Roche Holding AG (ROG) Earnings Call Transcript

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

Yes. Thanks a lot, Henrik. Welcome to all of you because of these ASRS Highlights 2020. Our virtual call to mainly present, but only -- not only to present the PDS data, but maybe, Lisa, if you could kindly go to the slide for the overview. Thank you. Thanks a lot. So we have with us Atul Dandekar. He is the Vice President and Global Franchise Head of Ophthalmology. Atul will share with us the need, real-world outcomes that they have still significant room for improvement. He will talk about the PDS, the bispecific that they are addressing and it is addressing high medical needs. He will talk about our really broad pipeline. I think it's fair to say that we have the broadest pipeline, ophthalmology pipeline in the industry. We have 5 attempts in Phase III. We have 9 new molecule entities in Phase II and III and -- on the market. And last but not least, he will also address the patient needs and the patient preferences. This will be followed by Chris Brittain. He is our Head of the Product Development for the Ophthalmology Franchise, talking about our broad development program, PDS, but also faricimab data that we expected by year-end, our bispecific new assets in Phase I/II gene therapy delivery system, so giving us a good overview of the pipeline of some new assets. And last but not least, we have Dante Pieramici with us. He is the Director of the California Retina Research Foundation, 60 NIH trials. He was involved in 110 peer-reviewed articles published and will present the PDS data for us. And let me already thank also, Lisa Tuomi from our team, who basically was instrumental in helping to set up these trials, was working on the slides and so on. So thanks a lot, Lisa. So if you could kind of go to the Slide 5, it's very briefly only. And before we go into the presentation, let me again reflect a bit on our half year. We have now 34 breakthrough designations as Roche -- in the Roche Group, which is the highest number, which is -- in the industry, which is also a testimony of our differentiated pipeline and attempts. We had 4 pivotal trial recruitments finished in the first half year. New pivotal trial starts in the first half also for mainly in oncology, but not only in oncology. Next slide, please. And importantly, we had done also -- we will have major advances and upcoming launches in the second half. And if you look at this one, we do expect to launch 3 NMEs in the second half. We have 7 upcoming pivotal trial starts. So it was not much impacted by COVID, I have to say. So the teams did actually an excellent work in order to get the whole pipeline on track. And here, you can also see our diagnostic efforts with 4 new launches, mainly in the COVID area, to help fight the current crisis also from a diagnostic point of view. Next one. Many of you are familiar with our replace and extend strategy. And the focus of the day is on Lucentis. You can see here that we have the attempt, and actually it's really looking good, to replace Lucentis at a certain point in time with a Port Delivery System with faricimab, but there's more in the pipeline as we can share with you today. And with this one, I would like to hand over to Atul. Atul, the floor is yours. Thank you.

Great. Thanks, Karl. Good morning, and good afternoon, everyone, and many thanks for joining us today on this call. I'm Atul Dandekar, and I head up the Global Franchise for Ophthalmology at Roche. And we are thrilled to share the PDS Phase III data with you today. And we are indeed very lucky to have Dr. Pieramici with us since he, along with many of his investigators, helped us refine the PDS program and get it successfully to this important milestone. Now before we get to the R3 data, I'll take the next 10 minutes to walk you through our ophthalmology strategy, and more importantly, how we are executing to the plan. So as you can see from this slide, as you are aware, retinal therapy has accounted for sales of $12 billion in 2019. And we anticipate that this segment will continue to grow, driven by the aging population, increasing prevalence of diabetic eye disease and product innovation. Interestingly, majority of this $12 billion segment is made up of just a single class of agents, which is anti-VEGF injections primarily. And the last time we saw a new class of agents in this segment was the launch of Lucentis in 2006. So while the rates of blindness due to neovascular AMD in many countries have halved since the introduction of anti-VEGFs, we believe the therapy area is ripe for new innovation that goes beyond anti-VEGF injections. Next slide, please. Now pivotal challenge in this area is how do we get in the real world the same outcomes that we see in our clinical studies. As you are aware, in pivotal studies, patients have shown gains of roughly around 10 letters. But as this retrospective analysis of more than 49,000 U.S. patients in their first year of anti-VEGF injection shows, despite the best efforts of our retina community and our patients, patients on an average are gaining about 1 letter. And as soon as you go below the median of 7 injections a year, they start losing vision. Now there are many reasons for this, but a key issue for most patients, given their age and comorbidities, is that they really find it hard to make it to the retina clinics on a monthly-by-monthly basis. Now we believe, at Roche, that we have reached an efficacy ceiling with anti-VEGF