Roche Holding AG (ROG) Earnings Call Transcript

Operator [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 under the presentation. At this time, it's our pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.

Okay. Thank you. Thanks, Henrik, and welcome to our IR call focusing on our ophthalmology franchise and the latest data presented at ASRS and also some new real-world data for VABYSMO and SUSVIMO. Let me quickly take you through today's agenda. Can I have the slide, please. Yes. We have 3 speakers with us today. First will be Nilesh Mehta, our Global Franchise Head for Ophthalmology, responsible for global product strategy. Nilesh will provide us an update on our overall franchise strategy. Second will be Christopher Brittain, our Vice President and Global Head of Ophthalmology, responsible for product development. Chris will provide us an update on our early and late-stage ophthalmology pipeline, including the platform technologies needed. And third, we have with us today, Dr. Arshad Khanani, a well-known retina specialist and [ Vabysmo ] Clinical Investigator who will lead us through several data sets. Firstly, through the RHONE-X 4-year follow-up data for Vabysmo in DME, which were just presented at ASRS. And secondly, as he leads ongoing efforts to collect independent community support to real-world data for Vabysmo and Susvimo, he will also take us through the TRUCKEE study, which collects real-world data for Vabysmo and AMD and the SUMMIT study, which collects real-word data for Susvimo in AMD. Overall, our call is scheduled to go 75 minutes. We have planned for roughly 50 minutes of presentations and 25 minutes for the Q&A. And for the Q&A session, we will also be joined by Hugh Lin, our Lifecycle Leader for Vabysmo and by Jake Schumacher, our Executive Marketing Director in Ophthalmology. Can I have the next slide, please. Just as a quick introduction, let me summarize our fast-growing launched ophthalmology portfolio at a very high level. Sales in the first quarter reached CHF 0.9 billion and grew plus 58% year-over-year primarily driven by Vabysmo. Vabysmo is now approved in 98 countries and so far, reimbursed in 35 countries, including the EU5 countries. Market shares for Vabysmo in May in the U.S. have reached 27% in AMD, that's up from 24% seen in Q1, 19% in DME, up from 18% and 15% in RVO, up from 8%, with naive patients accounting for more than 40% of all patient starts. We have also more than 20% share in the early launch countries, U.K. and Switzerland, and double-digit market shares in Japan, Germany and France. In Q2, we just announced the U.S. approval for the prefilled syringe, which will be launched in coming months. Surveys following the prefilled syringe approval indicate quite some interest for this offering amongst ophthalmologists. And finally, we also have a rapidly growing body of -- we have got evidence confirming the drying effect and durability of Vabysmo, something we will hear more about later today by Dr. Khanani. And let me also quickly update here on Susvimo, which we are really excited about and which we see as a blockbuster opportunity all by itself. Susvimo just started to relaunch in the U.S. and AMD, and we have completed the FDA filing for 2 additional indications in DME and diabetic retinopathy, where we expect approval early in 2025. Can I have the next slide, please? Let me also quickly provide an update on the upcoming news flow for the remainder of the year. From the -- on the left side, just going for pharma from the top to the bottom, tiragolumab, we can confirm the SKYSCRAPER-01 results for the second half. For inavolisib, we have a PDUFA date set now for November 27 for first-line approval in PI3 kinase-mutated, hormone receptor positive breast cancer. Prasinezumab here, we expect Phase II PDUFA results in Parkinson's disease in the fourth quarter. If positive, these data will be shared with health authorities. Evrysdi and GYM329 SMA results are expected towards year-end. Next, trotinemab in Alzheimer's disease. We will provide an update here at CTAD. This is end of October, beginning of November with more patients, more than 100 from the original dosing and the extension cohorts. Fenebrutinib, our BTK inhibitor in multiple sclerosis. We will present Phase II 48-week follow-up data at [ ECTRIMS ]. This will be mid-September. Data will also include relapse data for the first time. For Gazyva in lupus nephritis, we expect now the pivotal Phase III results in the third quarter already. And for our anti-TL1A antibody we will have Phase III starts for ulcerative colitis in Q4 and for Crohn's disease in Q1 '25. We expect to announce additional Phase II starts and indications outside of IBD at Pharma Day. And then moving on to ophthalmology. Our IL-6 vamikibart in ophthalmology will have data in DME in the second half. Chris will go here into more detail during his presentation. Unfortunately, we have also announced today that the ASO Factor B failed in geographic atrophy, which was a Phase II called the GOLDEN STUDY, and therefore, this molecule will not be moved forward. And finally, to finish here on CVM, we will have Phase I results for CT-388. That's our weekly injectable GLP-1 GIP agonist and for CT-996 our once-daily oral GLP-1 agonist to be presented at EASD. Can we please go to next slide. Before we start with the presentations, let me also quickly provide an update on the upcoming IR events. On September 13, we have now an IR call around EASD, where we will cover CT-388 and CT-996 data. On September 30, we will again host our annual Pharma Day in London as a live event and then on the first days of November, we plan now for an IR call focusing on our New York neurology franchise and the updated trotinemab data presented at CTAD. And finally, we plan to end the year with our fourth Digitalization Day, which will be end of November, beginning of December. We'll keep you posted as soon as these dates get finalized. And with that, let me hand over to Nilesh for an update on our ophthalmology franchise. Nilesh, please?

