Roche Holding AG (ROG) Earnings Call Transcript & Summary

You're invited to send in questions for this throughout the entire session using the Q&A functionality of Zoom. In addition to that, you may also raise your virtual hand to address your questions verbally. [Operator Instructions] One last remark, if you would like to follow the presented slides and as well, please feel free to go to roche.com/investors to download the presentation. At this time, it's my pleasure to introduce you to Bruno Eschli head of Investor Relations. Bruno, the stage is yours.

Thanks, Henrik. And could I have the first slide, please? So welcome to our first IR call in 2023, focusing on our fast-growing ophthalmology franchise. And let me quickly guide you through today's agenda. We have 3 speakers with us today. The first one will be Nilesh Mehta, our Global Franchise Head of Ophthalmology, responsible for global product strategy. Nilesh will provide an update on our overall franchise strategy. Secondly, we have Christopher Brittain, our Vice President and Global Head of Ophthalmology, responsible for product development. Chris will provide an update on our early and late-stage ophthalmology pipeline, including latest platform technologies added, such as for example, our cell-based therapies or the development of digital tools. And finally, we are very pleased here to have with us today Dr. Veeral Sheth, a well-known retina specialist and a Vabysmo clinical investigator, who will lead us through all the 3 pivotal studies presented at Angiogenesis. He will -- these studies are, so firstly, the Phase III studies, BALATON and COMINO, for Vabysmo in RVO; secondly, the Phase III study, PAGODA for Susvimo in DME; and thirdly, Phase III study, PAVILION Susvimo in DME in diabetic retinopathy. Overall, the call will go for 90 minutes. We will have 45 minutes planned for the presentation, and this will be followed by 45 minutes to take your Q&A. During the Q&A, we will also be joined by [ Yu Min ], life cycle leader for Vabysmo; and by Pierre-Alain Delley, our life cycle leader for Susvimo. Could I have the next slide, please? So before we start with the presentations, I just wanted to make a quick upfront comment on what an exciting year actually lays behind us. And last year, at around the same time at the same place, I showed a slide citing various polls amongst ophthalmologists. Firstly, on the high unmet need still remaining for patients with AMD and DME; and secondly, on the ophthalmologists' willingness to switch their patients to Vabysmo or to consider Vabysmo as an initial therapy based on the pivotal Phase III data which we had presented. So today, 1 year later and 4 quarters into the launch and with additional real world data being collected and confirming Vabysmo's differentiated efficacy and safety profile, we clearly see these changes in the paradigm treatment now happening. As you can see on the left side, Vabysmo has achieved an excellent market uptake, also when compared to historic launches like for example Lucentis or EYLEA. And actually, the identical graph we could show for the U.S. And what you also can see here clearly is the accelerated momentum, which we had last quarter after we got the J-code in October. As mentioned before, we see roughly 70% of the patients being switches from EYLEA, 15% to 20% of the switches are coming from Lucentis. And amongst the remaining part, we see an increasing number of newly diagnosed patients. On the right side of the slide, you see 2017 and 2022 sales splits according to our main business areas. And the graph show recent development successes, especially for our drugs like OCREVUS, Evrysdi, Enspryng and HEMLIBRA, which have allowed us to successfully enter new markets and have led to a diversification of our pharma portfolio outside of oncology. Only within the last 5 years, Roche emerged as an industry leader in neuroscience and hemophilia A. And going forward, we actually expect that this broadening will continue, but also becoming a leader in ophthalmology. 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, everybody. It's a great pleasure to virtually connect with many of you again and provide an overview of progress within Roche Ophthalmology. Next slide, please. So 2022 was a year of significant progress. This is the fruition of efforts made over many years. Last year, Roche made progress with launches, additional positive Phase III data, both in longer-term follow-up with approved indications in neovascular AMD and DME, as well as new indications, as just highlighted by Bruno. And we progressed the pipeline. You'll hear later from Chris and Veeral on the data that was just presented at the Angiogenesis conference. I like to think of this being a pivotal year where the franchise made the transition from Phase III potential, which we've been discussing with you over years, to patient reality. If we move to the next slide. This is not news to many of you. And retina continues to be the largest value segment within the ophthalmology market, and it's continued to -- forecast to grow even further, driven by [ EPI ], the growing populations of aged people around the world, as well as diabetes. But in addition to that, we think it's going to grow through innovation addressing unmet need. Next slide. So let's maybe look at how we frame the unmet need in retina. We see patient outcomes compromised by discontinuation, undertreatment and efficacy beyond anti-VEGF. Let's go into each of those. 