injections and that there are 2 potential risks to get better outcomes: One is novel mechanisms of action that can be combined with anti-VEGFs so that we can raise the efficacy and the durability bar; and two, a continuous delivery platform like PDS that substantially reduces the treatment burden. Next slide, please. So we see faricimab and PDS as 2 components of a very complementary portfolio. Now we are looking forward to the Phase III results of faricimab later this year, DME in December and then AMD in Jan of '21. And the aspiration here, depending on the data, of course, is that faricimab has the potential to become the new standard of care IVT, raising the bar on efficacy and/or durability. And PDS, with the exciting Archway Phase III data, we believe, is the start of a new paradigm of continuous delivery. Now PDS with the customized ranibizumab formulation is potentially just the start of a new segment, and we believe we can build this platform by offering new product solutions that can be used inside the PDS. Our strategy is to offer 2 innovative product solutions to the retina specialists and patients who haven't really had too many choices beyond anti-VEGF injections in the past 15 years. Next slide, please. So our strategy has been fairly simple and consistent over the past few years. We are leveraging 4 key levers to pursue retinal conditions with high unmet need. Number one, we want to bring forward new mechanisms of actions like Ang-2. As Karl said, we now have a total of 8 first-in-class programs in Phase I and Phase II in addition to faricimab. We also see PDS as a platform play and we are combining this with new MOAs. An example is the VEGF/Ang-2 DutaFab, which is in Phase I right now. And we are accelerating this into the PDS platform. So basically, what we would like to do is combine the best of faricimab and PDS and provide that in the same product. The third lever is our internal R&D engine, pRED in Basel as well as gRED in San Francisco, our super focus on ophthalmology. And now with Spark as a part of the Roche family, we are well positioned for gene therapies, too. In addition, we are working very closely with innovative companies like 4DMT and Ionis. And the fourth lever for us is PHC, personalized healthcare. And our PHC team is working on remote monitoring and AI-based algorithms. Now the idea here is we bring to market integrated solutions that support the retina community and reducing vision loss. Next slide, please. In terms of pipeline strategy, our focus is squarely on retinal disorders with high unmet medical needs. So in addition to the usual suspects, neovascular AMD, diabetic retinopathy, we are very much focused on geographic atrophy and we are also pursuing blinding monogenic conditions. In the near term, we are looking forward to the global launches of faricimab and PDS and building a global retina presence on the back of a strong portfolio. Now in Phase II, we have an oral drug that may potentially allow early treatment of diabetic retinopathy without the IVT burden. For geographic atrophy, we have a complement-based approach through our partnership with Ionis. This is the complement factor B. And we have an exciting first-in-class non-complement approach with our anti-HtrA1 antibody and another non-complement-based approach in Phase I from GA. In Phase I, we also have 2 DutaFabs for AMD. Now one of them combines a completely new mechanism of action with VEFG. And the other one is the one I mentioned, which is the VEGF/Ang-2 DutaFab in PDS, and that has been accelerated. Last but not the least, we are very excited about our partnership with 4DMT. These are gene therapies utilizing their Directed Evolution platform, specifically for IVT use. You may have seen the press release this morning. 4DMT announced the first patient dose for Choroideremia program. So that's already in patients. And we also expect another program to start in XLRP. And with Spark now part of the Roche Group, we foresee further acceleration of gene therapies in our optha portfolio. Next slide, please. Now a key pillar of achieving our vision of treating vision loss early is personalized healthcare. And we are focusing on 2 main areas: Remote vision monitoring, using our apps like Home Vision Monitoring, which is right now in a pilot with Moorfields, to enable early detection of vision changes. Remote monitoring tools will be a critical component of delivering the full benefits of a program like Port Delivery System. Similarly, we are using 3 million images and data from more than 10,000 patients that we have in-house to come up with imaging algorithms that detect disease progression. Next slide, please. So in conclusion, our strategy execution is well on track with pivotal readouts in 2020. We plan to deliver the faricimab DME top line in December and the neovascular AMD top line in Jan, early next year. The Port Delivery System DME study called Pagoda is recruiting well, and we plan to start a study in diabetic retinopathy soon. As Karl mentioned, the early and mid-stage pipeline is progressing well, and we are particularly pleased to get gene therapy studies going. And we have accelerated our VEGF/Ang2 DutaFab program to essentially combine the benefits of faricimab and Port Delivery. Lastly, we are seeing good solid early progress in our optha PHC initiatives, with more to come in 2021. I would like to now hand over to Chris, who heads up our clinical team, to provide a more detailed overview of the selected pipeline assets. Chris?