Thank you so much, Bruno, and good morning and good afternoon to everybody. It's a great pleasure to be with you all today. I'm really pleased to provide a quick overview of the retina market, the unmet need and the momentum Roche is generating in delivering innovation and impact across our late-stage programs for Vabysmo and Susvimo. Next slide. As you probably know, ophthalmology is broadly split into front-of-eye and back-of-eye diseases. Back of eye mostly retina, conditions of retina is both the largest segment, representing approximately $15 billion in sales across key indications, neovascular age-related macular degeneration, diabetic macular edema and retinal vein occlusion and is forecast to grow driven by aging populations around the world and diabetes rates, but also the introduction of novel approaches to address the still considerable unmet need in the area. Next slide. We all know that with the advent of anti-VEGF therapies, a great amount of improvement has already been delivered to patients, but outcomes can also be improved with better dosing. We know that many health care systems and providers often cannot deliver sufficient doses that allow patients to experience the types of outcomes demonstrated in clinical trials and then replicate these when shown in clinical practice. So we know that improved drying, which underpins the ability to extend interval and provide sustained efficacy across dosing will improve outcomes and drive prescribing behavior. But also we're working on improving efficacy on both vision and anatomy with novel approaches, which will allow more patients to achieve better vision outcomes. So on the slide, you see that, only half of patients are achieving around 20/40 vision. So there's a lot of unmet need still to drive. Next slide. So with both the Vabysmo and Susvimo, I think Roche provides innovative options to retinal specialists for their patients. Vabysmo, the first dual-pathway inhibition in retina and demonstrated that 8 out of 10 patients could achieve Q12 week or more dosing in both neovascular AMD and diabetic macular edema. That's driven by improvements in drying and anatomic versus afilbercept. And now with the unique Susvimo device, it's an ability to deliver equivalent outcomes to monthly intravitreal injections with 6-month dosing in neovascular AMD and Phase III data in both diabetic macular edema and diabetic retinopathy. In diabetic retinopathy patients were dosed over 9 months, and I'll share some more data from those in subsequent slides. Next slide. In conversations with the retina community, I'm often asked about the approach taken by adding novel modes of action beyond the established anti-VEGF. And this slide shows that retinal conditions involve multifactorial pathologies with the growth of pathologic blood vessels driving neovascularization, but that's also driving vascular leakage, inflammation and fibrosis continue to play a part in pathology. As you can see from the bottom of the slide, Vabysmo showed improvement effect across a number of markets, such as drying of central subfield thickness, macular leakage as well as hyper-reflective foci a surrogate measure of inflammation and epiretinal membrane which is linked to fibrosis in comparison to aflibercept. The results of the macular leakage were also replicated across both DME and RVO indications really adds to our confidence in the dual mode of action. Next slide. Here, I want to show a network meta-analysis, which was conducted. This is an approach to make indirect comparisons across trials, which we know is a little bit of a no, no. But we do know that we have Phase III data of Vabysmo versus aflibercept 2-milligram, and then there is Phase III data of aflibercept 2-milligram versus 8 milligram. If we combine these studies, which involved about 5,000 patients, at the 12-week endpoint where dosing was the same, you can see that in both diabetic macular edema and in neovascular AMD, the central subfield thickness measurements favored Vabysmo. So all the points are left of the vertical line. So we really see the impact of the Vabysmo in retinal drying across these indications consistently. Next slide. These features are really driving the continued growth of Vabysmo, which has been one of the most successful launches of recent years across prescribed medications. Currently approved, as Bruno mentioned in 98 countries and with fast reimbursement supported by strong market shares as well as continuing penetration in the first-line setting. Furthermore, with the approval of retinal vein occlusion in the U.S. and in Japan and a positive CHMP opinion in the EU also, the flexibility to dose with -- from Q4 to Q16 in label and the approval of the prefilled syringe, and you can see a nice image of that at the top right. We expect the momentum to continue to grow towards establishing Vabysmo as the standard of care in diabetes and retina. Next slide. An additional point I'd like to raise here is that the real-world utilization of Vabysmo we're seeing and many doctors mentioned for the first time, outcomes in clinical practice, which reflect those seen in clinical trials. The left shows the durability pie chart from TENAYA and LUCERNE Phase III studies. And the right show actual data from the Moorfields and Liverpool hospitals in the U.K., which shows very similar outcomes that are being actually experienced in the clinical practice setting replicating those seen in clinical trials. So now to Susvimo, if we move to the next slide, this will be the next blockbuster for Roche in the ophthalmology franchise. As a reminder, this is a device about the size of a grain of rice which can provide continuous delivery of a special formulation of ranibizumab and requires only twice a year refill or as I like to say, a recharge of the device in the studies. 93% of patients who had all experienced IVTs preferred Susvimo. We voluntarily recalled the product, and I'm thrilled that with the amendments made the FDA approved its reintroduction recently in neovascular AMD, and I'm told surgical procedures are already scheduled for today. On the next slide, I'll share data from DME and DR study, but currently, other studies in neovascular AMD, the VELODROME study as well as BURGUNDY study, which is the port delivery system with a novel molecule, zifibancimig, from the DutaFab platform, which is a VEGF-Ang-2 combination bispecific have already commenced in Phase I and II. And these really point to the platform nature of this molecule and this platform. Secondly, I'd just like to reiterate that with the initial feedback that we've had with the lubricated needle, the procedures seem to have a much better experience than the first generation. Next slide. As I mentioned, I'd like to highlight some of the data from the Phase III with Susvimo in diabetic macular edema on the left and diabetic retinopathy on the right. On the left, you see the familiar dosing and BCVA curve in diabetic macular edema, delivering equivalent outcomes to monthly ranibizumab in terms of best corrected visual acuity. The slide does not show -- this is corresponding with the central subfield thickness. And on the right, in diabetic retinopathy, which was dosed every 9 months as well, we see excellent results. No cases of endophthalmitis were observed in either study in the Phase III setting. Before handing over to Chris, I really want to conclude by saying that the momentum with Vabysmo across its performance and patient penetration: the drying, which I've shared with you; the width of indications, so promptly delivered; flexibility of dosing with Q4 to Q16 in label augmented by the real-world data that we're seeing as well as consistent safety. And now with the approval of the prefilled syringe will really drive towards the Vabysmo being the IVT standard of care in the future. Furthermore, we've made significant momentum with Susvimo and the PD platform, which will continue to bring the option of continuous delivery and even greater certainty of outcomes for patients and it's an exciting time for Roche and the of the franchise. Thank you for your attention, and over to Chris.