1/3 of patients discontinue on any treatment in spite of the benefits they see in vision when they're treated. In the real world, the ability for health care systems and providers to deliver sufficient doses that sustain outcomes is simply not possible in many circumstances. Also, we know that, even in a Phase III setting, where patients are treated and followed up robustly, only about half get to 20/40 vision, which is about 70 letters, usually that required for driving. And hence, our approach has been to innovate beyond anti-VEGF alone and address the multifactorial disease processes that occur and that can then deliver deliverability with sustained outcomes. Next slide, please. And that kind of nicely segues me into the Vabysmo Phase III 2-year follow-up data that really confirmed and then augmented the 1 year. We -- in the matched dosing arms, if you see on the left-hand side of this slide, in DME, Vabysmo showed greater drying than the comparator, aflibercept. In previous studies where additional anti-VEGF has been used, we haven't seen such an effect; and durability increasing to over 60% of patients achieving Q16 every 4 months in both neovascular AMD and consistently in DME; and 80% achieving Q12 dosing every 3 months or more. So these are the data from the Phase III studies. And let's take a look at what we know is happening in the clinical practice setting. We move to the next slide. And I think this is the evidence is that really Vabysmo is working very well and is very consistent with the Phase III studies. What we're particularly pleased is that, in such a short period of time, we're able to share clinical practice data after the phase -- pivotal Phase III data. As you could -- as you would expect, most of the initial use is coming from switch patients whom doctors believe to have persistent fluids and where outcomes could be improved, about 2/3 of this coming from aflibercept. And what we're seeing is that they're noticing positive anatomic impact across a number of markets, including central subfield thickness, intra and subretinal fluid. And along the way, this data is really confirming the safety profile in clinical practice, and this continues to build confidence in greater first-line use for Vabysmo. Moving to the next slide. And the result of both the Phase III data and this real-world clinical practice data saw really encouraging and positive launch for Vabysmo. Vabysmo made a very encouraging quarter 4, and we're seeing continued growth in the new year, proving that our sales in Q4 were not a blip. And we're looking forward to sharing further updates as we move through the year. I'd like to highlight that health care systems also see the value of Vabysmo. This is demonstrated with over 50 approvals in a number of countries and as well a number of national reimbursements in a really relatively short period of time, just over 11 months since the first U.S. approval. That and the reassurance of the safety profile, with over 450,000 vials, and this number continues to grow on a daily basis, is continuing to drive further first-line use and expansion into that space. Furthermore, you'll hear more about broadening the additional indications. So retinal vein occlusion is the third biggest unmet need in retina. So the uptake and the real-world experience continue to provide confidence to us that Vabysmo is positioned to be the new IVT standard of care in retina. Next slide. So let's take a look at beyond IVT delivery. And I want to, on this call, reassure you of our commitment to the port delivery system platform and Susvimo. It's the only type of device of its kind in the world. We took a difficult, I think responsible, decision to voluntarily recall Susvimo based on some manufacturing variability that we uncovered. This is a technical challenge to overcome, and the teams have already made significant progress to understand it better. And we look forward to kind of bringing this platform back to the market in about a year. I want to reiterate the commitment to the platform. It has a potential to provide continuous medicine to the retinal tissues which require it, and in a manner that no other alternatives are unable to and thereby deliver on the promise of outcome certainty. The recent data from the Phase III PAGODA and PAVILION studies, which you'll hear more about, as well as some of the pipeline molecules destined for the PDS only further reinforce our commitment to its part in addressing unmet need in retina. I hope that gives you a good overview. And with that, I'd like to hand over to my colleague, Chris Brittain.