Great. Thank you, Atul. If you go to the next slide, please. Thank you. So again, good morning, good afternoon, everybody. Really excited to be able to share a little bit more detail on our -- on some of our pipeline. I'm going to box this presentation in, starting -- sorry, finishing with some of the top end details on the Port Delivery System, but really starting with the other jewel in our Phase III pipeline, which is obviously faricimab. And in the middle, I'll go into some of our Phase IIs and our Phase Is. So starting with faricimab, just as a reminder to everybody on the call, this is the first bispecific molecule in ophthalmology. And this targets both anti -- this targets both VEGF-A and Angiopoietin2. The goal, obviously, of the anti-VEGF is well-established through the 5 currently available anti-VEGF monotherapies, but the anti-Ang-2 component really is aimed here in terms of improving vascular stability and reducing retinal inflammation. Now we had a very robust Phase II clinical development program, which involved over 500 patients. And I really want to start off by discussing the neovascular AMD approach. The Phase II in neovascular AMD was the STAIRWAY study. And as you can see here, really, we looked at 2 elements. First of all was the efficacy; and second piece with neovascular AMD, obviously, is the durability. And as you can see here, it's consistent in terms of efficacy, it's consistent with monthly anti-VEGF monotherapy, but the exciting piece about the results in neovascular AMD are the durability results. I really want to draw your attention here into the fact that 65% of patients, 12 weeks after the last faricimab dose, have no disease activity and therefore could potentially benefit from Q16, so it's up to 16-week dosing. So if we go on to the next slide, please. This resulted in the Phase III studies, TENAYA and LUCERNE, which are identically designed studies, 640 patients per arm in 2 arms. First of all, we're comparing against aflibercept, 2-milligram, 8-weekly. But as you can see here, the faricimab arm really gives the opportunity for patients to move between the 8-weekly, 12-weekly and 16-weekly durability with the primary end point of between 40 weeks and 48 weeks. At the 64-week time point, patients can then progress to a personalized treatment interval, which is comparable to the current treatment extend paradigm, which is the common treatment approach for retinal specialists. And that will provide evidence to support that treatment approach, and that happens after week 60. If we go into the next slide. So the other opportunity, obviously, if we see durability and efficacy, and within diabetic macular edema, we're really excited to show the results, which many of you will have already seen, which was those results in BOULEVARD, our Phase II study, which demonstrated opportunities in both efficacy and durability. On the left-hand graph, you can see that at week 24, there was a statistically superior efficacy outcome for the faricimab 6-milligram arm, which is the blue line, compared to the monthly Lucentis arm. And importantly, on the right-hand side, you can see clearly that the durability is also significantly improved with the median time to disease reactivation of 15 weeks for the faricimab 6-milligram arm versus only 8.5 weeks for the Lucentis arm. So the message here is that faricimab has 2 shots on goal, both for efficacy and durability. And for these reasons, the diabetic macular edema studies, YOSEMITE and RHINE, do address both of these elements. Firstly, just to reiterate that the comparator is aflibercept 2-milligram, 8-weekly, but then if you look at the 2 arms for faricimab, you have, first of all, after a loading dose -- a loading regimen, you have an 8-weekly treatment arm, which is Arm A, and that will give us an opportunity to demonstrate superiority. And in Arm B, we go after 4 initial initiation doses into a personalized treatment interval, which, as I say, is comparable to a standard treatment and extend treatment paradigm, and that will enable patients to go between 4 and 16 weeks. So we're really excited about the opportunities for both the neovascular AMD and the diabetic macular edema programs in -- for faricimab. And just to reiterate what Atul said, the YOSEMITE and RHINE studies will be reading out in December of this year, then neovascular AMD studies will be reading out in January of 2021. So we're really excited to look forward and look forward very much to those data. If we move forward to the next slide. So outside of the Phase III programs, one of the largest unmet medical needs areas within ophthalmology is geographic atrophy. And again, I'm super excited, the fact that we have not 1 but 2 programs which are currently actively enrolling despite COVID-19 in geographic atrophy, secondary to AMD. So this is the fact that they're still actively enrolling is just kind of real -- a real sign of our commitment and also the great collaboration which our investigators and our patients have put in and their trust in our clinical studies. So this is really exciting. The first study which I want to highlight is the Phase II anti-HTrA1 study. Just as a reminder, the rationale for this treatment is that the ARMS2-HtrA1 