Great. Thanks so much, Nilesh. Moving over to the next slide. So I'm delighted to be able to share a little bit of an update on the progress of our ophthalmology pipeline. So as you've just heard from Nilesh and from Bruno, we've really been able to execute our strategy in ophthalmology very, very robustly, not just in the commercial domain, but also the research and development domain. So over the last few years, we've had, as you've had previously 9 positive Phase III clinical trial readouts. And hopefully, you'll be able to see some of the continuing excellence in execution of the strategy for our R&D programs as we progress them. So today, as you can see with our -- with this kind of graph on the left, we're continuing broadly 3 approaches. We have today's therapies, where we're continuing to address and treat people who suffered from vision loss in the classic retinal conditions, whereby we can improve, but we generally don't bring everybody back to the level of visual acuity and visual function, which they had before they suffered from disease. So we have great outcomes, as Nilesh said, with Vabysmo, but still there's a significant unmet need, which we need to address there. We're also continuing with our approach to address patients who've lost significant vision and have had significant damage to their retina, and this is through restorative approaches. I'll talk a little bit more about it in a moment, but the example that we're working on is the OpRegen program, which is an allogeneic cell therapy, but we also have an early research and optogenetics approach, which will be in place to replace damaged photoreceptors by converting live cells and viable cells to make them photo responsive. And at the top, obviously, we continue to explore opportunities to prevent vision loss. Be that through novel mechanisms of action, identify novel biomarkers to identify patients at higher risk of vision loss, and to protect key retinal images. If you can go to the next slide, please. And so we have these 3 broad approaches, be it the extended durability and future technologies; novel mechanisms of action; and digital capabilities. Now in terms of the long-acting delivery and extended durability, I'll talk a little bit in a moment about our port delivery platform. You'll have heard that it's -- the great news that we're expecting. The first new implantations to occur today. But we also have other approaches for extended durability and technology. So I've just mentioned the cell therapy, which has achieved FDA Fast Track designation, but the gene therapy with the optogenetics approach, and we've been partnered with Avista to acquire novel AAV technology, which is much more specific in really a next-generation AAV platform for intravitreal utilization. In terms of novel mechanisms of action, you can really see the benefit for patients, as shown clearly by the success of Vabysmo's launch, we also have additional and quite a large number of additional mechanisms of action in our pipeline. I'll talk briefly about IL-6 later on, but you will have known from a number of years ago that we've got our partnership with Sema 3A, with a novel Semaphorin-3A therapeutic to address retinal ischemia. We'll also be looking at new indications and potential for combination therapies because many of these diseases are clearly going to require combination therapies, be them through a bispecific or multiple mechanisms of action through different products. And finally, our digital capabilities. We really have a world-leading opportunity in terms of the number of patients in whom we have data on the omics, clinical data and imaging data, and we've brought all this in-house through our clinical trials and also through multiple partnerships. Really, this helps us to identify patients who are most likely to respond the best to different therapeutic approaches. We have remote vision monitoring tool, which is my vision tracking, and this is under a commercial launch in the U.S. currently, potentially, therefore, able to support vision function monitoring at home to really improve outcomes for patients and to support physicians and disease burden. And finally, we have a number of partnerships and internal programs looking at the use of artificial intelligence to support clinical decision making. If you go to the next slide, please. So I've mentioned about the robustness and strength of our pipeline. I've mentioned already the 9 successful Phase III programs, which we've seen, which have enabled the launch of Vabysmo and Susvimo and the anticipated approvals of Susvimo and DME and potentially DR in Q1 of 2025. But we also have a number of Phase III programs ongoing, which I'll talk about, vamikibart, which is the IL-6 program intravitreally administered the Enspryng program, which is satralizumab with thyroid eye disease. But we also have a number of exciting Phase II and Phase I programs with a number of exciting novel mechanisms of action. This is clearly, in our opinion, a world-leading retinal disease pipeline. If we can go to the next slide, please. So vamikibart is the name of our intravitreal IL-6 monoclonal antibody. It has a modified Fc region to ensure rapid systemic clearance, and we moved swiftly from a large Phase I program, which demonstrated some exciting data in patients with uveitic macular edema that you can see here, whereby, approximately 30% of patients gained 15 letters or more and we've moved into 2 identical Phase III studies globally managed. And we are awaiting currently Phase II data for this program in patients with diabetic macular edema. As I talked about earlier, execution and strong strategy are 2 of our mainstays. And in terms of execution, I'm been delighted that the MEERKAT study is already fully enrolled for this program. We're just waiting for the second Phase III, the SANDCAT to enroll. Data is expected for UME in 2025, therefore. If we go to next slide. Moving on to Enspryng or satralizumab in thyroid eye disease. Again, you will know that this is a major unmet medical need in ophthalmology. There's only -- the only approved product is only approved in the U.S. So we are excited that we are able to initiate 2 Phase III programs. Again, these are recruiting extremely well across the world. And we're really looking forward to being able to provide not just a novel mechanism of action to treat these patients, but something with well differentiated safety profile as well. We've seen with other IL-6 therapeutics that this approach of blocking IL-6 in patients with thyroid eye disease has been clearly demonstrated in a number of investigator-initiated studies. And therefore, we are really looking forward to being able to share our Phase III data in 2025. The studies, which are ongoing called SatraGO-1 and SatraGO-2. And if we go to the next slide. The OpRegen program, as a reminder, this is partnered with Lineage Cell Therapeutics. This is an allogeneic RPE cell therapy, potential here is significant because we see there's a potential to even not just stabilize but potentially to improve visual acuity. There was some data from our Phase I study, which showed that if the cells were injected under the retina and under the area of geographic atrophy, not just we didn't just improve the structure of the retina. And if you look at the OCT scans on the far right-hand side, the top one, you can see there's significantly greater structural damage and on the bottom one, you can see some quite improved structure there. This structure resulted in gains in visual function. So we really don't just see this as an opportunity to slow progression, but we see potentially as an opportunity to improve visual acuity and improve structure. This evidence of structural improvement has been maintained out to 24 months during this ongoing Phase I. This program is currently in Phase II with us at Genentech and Roche and we're excited to see what this extremely novel therapy will be able to do for patients across the world. Go to the next slide. And then finally, this is the reminder of the opportunities that we see with the Port Delivery Platform. So Susvimo is the first products using this platform. And as you've seen, we're able to maintain visual acuity out to 6 months, sorry, out to 5 years, broadly with our long-term data but with retreatment every 6 months, we see a significant potential to incorporate other therapeutics within the same device. And the zifibancimig is the first program to go into this device outside of ranibizumab. So zifibancimig is one of our DutaFabs, and we actually have 3 DutaFabs in clinic at the moment, 2 others whose mechanisms of action we've not declared. And on top of that, 2 additional preclinical programs which could potentially go into the Port Delivery Platform, giving us a total of 5 programs that have the potential to go into the Port Delivery Platforms from research through to clinical development. But the zifibancimig is the first one, and we're thrilled that the Phase I is ongoing and we've actually have patients in clinic being treated with zifibancimig, which is our VEGF-Ang-2 DutaFab, that are currently being treated. The benefits of the DutaFabs are they're actually the same size as a fab fragment. Highly concentrated, highly potent and extremely stable. So really ideal as a platform technology to go into the Port Delivery [implant]. So there's an awful lot more to come for the Port Delivery implant, and we're thrilled about the commercial relaunch. And next slide. And with that, I'm excited to share and pass over to Dr. Arshad Khanani, retinal specialists and one of a world-renowned clinical investigator. Thanks, Arshad.