Thanks, Nilesh. So as you've seen, patient uptake of Vabysmo is going from strength to strength. And in fact, we are now seeing in the pipelines of other companies that faricimab is being used as a comparator in their randomized controlled trials, reinforcing our belief that Vabysmo is the new standard of care. But now I wanted to share a deeper dive into what's come out in our pipeline. So if we can go to the first slide, please. With the platform that Vabysmo and Susvimo have given us, our research engines are taking a two-pronged approach to alter the trajectory of vision loss experienced by so many people across the world. If you consider that anatomical damage generally precedes function loss, and that the end game for many of these conditions is functional blindness, we are aiming to firstly address this area at the top-left of the graph: To preserve vision in early stage disease. And a great example of this is the PAVILION data, which Veeral will be sharing with you -- with us later. And secondly, to restore functional vision to those suffering from end-stage disease in the bottom right of this graph. And the great example we have here is through our OpRegen cell therapy program in geographic atrophy, which is in clinic, and additional early research work in the area of optogenetics. So if we go to the next slide. We aim to achieve this strategy through these 3 linked approaches. Firstly, identification of biomarkers and their integration with patient monitoring and clinical decision support to help identify the right treatment for the right patient. And secondly, through new mechanisms of action and new indications. So having demonstrated that Vabysmo -- with Vabysmo, we've now started -- sorry. Having demonstrated the benefits of dual pathway inhibition with Vabysmo, we've now started 2 Phase III studies specifically addressing inflammation with our IL-6 program. Now many of these novel MoAs that we have in our pipeline will open up the potential for combination therapy in diseases such as geographic atrophy, diabetic macular edema, which were well recognized to be multifactorial. And finally, we continue to investigate additional extended durability approaches in addition to the port delivery technology, and novel approaches such as cell therapy and gene therapy. A recent example of which was the gene therapy -- it was a deal with the gene therapy company, Avista. Next slide. And so this leads us to the current state of play of our pipeline. On top of Vabysmo and Susvimo, we have 9 additional new molecular entities in clinic, which 1 is in Phase III, and that's the IL-6 program; 3 are in Phase II, one of which is the Vicasinabin molecule, which is, again, the top left of that graph, which has been in patients with diabetic retinopathy; and 5 molecules in Phase I. We believe that this represents the strongest pipeline in ophthalmology. And within this, we expect, as I say, this Phase II Vicasinabin diabetic retinopathy study, to read out in the second half of this year. Next slide. Now I want to take a little bit of a more detailed look at the IL-6 program. First, it's just important to know that IL-6 -- and to remind everybody, that IL-6 is a truly pleiotropic cytokine and is involved in many pathways, including angiogenesis, blood rectal barrier breakdown, leukocyte adhesion and chemotaxis and of course information. IL-6, as you can see on the right here, has also been shown to be upregulated in multiple retinal diseases, including diabetic retinopathy, vein occlusion and retinal detachment. Next slide. Our anti-IL-6 mAb molecule binds IL-6 and has a modified Fc region which enables rapid systemic clearance, important for our ophthalmic products. While the impact on patients of DME remains well recognized, and we have 2 Phase II studies ongoing in this disease with anti-IL-6, we are pursuing a fast-to-market strategy in the uveitic macular edema indication due to the high unmet need in this indication. UME is the accumulation of fluid in the retina that occurs as a complication of uveitis in about 1/3 of uveitic patients. And there's a rough idea. There are approximately 0.75 million patients that have uveitis in the EU and U.S.A. alone. Moving on to the next slide. You will recall that we have mentioned the DutaFab platform repeatedly over the years. And as a reminder, these are the next generation of intraocular bispecifics. Now the size of a fab fragment is similar to ranibizumab, but with the ability to target multiple moieties. They can be highly concentrated, are engineered for higher affinity and are extremely stable, meaning that they are also compatible with the portal delivery implant. In fact, they're all going to be primed for entry into this device. I'm really excited to say, though, that 3 DutaFabs are actually in clinic in Phase I with the most advanced being the VEGF Ang-2 program. Next slide. I now want to switch over to geographic atrophy. Now as we all know, February is a big month with the potential first approval of any therapy for patients with GA. However, what's very clear is that, even if any therapy is approved this year, a lot of unmet need will remain for the over 5 million GA patients globally, both in terms of efficacy, durability of treatment and patient convenience. This is because GA is a complex multifactorial disease and complement is only one part of the story. Next slide. So our approach to GA involves 2 programs. Firstly, targeting complement factor B systemically with an antisense oligonucleotide to inhibit complement factor B production and thus reduce the activity of the alternative complement pathway. This systemic and subcutaneous approach has the potential upside of treating both eyes simultaneously and potentially being self-administered, thus allowing much -- greater and more convenient care for the patient. Next slide. Secondly, OpRegen is an allogeneic RPE cell replacement therapy that is in Phase II presently looking at both restoration of RPE loss in areas of GA and also optimization of the surgical procedure used to safely and effectively deliver the cells subretinally. As presented last year, the Phase I did show restoration of retinal structure in some patients on top of gains in visual acuity. So we're excited for the continuation of the OpRegen program. Next slide. Now in closing, I'm excited also to share that our personalized health care program continues to go from strength to strength, with both development of algorithms to improve personalized patient management and also the release of the next version of the home vision monitor in the second half of this year. For those of you that don't know, this device has already demonstrated significant success during COVID and actually won the U.K. Health Services Journal Award in '22 for the Virtual Care Initiative of the Year, which has performed in partnership with Moorefields Eye Hospital. Now this is a great example of the collaborative approach we take with so many partners in the development of our therapeutic pipeline. And with that, I'm very happy to introduce Dr. Veeral Sheth, medical retina specialist and Partner and Director of Clinical Research the University Retina and Macula Associates Chicago to talk about the latest Susvimo and Vabysmo data. Over to you, Veeral.