is the top genetic locus identified for AMD risk, not just for progression to GA but also potentially for progression of an enlargement of GA lesions. The mechanism of action is fairly complex, but the HTrA1 is a serine protease, which breaks down extracellular protein. And this, we believe, results in the retinal atrophy. And the exciting news from the Phase I, upon which the Phase II is based, is that we have a pharmacodynamic biomarker, which suggests that this treatment, which is an intravitreal treatment, can have results which last up to 8 weeks. So we'll be looking at both 4- and 8-weekly injections in Phase II. If we can go to the next slide. The second study we have is a subcutaneous injection of an antisense oligonucleotide targeting complement factor B. Now just as a reminder, why complement? Well, complement remains a very important factor in the progression of age-related macular degeneration with 5 well-established gene loci with polymorphisms linked to neovascular -- linked to AMD. Now complement factor B is made solely in the liver. And therefore, we believe if we can address and cut off the source of complement factor B and its ability to move into the RPE and the Bruch's membrane and the eye, that we can actually prevent the complement -- the alternative complement cascade from overactivity. The other benefit from this approach is that the subcutaneous treatment regimen will be able to potentially treat both eyes. If we can go to the next slide. As Atul mentioned, one of our other core elements of our strategy is to look into gene therapy. Now there have been over 270 identified genes which have caused retinal disease, and over 95% of these gene mutations have initiated -- initially resulted in the death of rod photoreceptors. So if we go into the next slide. And it's for this kind of interest and well-established area of gene mutations within ophthalmology because there have been, historically, a lot of great genetic studies in eye disease. Number 2 reason that we're interested in ophthalmology for gene therapy is it's an enclosed system. And the third reason is that it's really great because we can provide low doses of the gene therapy treatment. So we've already seen an established treatment through LUXTURNA in terms of the first generation of gene therapy. This is a subretinal injection. And it's exciting to see some of the strong results coming out of that treatment as it's being used in patients in the real world. Our partnership with 4D Molecular Therapeutics has enabled us to identify ways of improving the vector for this treatment and optimize -- in doing so, optimize our tissue targeting. And our goal is really to move to the next-generation of gene therapy, which incorporates intravitreal injections. Intravitreal injections are a very well-established procedure for retinal specialists and have the potential to transduce the entire retina, which will enable it to be more applicable to a broader range of genetic conditions. Next slide. So as you heard from Atul, we're really thrilled to announce, just very early this morning, our first patient into the Choroideremia study, which is in collaboration with 4D Molecular Therapeutics. Now just as a reminder, this is an X-linked recessive disease which affects over 10,000 patients in the U.S. and the European region. And it's a progressive disease which starts in males at about the age of 17, and many of these people unfortunately go blind by the age of about 40 to 50. So we're really excited that this gene therapy has got the potential to address such an important area of unmet need. Next slide. Now just before we move over to Dr. Pieramici's presentation of the data, I just want to briefly summarize where we are with the Port Delivery System and just to remind you a little bit about it. On the left-hand side here, you can just see the implant. So this is an implant. The Port Delivery System is an implant system which consists of injection, refill syringes, the tools to implant the device and the device itself and the drug. The device itself is approximately the size of a grain of rice. And the procedure is, in terms of the initial implantation, it's performed under local anesthetic in the operating theater, but the refills are in-office refills in a similar manner with slightly more -- what might take slightly more time but are performed in-office. The formulation of ranibizumab is customized. So just to highlight, this is not the same formulation as Lucentis. The Phase III design is based on the LADDER results, which, as you can see in the graph on the right, demonstrated that up to 80% of patients were able to progress to the 6-month time point without requiring refills. Now this is based on a PRN, so an as-required treatment regime, and the goal of that was to identify how long patients can go before they require the treatment. Just other important pieces to note. Atul already mentioned that we have our Phase III ongoing, actively recruiting in diabetic macular edema. And if we go to the next slide, and even more excitingly, we have the opportunity to really accelerate other molecules into the Port Delivery System platform. So we've talked about the DutaFabs, which are essentially the same size as