Thank you, Chris. It's a pleasure to be here. I've served as an investigator for essentially all trials Phase II forward for Vabysmo as well as all trials for Susvimo. So today, my goal is to overview the latest 4-year data from the RHONE-X study that I recently presented at ASRS, followed by a summary and update on TRUCKEE and the SUMMIT study. These are non-pharma supported collaborative studies that we have launched to look at the real-world safety and efficacy of both Vabysmo as well as Susvimo. Next slide. Next slide. So looking at RHONE-X. RHONE-X is the largest extension study to date in patients with DME. This trial looked at long-term safety as well as efficacy of faricimab treated and extend in patients with DME. As you recall, the parent Phase III YOSEMITE and RHINE studies enroll patients with DME and after those studies ended, all patients that did not continue -- discontinue treatment had an opportunity to roll over to RHONE-X study for additional 2 years because we wanted to establish safety and efficacy over a total of 4-year period. In terms of dosing, all patients were initiated with faricimab, treat and extend up to Q16 week dosing in RHONE-X using the same treat and extend criteria that we used in the YOSEMITE and RHINE studies. As you recall, faricimab had 2 dosing arms in YOSEMITE and RHINE studies, and then we had that aflibercept control, faricimab Q8 weeks, faricimab treat and extend, and then, of course, on label aflibercept Q8 weeks with 3 loading doses. Next slide. So here are the results, the robust vision and CST improvements that were seen in the YOSEMITE RHINE studies were actually maintained in the RHONE-X study with up to 16-week dosing with faricimab with greater than 90% of patients achieving absence of DME at the end of the RHONE-X study. I want to highlight a few things there. I think it's important for practitioners as well as for our field. When you look at the patients who started with faricimab, whether it's faricimab Q8 weeks, or faricimab treat and extend, you see about 87% to 89% of those patients having absence of DME, and that continued with treat and extend dosing in both of those groups. When you look at aflibercept, we had only 81.7% of patients with on label aflibercept dosing, achieving absence of DME. And that number increased almost by 15% to 95.4%. I think this is the first time we have actually seen switch data in a large clinical trial setting, showing the benefit of going from VEGF suppression with aflibercept to dual inhibition with Vabysmo. I think this data resonates with clinical practice because we have been using Vabysmo in a lot of previously treated patients, and we have seen improvements in anatomy in DME and now in a clinical trial setting with over 1,400 patients we actually get the confirmation that, yes, going from aflibercept to Vabysmo in patients with persistent disease activity, actually improves their outcomes. And this was all achieved with approximately 80% of patients on Q12 weeks or greater dosing at the end of RHONE-X study and highlighting the benefit of dual inhibition in terms of sustained disease control and durability. Next slide. So just to summarize, these were the discussion points at ASRS, I think the most important to me is, again, to highlight that this is the largest long-term extension study that we have done in our space, which is very exciting to see. And we had an excellent patient retention of around 82%. So why would patients stay in a trial for 4 years total? That's because they're getting the value and the benefit of treatment, and we have significantly decreased treatment burden. Because it was faricimab treat and extend up to Q16 weeks, these patients only came in when they needed treatment, really decreasing the treatment burden. So I think there is value here to highlight the fact that if we can decrease treatment burden for our patients, we may have better compliance in the real world. As you all know, the real-world outcomes are not anywhere close to clinical trials because of the frequency of treatment and I think here, we have an opportunity to lower treatment burden with dual inhibition, with Vabysmo. Of course, safety is important. Safety, faricimab was well-tolerated. We did not see any new adverse instruments that were not consistent with what we have already seen in YOSEMITE/RHINE. The IOI rate was comparable with no cases of retinal vasculitis or occlusive retinal vasculitis seeing RHONE-X study. Again, BCVA and CST improvements were maintained in RHONE-X with majority of the patients, 80% going 3 months or longer. And absence of DME was achieving greater than 90% of patients with -- treated with faricimab, especially the switch patients, that number increased by approximately 15% because of going from VEGF supression to dual inhibition of VEGF-A and Ang-2 with faricimab. And RHONE-X has really demonstrated the long-term safety and efficacy of dual inhibition with Vabysmo in our patients with DME. Next slide. So we have done the [ TAHOE ] study and presented the data, which was in DME. It's a smaller data set. So today, I want to focus on the larger data set, which is the TRUCKEE study. And we have data for 2 years now and these patients were real world patients, and this could not be possible without all the collaboration from all the investigators insights you're seeing on the left. Again, this is non-supported, this is a collaborative study. As a group, we have really volunteered over time and efforts to learn more about this first molecule with dual inhibition in our space in terms of safety and efficacy. Next slide. So again, just a reminder, no industry support, and this is the design of the study. Let's go to the next slide. So we are looking at all comers in terms of enrolling patients in this study because we wanted to see the benefit in real-world setting where patients come in different anatomic and vision parameters as well as naive and previously treated patients. As a reminder, the Vabysmo, TENAYA, and LUCERNE Phase III only recruited patients with naive wet AMD. So we had no data when we launched TRUCKEE over 2 years ago on patients with switch. So obviously, when a new drug comes to market, we are mainly using it on patients who are really high need to actually see the value. If you use it a naive patients, sometimes it's hard to know the benefit. So we are taking patients who are -- have persistent disease, who have high need