Thank you, Chris. As Chris mentioned, my name is Veeral Sheth. I'm a retina specialist in the Chicago land area, and I was a principal investigator on all the studies that we'll be discussing today. Next slide, please. Here are my financial disclosures. We go ahead to the next slide. As Bruno mentioned earlier, and as Chris just mentioned, we're going to be talking about 3 specific clinical trials. One looking at faricimab, and in this case, a Phase III study looking at the treatment of retinal vein occlusion. And then we'll pivot to 2 port delivery system clinical trials in Phase III that were just presented, as far as data goes, at Angiogenesis this past weekend. So we'll go over a little bit of that data as well. Let's go to the next slide. So first, we're looking at faricimab in retinal vein occlusion. These are results from the BALATON and COMINO Phase III studies. BALATON was a clinical trial looking at branch retinal vein occlusion, whereas COMINO was looking at central retinal vein occlusion. Let's go ahead to the next slide. Again, these were Phase III randomized, double-masked, multicenter trials designed to evaluate the efficacy and safety of faricimab versus aflibercept. You can see the key inclusion criteria here. And of note, the primary endpoint in both of these studies was the change from baseline in BCVA at week 24. Patients were randomized into 1 of 2 groups, 1 receiving faricimab every 4 weeks, and the other receiving aflibercept every 2 weeks -- 4 weeks. And this was going through week 24. Again, that's where the primary endpoint is, and that's really the data that we're going to focus on today. Interestingly, this trial is set up at week 24 to transition patients to faricimab, into a personalized treat-and-extend regimen. In other words, these patients will convert all over to faricimab, and their dosing interval could have been extended. And we're looking forward to seeing what that data shows once that study wraps up. So we'll go to the next slide and really just focus on the 24-week data. We saw that faricimab achieved robust vision gains and reductions in CST across the studies and that the results were comparable between treatment arms in both trials. So first, looking at the top here. This is the BALATON data, where we saw 16.9 letters gained in the faricimab group versus 17.5% in the aflibercept group. And as far as central thickness of the OCT goes, we saw 311-micron improvement in the faricimab group versus 304 in the aflibercept group. Similar trends in the COMINO study as well, where we saw 16.9 letters gained in the faricimab group at 24 weeks versus 17.3 in aflibercept. And again, nice CST results as well, 461 microns of improvement in the faricimab group versus 448.8 in the aflibercept group. The next slide, please. Now this next slide is really kind of where, as a clinician, as someone that was involved in these studies, but more importantly, as someone that treats patients in the office, this is where I really focus on. For us, faricimab represents a new mechanism of action. And so what we want to see in these newer therapies is, anatomically, are we seeing significant differences? And so here, what we saw was that more patients achieved absence of macular leakage with faricimab versus aflibercept at that 24-week end point. And so if you look at the left here, BALATON, we saw 33.6% of patients receiving faricimab achieving that absence of macular leakage versus 21% in the aflibercept group. And in COMINO, we saw the same trend, 44.4% in the faricimab group achieving absence of macular leakage versus 30% in the aflibercept group. Again, this is kind of, to me, where we want to see that progress, and I think this is translating to better patient outcomes. Let's go ahead to the next slide. Faricimab was well tolerated with a safety profile similar to that of aflibercept. Again, it was mentioned earlier, the TRUCKEE study. The TRUCKEE study is a real-world study that we looked at. Again, we're one of the investigator sites for that study. And what we're seeing in these real-world data sets is good, not just efficacy but safety. In today's environment, this is paramount. And so again, fortunate to see in this Phase III study similar trends, and again, a nice safety profile for faricimab. Let's go ahead to the next slide, please. So from there, we're going to pivot again from faricimab to port delivery system. We had 2 really nice presentations on Saturday. This first was looking at port delivery system with ranibizumab in patients with diabetic macular edema. This is the primary analysis results of the Phase III PAGODA trial presented just a few days ago by Arshad Khanani. Let's go to the next slide. PAGODA was a Phase III study designed to evaluate efficacy, safety and pharmacokinetics of PDS Q24 weeks for diabetic macular edema. And here, you can see the study schema, where patients were randomized into 1 of 2 groups, the first being the patients that received PDS implantation just after receiving 4 loading doses of ranibizumab. So at week 16 of the trial, they were able to get their PDS implant. Versus the other arm, the second arm is the intravitreal ranibizumab, 0.5 milligrams Q4 weeks, so again, about a monthly injection schedule up through that primary endpoint, which was at 64 weeks. What the primary endpoint was looking at was non-inferiority of PDS at Q24 weeks compared with monthly intravitreal ranibizumab 0.5-milligram injections based on the change in BCVA score from baseline averaged over weeks 60 and 64. So let's go ahead and look at the data. Next slide. We saw that PDS Q24 weeks result in vision gains and CST reduction that were comparable to monthly ranibizumab through week 64. We saw -- if you look on the left here, the vision changes, so BCVA change from baseline, again. We see, at 16 weeks, a little dip in the PDS group, which is very much what we would expect, just given the postoperative vision changes. But that line matches back right up after a few weeks after the postoperative period. We saw in the PDS group 9.9 letters of vision gained at the 60, 64-week endpoint versus 9.3 letters in the monthly intravitreal injection group. From a CST standpoint, on the right, we see that the patients that received the PDS demonstrated a 203-micron reduction in CST thickness versus a 199-micron reduction in the monthly injection group. Let's go ahead to the next slide. We see that with PDS Q24 weeks, we saw clinically meaningful DRSS improvements over time. This is looking at diabetic retinopathy scores. We saw PDS group showing 39% in that greater than or equal to 2-step reduction in DRSS versus 41.9% in the monthly injection group. Let's go ahead to the next slide. And this is another kind of, for us, as clinicians, really what we want to see play out in the real world as well, which is 95% of the PDS Q24 week patients did not need supplemental treatment through each of the refill exchange intervals. And over on the right, you can see what might have triggered a supplemental therapy. It's either a vision change or a CST, OCT thickness change or a combination of those things that would have triggered a supplemental therapy. But really nice to see not -- greater than 95% of these patients did not need supplemental therapy. Let's go to the next slide. And the ocular adverse events of special interest were well understood and manageable. No cases of endophthalmitis or retinal detachment were reported in the PDS Q24 week arm, and this is after implantation through week 64. And just I think that this is just demonstrating what we've learned over the life cycle of PDS clinical trials. And I