. And yes, all the best to you. Bye-bye. Thanks a lot. Keep safe. Bye-bye.