on standard of care agents and switching to see the benefit of dual inhibition. In this study, we are collecting demographics, prior treatment history, efficacy outcomes based on vision and anatomy as well as durability and safety. So looking at next slide, we see that these are the demographics. We have a large number of eyes in this study, and this is as of last data cut, and obviously, we'll have more data cuts in the future. You see that majority of the patients were switched from aflibercept. And this is not surprising because aflibercept 2-milligram has been the standard of care, branded agent before Vabysmo came to market, and I think physicians wanted to see how we can help our patients who are on aflibercept by switching them because of the new mechanism of action in addition of VEGF-A, we have Ang-2 suppression. And then, of course, the naive patients about 10%, and that number increases. So usually, when a new drug comes in, you're trying tough-to-treat patients and you establish that it's more efficacious, whether it's on CST or some other parameters. And then after you get comfortable with efficacy as well as safety, you started in the naive patient population. Next slide. So looking at efficacy after 3 injections of faricimab in all switch patients. These are all patients that were switched from prior anti-VEGF. And we have a large number of eyes here, [ 1,735 ] eyes. And when you look at the previous interval, it was about 45 days in these patients. So as I said, anywhere, anybody with 4 to 6 weeks, a need for injection, whether they have persistent fluid, whether they cannot be stretched are in this data set. And what you see is that after 3 injections of faricimab, we are able to increase the durability in terms of decreasing their treatment burden. Of course, these are high-need patients. So we have 9 days improvement after 3 injections. But I think to me, as a clinician, the most important thing was anatomic control. When you look at patients, you're seeing improvement in CST, which is what we treat patients on based on OCT and stable visual acuity and then decrease in PED height, which is also a marker of disease activity. So as clinicians were using OCT to control disease and dryness leads to better durability. So having improvement in CST leads to increase in treatment interval, as we see here. Next slide. When you look at aflibercept switch patients, we see another consistent data set, again, 8.4 days and significant reduction in CST and PED height after 3 injections, again, highlighting the benefit of dual inhibition of VEGF-A and Ang-2. Next slide. Treatment-naive patients perform very well in the real world. Remember, clinical trials of inclusion and exclusion criteria. Here we are taking all comers. We have 186 eyes and we saw visual acuity gains after 3 injections as well as significant decrease in CST and PED height, highlighting the benefit of dual inhibition. Next slide. So in terms of fluid resolution, if you look at all switch patients, aflibercept switch patient as well as naive patient, we see a consistent story. We see that we are actually benefiting our patients in disease control by decreases intraretinal fluid and subretinal fluid, irregardless of patient population. Next slide. After 6 injections, we have 771 eyes. We actually are able to increase the treatment interval further in all switch patients to about 12.6 days, highlighting that sometimes aggressive treatment and multiple injections lead to better disease control, especially which you have a new MOA in work here with Ang-2 inhibition. And we saw that there were anatomic outcomes actually continue to improve with greater reduction in CST and PED heights reaching a p-value that's significant with stable visual acuity. Next slide. Similarly, aflibercept switch patients, we saw the same thing with 6 injections, about 2 weeks which is very meaningful for these patients who are very, very high need, where a day or 2 can make a difference. We're able to extend by almost 2 weeks with, again, by improving anatomy and stable visual acuity. Next slide. Naive patients score has small number of eyes, 90 eyes, but what we see is we see continuous improvement in anatomy after continuous injection of faricimab in this patient population with increases in visual acuity. Next slide. Again, fluid, same story as before. We continue to have improvements in every single parameter that are clinically relevant, whether it's intraretinal fluid or subretinal fluid, again, across all patient populations. Next slide. When you look at 9 injections, again, we are able to see that we continue to improve on anatomy with stable visual acuity and the treatment interval stabilization around 2 weeks, again, highlighting the benefit here. Next slide. And aflibercept switch patients, again, improvements in anatomy, stable vision and durability. Next slide. Naive patients, we are able to gain more vision. Of course, there is small number of eyes here, 28 eyes, but you can see we're getting visual acuity gains that are comparable to clinical trials here with significant improvement in CST and PED, all reaching a significant p values. Next slide. Retinal fluid after 9 injection. Again, the same story. I don't want to bore you, but with this new dual inhibition, we are able to control disease much better than what we have seen in the past. Next slide. Now we did a fluid quantification study. This is an independent study with partnership with Notal. They did it voluntarily, nobody paid them for it. And we're basically analyzing the fluid quantification with using the AI algorithm. So the intraretinal fluid, subretinal fluid data I documented was site reported. This is an independent algorithm running to see how we are helping patients control disease. As a reminder, we treat patients based on OCT and on OCT, they can quantify fluid, even to nanoliter levels. Next slide. So when you look at the fluid quantification, eyes with greater than 5 injections, whether you have all eyes, prior aflibercept eyes or naive eye, you see the consistent story. You see that there is a significant decrease in fluid volume and majority of the eyes have decreased in fluid, as you can see, around 80% to 90%. And many of these eyes actually resolve fluid, which is very difficult in these tough-to-treat patients. The other thing to highlight is the interval between the last treatment and faricimab was around 35 to 37 days