think, surgically, we're seeing better results. And here, again, very reassuring, no cases of endophthalmitis or retinal detachment. Let's go to the next slide. This is the final PDS study that was presented a couple of days ago. This is looking at PDS with ranibizumab in patients with diabetic retinopathy. So a little bit of a different indication than PAGODA, where we were looking at diabetic macular edema. Here, in PAVILION, we're looking at diabetic retinopathy. And this was the primary analysis results of the Phase III PAVILION trial presented by Dr. Pieramici. Let's go to the next slide. So because this is a little bit of a different indication that PAGODA, I think it's worth taking a minute to discuss diabetic retinopathy in general, and the context, especially coming from a clinician that sees this, unfortunately, all too often in the office. We see that diabetic retinopathy affects over 1/3 of patients with diabetes and is a leading cause of vision loss in adults worldwide. We know that patients with moderately severe or severe NPDR are at high risk of progression to PDR and vision loss, PDR being proliferative diabetic retinopathy. This is really one of the endpoints we try to avoid in all of our patients with diabetes. Current diabetic retinopathy treatment guidelines generally recommend treatment upon onset of proliferative diabetic retinopathy or diabetic macular edema. In other words, today's day and age, we're really only treating patients when they achieve that severe disease, proliferative diabetic retinopathy or diabetic macular edema. Observation with no treatment is currently a common practice for diabetic retinopathy given the treatment burden. And really, if we look at these bar graphs on the right here, the ones that are most clinically relevant to me are when we look at that moderately severe NPDR group and that severe NPDR group. We've seen that moderately severe NPDR group, 26%, in 1 year, can progress to proliferative diabetic retinopathy. And if you're looking at the severe group, it's twice that, about 52% progressing to proliferative diabetic retinopathy. Again, that's really where we get into trouble with our patients losing vision from vitreous hemorrhage or diabetic macular edema, and again, an endpoint that we would like to avoid if we can. But because of practical implications, treatment burden and things of that nature, we oftentimes don't treat these patients before they get to that point. So again, an unmet need for treatment options that prevent the progression of NPDR to PDR and development of vision-threatening complications, including DME. So with that context in mind, let's go ahead and look at the study here. Let's go to the next slide. So again, PAVILION was a Phase III trial designed to evaluate efficacy, safety and pharmacokinetics of PDS Q36 weeks for diabetic retinopathy. If that 36 weeks looks different, it is, because this is the first PDS study we were looking at with that 36-week interval. All of the prior studies we've discussed in Phase III have been Q24 weeks, just like the PAGODA study. So here are the 2 treatment arms that we see patients randomized, to the first being the patients that received PDS implantation. This is a patient group that received 2 loading doses 4 weeks apart of ranibizumab. And then within 2 weeks of that second loading dose, received their PDS implant. Versus the control group and the control arm here was a group that was clinically monitored. They did not start on therapy but could have received supplemental treatment along the way if they hit certain parameters, and we'll talk about that in a moment here. The primary endpoint on this study was superior efficacy of PDS Q36 weeks compared with control based on proportion of patients with greater than or equal to 2-step improvement from baseline on the DRSS scores at week 52. Let's go to that next slide. All right. So here's the data. A greater proportion of patients achieved that greater than or equal to 2-step improvement on the ETDRS/DRSS, and retinal anatomy was maintained through week 52. So on the left here, we're looking at that greater than or equal to 2-step improvement. And what we saw was patients that received the PDS, 80.1% of them at week 52 achieved that greater than or equal to 2-step improvement in DRSS score versus only 9% of the control group. When we look at central retinal thickness, now again, this -- we have to put this in a different context than our PAGODA trial, which was looking at DME. Here, we had patients that entered the study that could not have diabetic macular edema. In other words, their beginning CSTs were pretty good to start with. But even there, we see a trend towards improvement in the PDS group versus the control group, which we don't see much change at all in their central thickness. Again, just stability and anatomy after PDS implantation. Let's go to the next slide. We want to -- again, this is what I kind of keyed in on before we dove into the data, which is we want fewer and fewer patients over time to develop vision-threatening complications, such as vitreous hemorrhage or diabetic macular edema. And indeed, we saw that in this data set. We saw -- if you look at all vision-threatening complications, including proliferative diabetic retinopathy, anterior segment neovascular change or diabetic macular edema, we saw that 7% in the PDS group went on to progress to that, but 47% in the control group progressed to these vision-threatening complications. When we break it down into individual components. If we look at just diabetic macular edema, 7.1% in the PDS group progressed to diabetic macular edema, whereas 47% in the control group progressed to diabetic macular edema. And when we look at proliferative diabetic retinopathy or neovascular change, only 1% in the PDS group progressed to that versus 42% in the control group at week 52. Let's go into the next slide. 100% of the patients treated with PDS Q36 weeks did not receive a supplemental treatment through week 52. And you can see here, I mean, very important to kind of go over what the supplemental treatment criteria were. In this case, what would have triggered a supplement or the need for ranibizumab injection, for example, would have been the presence of diabetic macular edema in these patients or the development of proliferative diabetic retinopathy or neovascularization as assessed by the investigator. And what we saw was none of the patients in the PDS group required supplemental treatment. We saw that only 60% of the control group did not require supplemental treatment. I mean, in other words, 40% did require some degree of supplementation or intravitreal injection for stabilization. Let's go to the next slide. And again, here, majority of ocular AESIs through week 52 were nonserious. Very important to note, no cases of endophthalmitis or implant dislocation were reported through week 52. Let's go to the next slide here. So I just -- a couple of thoughts to summarize. I mean, these are reassuring data points for us. For faricimab in general, it is nice to be able to now expand potentially, hopefully, the types of patients we're able to treat today. In clinic, we're treating neovascular AMD and DME. And hopefully soon, we'll be treating RVO as well. And with port delivery system, again, nice to see our diabetic patients doing well, whether they are DME patients. Or another huge unmet need for us is diabetic retinopathy patients even without DME. We see them doing better as well. So this is, again, reassuring from our standpoint as clinicians. I'm going to hand it over back to Bruno, I believe, for the next section.