ranibizumab, so just under 50 kilodaltons. So we can use the same device, the same release control element, exactly the same platform. And potentially, with these DutaFabs being able to target multiple targets, for example, the Ang2/VEGF DutaFab, we'll be able to really grow this, not just as a monotherapy platform, but as a multiple therapy platform. And this is going to be really important as we roll this out globally over the coming years. And as you can see, we have 3 DutaFabs in preclinical development. And finally, next slide, Lisa. So finally, before moving over to Dr. Pieramici, is the fact that we have had some, and I want to mention this, some phenomenal collaboration over the years with our investigators in terms of making the Port Delivery System a success. And one of the key areas is the training, which we've had. I can't emphasize enough the importance of training. And we have really -- I want to draw out 3 pieces here. Number one, all of our surgeons undergo training, utilizing our virtual reality platform, before any surgery. Number 2 is we have a great team, which we refer to as the Surgical Device Liaisons, which are seen in any medical device company, and they work on-site with our surgeons in the operating theater. And thirdly, we have facilitated excellent peer-to-peer education and training opportunities where we continue to improve the surgical skills, working very closely with our surgeons, to continually improve outcomes for patients. And so with that, it's with great pleasure that I'd like to hand over to Dr. Dante Pieramici, who is a lead principal investigator and has been on both the LADDER and the Archway studies. And importantly, he's also a lead partner in the California Retina Consultants, which is a very large multicenter, multi-practice specialty in California. So Dr. Pieramici, over to you.

Well, Chris, thanks very much. I'm actually personally very excited to be presenting this information to you. And I can tell you there's a lot of excitement in the retina community about the potential for the Port Delivery System to really offer something new for our patients. I've been a retina specialist since the mid-'90s, so I remember a time before anti-VEGF therapy. Anti-VEGF therapy has been wonderful for our patients, diabetics, AMD patients, and it's offered something remarkable, really. But as Atul mentioned, there's a shortcoming in the long run. I think patients do well initially. They do well when they're part of clinical trials. But over time, the burden of therapy means a reduction in therapy and eventually loss of the initial gains in vision. I think the Port Delivery System offers us a potential for great efficacy in the long term. So let's dive into this data that was just presented at the American Retina Society just a few days ago. Over 1,000 attendees, and I can tell you there's a lot of excitement amongst them as well. Well, the Port Delivery System with ranibizumab is a continuous intravitreal delivery system for a customized formulation of ranibizumab. It's an innovative investigational drug delivery system. It's permanent. It's placed surgically in the operating room. It's an outpatient procedure, local anesthesia, relatively straightforward. And it comes with a customized formulation of ranibizumab. It's not the typical 0.5-milligram dosage. It can be refilled multiple times in the office as necessary. And the procedure for the refill is a bit more difficult for the surgeon or physician, but easier, much easier on the patients. The LADDER trial, which is the Phase II trial, demonstrated that the 100-milligram dose had the same vision and anatomical outcomes with monthly ranibizumab injections. And as the LADDER trial showed, in the high dose group, the average need for a refill was 15.5 months. In addition, the Port Delivery System in the LADDER trial was very well tolerated. And these data supported the initiation of the Phase III trial, which is called the Archway trial. Next slide, please. The Archway, as I mentioned, is a Phase III multicenter randomized clinical trial that was designed to evaluate the efficacy and safety of the PDS, Port Delivery System, for the treatment of neovascular or wet AMD. This study included 415 patients and these are patients who had already been treated with anti-VEGF agents and had shown responsiveness to the drug, so keep this in mind. These are not naive patients without treatment. The patients were randomized to the Port Delivery System, 100-milligram per ml, that would be refilled in the office every 24 weeks versus monthly intravitreal ranibizumab injections, which is the gold standard. The primary objective of this trial is to evaluate for noninferiority and equivalence of the PDS 100 milligrams per ml refilled every 24 weeks versus the monthly ranibizumab intravitreal injections. The primary outcome of this study was a change in best-corrected visual acuity score from baseline averaged over weeks 36 and 40. And there were another -- a number of variety of anatomical and visual and safety outcomes that we're evaluating. We'll see some of these. Next slide, please. This is the treatment regimen. And I turn your attention to the top line, which is the Port Delivery System with ranibizumab