in the previously treated patients and that interval improves by almost 10 to 14 days to 52 and 51 days. Again, very consistent with the data I've shown you earlier. Let's look at the next slide in terms of improvement in fluid. We have seen rapid improvement in fluid and drying with faricimab in TENAYA and LUCERNE studies. Again, those were naive patients. Here, we have all eyes in previous aflibercept eyes. And if you see the curve in orange change to red, where you see that patients who are on aflibercept started with 44.9 days in terms of their treatment interval. Look what happens after switching them with a new MOA. You see rapid improvement in that fluid down in nanoliter levels from 150 to almost 90. So great reduction. And then you're able to continue to improve some of those patients who did not have that improvement right away because patients are very heterogeneous, they come with different disease parameters. And you can see that by the end, you are having majority of these patients with minimal fluid with extension from 44.9 days to 60.4 days. So again, increasing 2 weeks in these really difficult to treat patient population, independently confirmed by this AI algorithm. Next slide. And again, this is another way to look at it in treatment naive patients. We see exactly what we saw in clinical trials. Rapid improvement in anatomy after the first few injections. And then maintenance of anatomy with increasing durability. Next slide. So safety is a paramount important. There was a whole goal of TRUCKEE study, of course, safety for a new drug, especially with our experience in the past. We have safety on 3,412 eyes with the number of injections is 16,682 across the country. IOI per injection was 0.08%, endophthalmitis were 0.024%. All these events resolved. Many of them we challenged with faricimab because patients did not get durability or disease control with the other agent, and they restarted. There have been no cases of retinal vasculitis, retinal artery occlusion so far in this trial. So to summarize, TRUCKEE is an ongoing collaborative study. We can go to the next slide. Looking at faricimab in a real-world setting in difficult-to-treat, previously treated patients as well as naive patients, and we have seen the benefit of dual inhibition in terms of drying, in terms of controlling durability, very consistent with what we have seen in the clinical trials and safety appears to be also comparable to other agents we have seen in clinical practice. So over the next few minutes, let's jump on to the SUMMIT study. This is a poor delivery study that I recently presented the data at clinical trials at the SUMMIT. This data is still maturing. These are implants that were placed before the recall. Let's go to the next slide. Again, thank you to all the investigators. When you look at the SUMMIT study, it is very much like what we have done for TRUCKEE and [ TAHOE ]. We collect all data in terms of efficacy and safety, of poor delivery system. One thing to highlight that these are surgeons who have used it in commercial setting. So they are actually trained surgeons. And I think that's one thing I've seen with the port delivery system that there's a learning curve in terms of surgery, and after you follow all those steps and have some experience, you can really optimize the safety outcomes in terms of the risk and benefit profile for these patients. Next slide. So when you look at demographics, we have 46 patients and again, across the country, this is collaborative, non-pharma supported. Next slide. And let's look at the results. So this is ETDRS change. We convert Snellen to ETDRS you see that there is a drop in visual acuity just like as expected after the surgery that we have seen in the PDS trials. But then over time, the visual acuity is maintained, and we have data for 1 year on these patients. This is for me, very relevant because the visual acuity in the real world is never compared to clinical trial. And as you recall, from the Phase III ARCHWAY study, patients had maintenance of visual acuity. So these patients are looking at decreasing their treatment burden, decreasing fluctuations in anatomy and disease so that we can have long-term stable vision. Next slide. When you look at CST, these are the CST changes over time. Again, you see the maintenance of CST which is well controlled over 1 year of follow-up. Again, avoiding the real-world CST fluctuations that we usually see from misinjections and less compliance. Next slide. When you look at durability, as you recall, ARCHWAY had a fixed 6 months refill regimen, the Phase II had a PRN regimen, the LADDER study, with median time to refold, there was 15.8 months. In real world, most physicians kind of follow the Phase III protocol, but some also treat and extend or do PRN based on their comfort level. When you look at the average days until first refill, it was 258 days, around 8.6 months, which is remarkable in terms of these patients who were requiring frequent injections before enrolling in this study. Now in terms of supplemental injections, only 1 patient received an aflibercept injection, and that was because of logistical issues where it did not have the refill product in their clinic. And that's why refill exchange was not done, but rather given in aflibercept. So if you take that patient out, essentially no patients have required additional rescue or supplemental anti-VEGF injection really highlighting the benefit of Port Delivery System in a real-world setting in terms of decreasing treatment burden. Next slide. In terms of safety, I think we have learned a lot over the last 8 to 9 years in terms of proper surgical technique. We actually saw the recent Pagoda and Pavilion data looks much better than wet AMD program and part of it is the learnings we have implemented. Any surgery that comes in, we need to optimize, and that's what has been done here. I told you these are experienced surgeon. We don't have any ongoing events at this point. We did not see any cases of endophthalmitis or congenial retraction in all of these postsurgical adverse events resolved over time. So I think there is the learning curve, as I said, and I think with in the hands of experienced surgeon and training the new generation of surgeon we'll be able to utilize this Port Delivery platform to address common retinal diseases in a safe and effective fashion. Thank you very much. I will pass it to Bruno now.