Thanks a lot, Veeral, for having taken us through the data. And I think with that, we will open the Q&A session. The first 1 in the row is Tim Anderson from Wolfe Research. Tim, please?

A couple of questions that are commercial in nature, if I can. Slide 6 shows quarter post-launch data, Vabysmo beating 3 other brands. But it's only 4 quarters into the launch, I'm just wondering if there's any sort of bolus effect from patients who are non or inadequate responders that might be inflating the near-term ramp for a few things, subsequent quarters will show continued quarter-on-quarter uptake. And then I'd just love to get your perspective. I know it's not your brand, but high-dose EYLEA, very relevant to the future outlook for Vabysmo. How you think this will play out commercially and change the dynamics from what they are today once that product launches in the back half of the year.

Sure. Maybe I'll take a stab. Nice to see you, Tim, again. Thanks. I think on Slide 6, I think the intent there really was just to show how well is this tracking to historical norms, the launch. We've just been through a pandemic. We've seen different dynamics of clinic practice and adoption. But I think we're very encouraged by that. I don't think there's a significant bolus, so to speak. I think I mentioned that 2/3 of the switches coming -- all of the -- a lot of it, the business is coming from switches, 2/3 from aflibercept with patients that had persistent fluid. And there's a time where you would try a new agent there. With the safety profile being more confirmed and confident as well as the J-code coming through with reimbursement confidence, we're seeing a greater first-line use. So our understanding, this isn't a bolus at all. The second piece, I think you talked about high dose EYLEA. So maybe I can kind of just take a look at that. So we've seen the PHOTON and PULSAR results presented. And what we see from that is more anti-VEGF. And what we -- I think the community would like to see is more long-term data. They'd like to see more CST data in terms of anatomy moving forward. From our side, I don't want to really comment on other people's products. What I'd like to say is that, from a Vabysmo perspective, this is the first bispecific antibody. We're seeing sort of increased drying. We're seeing really strong anatomical impact when patients are switched over. And that's leading to kind of confidence in the durability as well as the confidence to move into first line.

Did we -- Tim, did we answer all your questions? Or you had a question also on high dose EYLEA and how this plays out in the market? Tim, have we answered your questions?

On high-dose EYLEA, well, I mean, no, you didn't really answer that question. I would just love to get your perspective for how you think that's going to play out. I understand it's a competitor brand. But Regeneron is willing to talk often about your product and kind of throw shade on Vabysmo. And I didn't know if you think there are particular shortcomings with their product and that sort of thing. So I was giving you a chance to kind of address things that they point out with your product.

So Tim, I think previously, we've pointed out that some of the numbers that being used there are occasionally kind of cross-trial comparisons. And we also probably want to have a look at the importance of retreatment criteria there. So what I was alluding to in terms of our practice is that, in the real world, as patients -- as doctors are treating their patients in clinic, we're seeing building confidence not only from switch patients but also going into earlier lines of therapy with our product. So I think you need to take that data and analyze it and scrutinize it more. In terms of playing out, this is a competitive marketplace, but we've seen that Roche can be a competitive player as well.

So the next question I would take from the Q&A here, sent in. It comes from Richard Parkes from Exane BNP. Richard is asking, can I ask Dr. Sheth to explain why the focus on macular leakage in the RVO studies, why he focuses while the focus on in the RVO studies rather than an anatomical measures, such as CST. I'm trying to understand the relative importance of those measures to physicians in managing RVO patients.

Yes. Great question. So I think, for us, when we look at new mechanisms of action, what we really want to know is what impact does that anti-ANG-2 effect have in our patients? And this is one of the trials where we actually looked at that. And so I think that's why, one, it's an important point to highlight. The second is, if we're looking at CSD thickness, we want to see -- we're only looking here at week 24 data, so it's hard to make kind of anatomic assessments in that short period of time. And so we're just looking for any signals. And so to me, this was a nice signal to see, that this mechanism of action is potentially impacting us. Now the good thing is that Roche is doing a good job of looking at this more specifically in future clinical trials, there's a diabetic macular trial that's going on right now, looking at anatomic change. And so from my standpoint, this is kind of the first signal we're seeing and hopefully the first of many to come. And so I think for me, that's personally why I'm looking at this and whether we're really differentiating or not in the real world.

Next question will come from Dominic Lunn from Credit Suisse.

Two questions. So on Vabysmo, how significant is the prefilled syringe in achieving internal ambitions for the drug? And does the current lack of prefilled syringe hold you back in any patient settings? And then secondly, on the future of the PDS, it's probably fair to say that Susvimo didn't start like you hoped it would, but you do say significant progress has been made with understanding the septum dislodgement issues. So I was wondering if you could elaborate on what that progress is. But also, vitreous hemorrhage looks higher. So I just wanted to get your overall level of confidence that these issues can be addressed.

Thanks, Dominic. Maybe I'll kick off with prefilled syringe and Vabysmo. Yes, so I mean we're fully committed to the prefilled service. We brought the vial to market faster, given how fast we recruited the studies and the impact we saw of bispecific inhibition of VEGF and Ang-2. So we're working on that diligently. We think it's an important characteristic, but you'll probably remember from the marketplace that a number of other products didn't have prefilled syringe still gained a lot of market share and adoption based on their clinical profile, and that's what we're confident with. Having said that, I would reassure you that we're working on that quite diligently to bring the prefilled syringe forward. It will make it easier for practices to adopt. On the port delivery system, in terms of the launch, actually, our launch was relatively in line. We'd always wanted a purposeful launch. This is a very different setting to the intravitreal setting, which has had many years of practice and patterns adopted. So I think it's going to be really important that we train on the surgical procedure. Obviously, we were disappointed to have to voluntarily withdraw the product. But I think that the launch was relatively well considered. We had more than the number of patients -- doctors that we had anticipated trained on the surgery. So we're looking forward to relaunching that product as we move forward. Your third question on the hemorrhages, I'd like maybe to address to Chris or Veeral.

Perhaps I can take that one. Yes. So great question. So yes, as you recall, in our Phase II neovascular AMD study, there were issues with vitreous hemorrhage. We then optimized the surgical procedure, and that rate of vitreous hemorrhage came down significantly in the Phase III ARCHWAY study in neovascular AMD. Now when we -- when you look at the diabetes macroedema population, I'll give you an example of the PAGODA study. There were a number of vitreous hemorrhages. However, it's really good news in that the vast majority were mild or moderate in severity, as in 90%, so 28 out of the 31 cases were mild or moderate. And the vast majority are recovering or recovered already, as in 94% at the time point of the data cut. And only 3 events of vitreous hemorrhage actually required an additional procedure. So the surgical training in terms of the outcomes for patients continues to improve and reduce the rate of vitreous hemorrhage. So I think this is being managed very nicely. I mean from a clinical perspective, Veeral, do you want to make any comments on those numbers?