arm. As mentioned before, it's an outpatient surgical procedure. The device is filled for the first time and then placed surgically. It is then refilled every 24 weeks, as you can see in the blue boxes on the top line here, but the patients also have a chance to have supplemental ranibizumab injections if there's evidence of disease activity 1 or 2 months prior to the refill. There are certain criteria that must be met to demonstrate disease activity based on visual acuity changes and OCT anatomy changes. Next slide, please. The baseline demographics and ocular characteristics were very well balanced across the treatment arms. On average, the patients were around 75 years, which is pretty typical for neovascular AMD trials. I would mention as well that the visual acuity at the baseline was very good in these patients, as would be expected in patients who had been previously treated with anti-VEGF agents. On average, the enrolling or baseline visual acuity was 20/32 in both groups. In addition, there wasn't a lot of retinal thickness at the time of enrollment because they have been previously treated patients that had neovascular AMD diagnosis for about 6 months and have had, on average, 5 prior anti-VEGF injections. 98% of the patients retained in the study through week 40, and there was no impact of the COVID-19 on this time point. Next slide, please. And so for the results. The PDS met its primary end point. At -- the PDS refill at 24 weeks was noninferior and equivalent to monthly ranibizumab injections. If we look at the change in visual acuity over this 40-week time period, it was 0.2 letters in the PDS arm, 0.5 letters in the intravitreal arm, for a difference of negative 0.3 letters. So it met the noninferiority and equivalent criteria. Next slide, please. Let's look at the visual acuity over the 40 weeks. Again, remember that patients had very good visual acuity at baseline, 20 over 32, and they maintain that in both arms at week 36 to 40 at 20 over 32. And you can see that in the graph here, there's very little change over time. There was a slight decrease in visual acuity in the PDS arm immediately following the surgical procedure, and this is pretty typical and was expected. It normalized by 10 weeks. And I would highlight the fact that on average, it was only one line of visual acuity. Next slide, please. This is the anatomy results, the OCT thickness changes. And again, remember there were previous injections, so most of the retinal thickness had been reduced at the time of enrollment of the patients. And as you can see, there was no difference between the 2 arms. There was absolutely a difference of only about 2 microns at 40 weeks between the intravitreal arm and the PDS arm, so the same anatomy. Next slide, please. 98% of the PDS-treated patients did not receive supplemental treatment. Remember, they had the potential to get additional injections if, prior to the refill, there were signs of disease activity. So on 98% of the patients, there was no disease activity prior to the refill. So if we look at the absolute number of treatments and compare the 2 arms, the PDS arm in blue and the ranibizumab intravitreal injection arm in green, there were 2.0 treatments, that includes the initial fill and the monthly refill and any supplements, an average of 2 in the PDS arm, compared with 10.7 intravitreal injections in the intravitreal arm for an absolute difference of 5x more treatment in the intravitreal arm. Next slide, please. Let's look at some safety signals here. These are the ocular adverse events of special interest. The most common ocular adverse event of special interest was conjunctival blebbing or thickening. And this occurred in about 6% of the patients. This was considered nonserious and many of them resolved over time. Vitreous hemorrhages or bleeding in the vitreous cavity of the eye, which was seen also on the LADDER trial, occurred in 5% of the patients. Once again, most of these were very nonserious, none of them required vitrectomy surgery and they resolved spontaneously. The incidence of cataract formation was similar between the treatment arms and there was no incidence of traumatic cataracts. Conjunctival erosions and retraction occurred in 11 patients. Nine of these cases could be repaired surgically. Two of the patients left the study with explantation. Endophthalmitis or infection inside the eye occurred in 4 patients. In 3 of the 4 patients, the visual acuity following treatment returned to baseline. One patient had a loss of visual acuity. This was associated with a case of Enterococcus endophthalmitis. I should note that this patient was also cleaning a septic tank in the postoperative period, and this may have been the cause. Most of the patients could be continued in the study following the cases of endophthalmitis and did not require explantation. Retinal detachment occurred in 2 of the patients, and these were repaired by vitrectomy surgery. So in general, the procedure was well tolerated. Next slide. These are the serious nonocular events or systemic events through week 40, and there was no difference between the 2 arms. In addition, none of the serious nonocular or systemic events were suspected to be related to the study treatment. These