Thanks, Arshad. With that we can open the Q&A session. Let me remind, please, everyone that we are still in a quiet period. We have the half year results coming on Thursday. So we will not be able to take any questions regarding the Q2 business performance. With that, the first question goes to Simon Baker from Redburn. Simon, please.

I will refrain myself to 2, please. I wonder if you could, in light of the news on ASO factor B, if you could give us any more detail there in your level of ongoing interest and confidence within geographic atrophy? And secondly, you gave us a very thorough view over the whole of the large ophthalmology portfolio. Arguably, with one exception, which is gene therapy, I just wonder if you could update us on your current activities in gene therapy. It's been a little quiet there since the Spark deal a few years ago.

Should I take that? And then Chris, if you want to just add on that. So our interest in geographic atrophies remains really strong. Chris can highlight some of the programs that we've got ongoing in our public domain. We also have ongoing research in the reds in GA as we look to see -- address the unmet need there. So Chris, do you want to take on the other gene therapy question and ASO Factor B?

Sure. Yes. Thanks, Nilesh. Yes, reiterate, obviously, the RPE cell therapy is in GA. So that's ongoing. And we do have early research continuing to innovate new targets in GA. Gene therapy, I kind of mentioned it briefly, but we do have interest in the primary route that we're going after is optogenetics. That's looking at converting retinal cells into photosensitive cells. We've seen some interesting papers in the peer-reviewed literature to demonstrate early success outside of Roche there. We believe that our partnership and our utilization of the Avista capsid has the potential to be a next-generation gene therapy. The advantage of optogenetics is really that you can treat many more patients. So it's obviously, with monogenic retinal conditions, they are more than 80 different genetic mutations, which characterize these. So therefore, if you go after single gene mutations, you have to have 80 different therapies. The optogenetics approach is therefore the route that we're going down. We're continuing to progress it. But yes, very, very excited about opportunities in gene therapy still.

Then next questions would come from Richard Vosser from JPMorgan. Richard?

Just a couple of questions, please. Just on the IL-6. So just looking at the data, there seems to be maybe not too much of a dose response and the highest dose maybe went a little bit below 0 on visual acuity when it's first given. So just maybe you could give us some understanding of how the reasoning behind the dose response that seems to be in that data. And you mentioned that some patients gained a lot of letters. Is there any sort of biomarker work in the Phase III that can be done to sort of identify the best patients for the IL-6. And then just one quick one on Vabysmo. So some reports early on in the year of higher IOIs, I noticed the real-world data was pretty low. So just any thoughts or latest thoughts on IOIs with Vabysmo and just reassure us there, please.