No, I think that's exactly right. I mean even if there was one red blood cell, we had to classify it as a vitreous hemorrhage. And the vast majority of these were mild to moderate. As you mentioned, Chris. I think practically speaking, we always expect something like that, but I think the rates and signals are pretty low.

Can move on, and the next questions will come from Matthew Weston from Credit Suisse as well, Matthew?

I was going to say full cold-press from Credit Suisse. Two questions, please, if I can. The first is just a very simple commercial one. Given that the launch is clearly progressing ahead of expectations, can you give us a confirmation that you have the manufacturing capacity to sustain the launch at the current trajectory? And then secondly, a question for Dr. Sheth, if I can. Dr. Sheth, it's always hard when we ask you to speak on behalf of the community of physicians, many of whom are going to do different things. . But the other dynamic that we're going to have in the industry coming up soon is biosimilar Lucentis. And I would be very interested how you see it playing out in terms of the balance of patients who are likely to see, let's call them marketed brands and those who are likely to move to what are probably going to be cheaper alternatives in terms of biosimilars.

Did you mean Matthew biosimilar Lucentis or biosimilar EYLEA as well?

Well, any of the above.

Okay. So thanks, Matthew. Maybe I'll take the first question and then hand over to Veeral on the [indiscernible]. So yes, thanks for the question on Vabysmo. The launch is progressing very well. And in terms of your question on manufacturing capacity, I think we have really confident sufficient supplies of Vabysmo available. So we're looking forward to doctors adopting it more and more and testing that, but we're very confident and able to supply the vials as the uptake grows. One comment just before we move to Veeral in this marketplace, and I've commented on it before, we're really looking forward to seeing and learning about biosimilar adoption in the marketplace like this, where other products have been used that aren't licensed as well at very cost-effective prices. So I'll hand over to Veeral in that context.

Yes, Matthew. Great question. I mean I just got back from a meeting where we were discussing biosimilars. And I think -- what I will tell you is there is very little consensus on how we're going to be using them or deploy them. And in fact, I'll go one step further and say there's still a lot of confusion on how to incorporate biosimilars into our practice. Just from a personal standpoint and in our own practice, we have not really looked at using biosimilars just yet. I think there's a lot of aspects to that. I think we like the options we have. We like the on-label options. Once you start introducing new treatments, there's stocking issues, there's payer issues, all these other things that we have to deal with, and we're still hesitant to kind of open that Pandora's box. And so I would say right now, to your point, there is really no consensus in our practice community or in our microcosm of our practice alone. But I would say, I think certain things will drive it. Payer -- payers asking for step edits and things like that may drive that a little bit. But right now, we are not looking at using a lot of them.

Matthew, did we answer all your questions?

Yes, that was everything.

Okay. The next one would be Simon Baker from Redburn.

Bruno, if I may. Just going back to Vabysmo and the questions that Tim and Matthew asked. It does indeed look like the launch is going extremely well. I just wonder if you could tell us if there are any remaining gating factors on access and coverage in major markets that you still have to overcome for Vabysmo. Secondly, on the IL-6, one of the hypothesis is that has emerged on glaucoma in recent years is that there's an autoimmune dimension to it mediated by T cells. Now if that's indeed true, then an anti-IL-6 could have a beneficial effect in reducing T cell activation. I just wonder what your thoughts were on the autoimmune dimension to glaucoma and the potential for your IL-6 if indeed there is one there? And finally, just a quick update on LUXTURNA. I didn't see it in the presentation, I didn't see it in the annual report. So I just wonder if you could tell us where we are with LUXTURNA.

Sure. Thanks so much, Simon. So maybe I'll take the first question on the Vabysmo and the reimbursement landscape. Maybe Chris then hand over to you for IL-6 and glaucoma. And maybe, Bruno, you can comment on Spark and LUXTURNA, if that's okay from our side. So it's a great question. We're really encouraged that in 11 months, we have 8 to 9 national reimbursements that have occurred since the approval of Vabysmo. But no, there are still a number of negotiations ongoing, Simon. So predominantly France, Italy, Spain are still to come on board too. That plus other countries into Europe and around the world. Approvals for Vabysmo in Europe was September last year. So you can imagine that that's an ongoing process. So more to come on that, but we're really encouraged by the fast adoption and payer recognition of the value that Vabysmo brings in this short period of time. Does that answer your question? And I can turn it over to Chris.

Yes. No, that was great. I just -- are there any additional hurdles to claim in the U.S.?

No. Permanent J-code, I think, was achieved in October, and then I think it's just local reimbursement that we're working through, not in the U.S. Okay. Maybe I'll answer roughly the good question, Simon, on IL-6 and use in glaucoma. So taking a step back, just as a reminder, we are a company who's like firmly established, we believe now in retina globally, and we're looking forward to expanding to novel indications across ophthalmology, which includes glaucoma and other front-of-the-eye indications. So we think glaucoma, we see kind of 2 broad unmet needs. Number one is better delivery of intraocular pressure-lowering therapeutics, by which I mean long-acting delivery to reduce the burden on patients in daily drops on multiple bottles. And the second is around neuroprotection. So clearly, the challenges with both. Otherwise, they have been developed already. Specifically, on the IL-6, to your question around T cell and auto immunity, I'd say right now, we are currently looking at all potential opportunities for the use of IL-6 in all indications. We've not made any firm decisions, but certainly, glaucoma would be one that we will be looking at in more detail to understand better the science behind that discussion. So thank you for the question, but I can't really give you anything concrete except to say that yes, certainly very interested in glaucoma therapeutics.