Chris, do you want to take the IL-6?

Sure. Thanks, Richard. Great question. So with the vamikibart, you've made me pronounce it wrong there. Vamikibart program, absolutely. So what we do is we do see strong suppression of IL-6 both with the -- with both doses that we've investigated and both doses that we've moved into the Phase II, sorry, into the Phase III program. So there is absolutely due to the complete suppression of IL-6 there is less dose response that you would expect if there is incomplete suppression at one of the doses. So hopefully that answers your question. But we've moved 2 doses into the Phase III, both of which we're very comfortable, fully suppressed, intravitreal IL-6. In terms of biomarker, that work is ongoing. We've not confirmed or we've not been able to confirm that there is. I mean the obvious biomarker is intravitreal IL-6 levels, does that predispose you to a greater or lesser response. We're looking for UME to treat all patients, and we've not been able to confirm the presence or absence of a biomarker yet. We'll obviously be looking that in the Phase II DME study when that reads out in the second half of this year. And we'll be able to share that data once it comes out. But not so much able to share at the moment. Nilesh, do you want to share on the comment on the Vabysmo?

Sure. Maybe I can hand over to Hugh, if I want. But just one comment to make, Richard. We have over 4 million vials in circulations and all of the data we've seen thus far is very much in line with IVTs, but Hugh, can comment further with any details.

Yes. So we're more than 2.5 years since initial launch of Vabysmo and as Nilesh mentioned, we have now 4 million vials in distribution. We continuously monitor all adverse events, including IOI, and we've not seen anything in our data that indicates any difference from what we saw in our Phase III trial. I think the other important thing is there's been a wealth of real-world data that's been produced, including our [ short ] study in TRUCKEE, where I think we now studied basically 400,000 injections and 35,000 patients in real-world studies. And those also show IOI rates that are very consistent with what we see in the Phase III. We will continue to monitor this. But I think the wealth of the data shows that we are doing exactly like we saw in our Phase III programs.

Hugh can I follow up on that, just real quickly. I think when a drug comes out to market, a new drug, within the 6 to 12 months period, we are able to see if there is safety differences and we are over 2.5 years now in the U.S. with extensive experience in a very broad patient population with many of them previously treated with anti-VEGF. So we really haven't seen anything in TRUCKEE or from that experience. Of course, there's always case reports that are published on any drug that comes out. But I don't think there is anything that is different than what we have seen in the trial, and that's where RHONE-X data over 1,400 patients is important to see if there were any safety things that we saw over long term and we haven't. And this data is coming out at the time, they're almost hitting 3 years in the U.S. also. So I think consistent of data is something that's important and not having events within the first 6 to 12 months kind of reassures us that this data that we have seen in the trial is consistent with the real-world practice.

Richard, did we answer all your questions?

Yes. That's excellent.

And the next one in the row would be Colin White from UBS.

Colin White, from UBS. Given how well Vabysmo is launched, I just was wondering if you could give us a bit of color on what you'd expected impact of the prefilled syringe is going to be on uptake on the acceleration of the growth or expansion of the opportunity? And then my second question was about Susvimo and the relaunch. Clearly, patients who have had the treatment seem to prefer it to the injections. But in each of the indications which is in development, as you relaunch it, what is your estimate of the proportion of patients that will opt for a permanent implant in the eye.

Thanks, Colin. So just on the Vabysmo in PFS, maybe I'll get to Hugh and Jake to comment from the U.S. and kind of a global perspective. A couple of things just to note here though, we launched with a vial early because we do think that the effect, the innovation is more important than the delivery. But in this marketplace, prefilled syringes, when you have a product are very important. You've seen the conversion when we've had products with a vial go to prefilled syringe. Adoption rates go very high. So 90%, 95% of market with pre-filled syringe adopt that way. It does help high-volume practices with the delivery as well as reduce marginally the rates of safety as well. So on that one, I'll kind of maybe hand for any further comments to Hugh and Jake and if Arshad has anything to say on PFS, that would be useful to cover that. And then let's come back to Susvimo straight after that.

Yes. Happy to chime in on this one. So in speaking with physicians, there's incredible excitement about the prefilled syringe becoming available. Many clinics have said I can't actually use it as my preferred agent because operationally, the extra time of drawing from a vial slows me down too much. So for instance, EYLEA 2-milligram in a prefilled syringe was able to serve that need with Vabysmo be able to provide that and providing the best drying excellent durability in the dual pathway inhibition. There's a lot of enthusiasm for converting a whole lot more patients. Exactly what that translates to in market share, we'll need to see. And it also have to do with how long we have the prefilled syringe ahead of 8-milligram EYLEA, who, of course, is trying to get one as well. And then on the Susvimo side, this is a new paradigm. It truly is a new paradigm putting a port in and having the medicine perfectly titrated and basically keeping the disease at bay consistently and over months and months as opposed to a bolus of medicine going in. So first step is really having the physicians understand the potential of treating their patients like this. And then operationally bringing that into the surgery center and making room for it in the surgery center in partnership with ambulatory surgical centers and hospital ORs. If we're successful with that, I think the potential is quite strong, but getting too specific this early is a little bit hard to do.

Arshad do you have any comments on either of those PFS from a clinician perspective in Susvimo as a trial list.