And maybe to finish from my side, Simon, I think there's not a lot I can say on LUXTURNA. I think we -- it's still on the market and available for patients. I think we have sales which we have not broken out, which are in the low double-digit million range, and we would expect it to remain roughly in this sales range. Then we would move on. And the next question would come from Peter Welford from Jefferies.

Just a couple left. Firstly, just returning, I guess, to maybe Dr. Sheth just with regards to his practice, again. Appreciate Matthew's comments whether this is not necessarily the consensus as a whole. But can you just talk a little bit about the type of patient in particular that you've put on Vabysmo so far? We appreciate the data, obviously, that Roche has given. Does your personal practice generally mirror this? And I guess, perhaps more importantly, at what stage are you at with regards to considering putting a patient first-line newly diagnosed in your office straight onto Vabysmo as that therapy of choice and perhaps what do you need to see to get there? Second thing then, can I just ask with regards to the port delivery system? Can I ask whether or not potentially, with that, you think there is a risk here of a -- I guess, I don't know if I were to use this, but I guess full start in the sense. We've seen this before in the eye market where companies have had an issue then at launch and have had to sort of go and sort of revise and restart again. I guess what do you think the risk is with Susvimo at this point because of what they've seen with the device deficiencies that actually to rebuild confidence in the medical community? What steps need to be potentially done to be able to do that? Thirdly then, just returning to LUXTURNA. Can I just ask more broadly, do you have any plans to go gene therapy in this market? Or do you believe that due to fabs and the implants are more than sufficient and actually a longer-term gene therapy sort of approach is, frankly, null and void at this point? And then just finally, can I ask you just on the GA market, what Roche's sort of thoughts are on this? I think there's been a lot written in terms of how this market could potentially develop over time as new therapies come. Are you worried about being, I guess, a latecomer to this market? Or what do you think you can bring that perhaps won't be addressed by the time you get to market with the GA therapy?

Great. Thanks. Veeral, do you want to answer the?

Yes. I will take that the first of the 4 parts there. So Peter, I think your question really is around practice patterns, and we're really kind of approaching or have just approached the 1-year anniversary of having Vabysmo approved in our offices here in the U.S. And so what I can tell you is the initial patients that we used Vabysmo on were switch patients. The majority of those being patients switched from EYLEA. These are patients that probably had some persistence of retinal or intrarenal fluid or patients that we just could not extend beyond 6, 8 weeks, for example, was kind of the majority of the patients that we switched over initially. And I think like anything else that's new, we learn a lot from those patients, and we saw a smooth transition for those patients. We saw a good number of them do better clinically. A lot of those patients are reflected in the TRUCKEE data set that you saw earlier today. And I think -- so we've since transitioned patients that are not just switching from EYLEA that are not doing this well, but we're switching some more patients over where we're looking at that durability effect, trying to get those 8 weekers out to 10 weeks or 10 weekers out to 12 weeks. So that was kind of the second phase of our implementation. And now we're at the point where we certainly are comfortable using Vabysmo as first line for neovascular AMD. Once the J-code became available, more of our diabetic macular edema patients kind of got rolled into that just from a payer perspective and being able to make sure we have coverage for that. And so certainly, I think at this point, I just pulled the data last week from our own clinic. Personally, I'm using about just over 50% of my patients receiving on-label injections are Vabysmo. And so we kind of just crossed that threshold with a number of kind of new patients now being started on Vabysmo as first line.

So I think we move to the question on port delivery if that -- Peter, if that answers your question. Yes. So port delivery, I think one thing to note, and I'll invite Pierre-Alain to comment on anything additional. It's a great question about full starts or not. So first of all, as I mentioned earlier, we definitely wanted a purposeful launch for this product. Secondly, something to note, a lot of the full starts that you may be remembering had safety issues. This is not a safety issue per se. This is a manufacturing variability issue, is the second point to note, and we're still looking to do that. The patient preference data, we see the physician adoption data for the patients that they have on port delivery system is still highly positive. I mean maybe Veeral can even comment on that. But certain patients, we -- certain physicians we speak to requesting the port delivery system back because the patients want the port delivery in their fellow eye when they get launched, so there's a preference there. Third is the competitive dynamics in this marketplace. There's very little that's similar to this and in other full starts, there has been alternatives. So I think it is different. We're not at all being complacent about that. We're taking really responsible thoughtful decisions about how we bring that back. But we think the unmet need for durability and consistent outcomes is very high. And we're not seeing anything approaching 6 months durability or 9 month durability with anything like the consistency of both visual acuity or anatomy that we're seeing with port delivery. It is an investment upfront in terms of the surgical implant. So we're very confident to bring this back, and we're planning quite a lot of pipeline around it. Pierre-Alain, I don't know if you wish to add anything to that.

No, it's very clear what's the technical challenge is. So we have multiple product classification standards and we have one single of these standards where we have an issue. And the teams are working currently to understand the source of the problem, and we have already some improvements options in front of us. So we are currently doing the testing, and it's just a matter of time until we are back with a product meeting the specification.