are elderly patients, and these are typical things that we see at the patients of this age category. Next slide. In addition to the objective data that I've presented, we also collected subjective information on the patient's preference called the PDS Patient Preference Questionnaire, the PPPQ, if you will. This was administered to all patients in the PDS arm at week 40. And remember, all these patients have had previous experience with intravitreal injections in this eye and many of the patients were being treated in the fellow eye with intravitreal injections. The PPPQ was a 3-item questionnaire that captured the patient's preference. Did they prefer intravitreal injections? Or did they prefer the Port Delivery System? Or did they have no preference? It also tried to calibrate the strength of their preference. Was it very strong, fairly strong and not strong? And also the reasons for their preference. Was it less worry, some less nervousness about the procedure? Did it require less time, less discomfort or fewer treatments? Next slide. Well, what did we find with the PPPQ? We found that a vast majority, 93% of the PDS patients, preferred the PDS over intravitreal injections. And of the 7% of the patients that didn't put down that they preferred -- the 6% of the patients actually really didn't have a preference. Only 3 patients preferred intravitreal injections. The reasons for preference of the PDS, in most cases, were fewer treatments, less discomfort of the procedure. It was a less worrisome or nervousness procedure overall, and it required less time. And I can tell you from my personal experience with a couple of dozen patients with the Port Delivery System, this is their feelings as well. In the patients who are receiving intravitreal injections in the fellow eye, their main question to me is when can they get the Port Delivery System in that eye as well. Patients tolerate this procedure well. The refills are pretty straightforward for them, less -- much, much less painful. And really, there's been a lot of excitement amongst physicians and amongst the patients themselves. Next slide, please. There were a lot of people involved in the Archway trial. This is a list of some of the primary investigators at sites all around the United States. Many patients, many study coordinators that took a lot of people to put this work together. And as I mentioned, there's a lot of excitement in the retina community about this. I think it was the top talk of the ASRS meeting that was online just over the weekend. Next slide, please. So to summarize, the Archway met its primary end point. The Port Delivery System that was refilled, mandated every 24 weeks was equivalent to monthly ranibizumab, preceding -- resulting in equivalent visions, equivalent anatomy, but it did show significant treatment durability with a significant reduction in the treatment burden. 98% of the PDS patients did not receive any supplementary intravitreal injections before the first refill for an absolute or relative difference of 5x fewer treatments than intravitreal injections. 93% of the PDS patients preferred the PDS over intravitreal injections. I think there is a favorable benefit risk profile. The PDS surgery device combination was generally well tolerated with surgical complications that we expect in some of these types of cases. The PDS overall maintained vision while reducing treatment burden through continuous delivery of ranibizumab. Next slide. Thank you very much for your attention. And I appreciate the opportunity to present this to you today.

Yes. Thanks a lot. Maybe, Henrik, if you could kindly remind us how to place questions to have here an interactive dialogue.

[Operator Instructions]

Yes. Thanks a lot, Henrik. So we have about 170 people on the call, which is a lot for such a specialized field. So thanks for your interest and in order say for you to also raise your hands and to get into a live webcast. Maybe first question via the web from Michael Leuchten. Can you drill into the patient compliance a bit more? So he's interested in the compliance of maybe the control arm or the active arm. Why would a patient that starts to have blurred vision not go to see the doctor? Isn't sight a strong incentive? That is his question.

Thanks, Karl. And thanks, Michael, for the question. I'll take it just briefly. I think, first of all, there is -- over the last few years, has been an increased opportunity for patients when they have visual issues to go to their physician much faster. I think the issue, which we've identified, is really about the treatment and the initiation and the continuation of the treatment, which is why they don't do so well sometimes in the real world. And this is really because of the burden of treatment. So some of these treatments, these anti-VEGF monotherapies, you have to have up to monthly monitoring and up to monthly treatments in some cases. And that's really a very large burden on the patient and their caregivers in terms of these regular appointments and visits to their physician. So I'd say yes, sight is a strong incentive, but unfortunately, the burden of the treatment is the issue, which gets in the way to your -- to truly successful outcomes.

And Chris, I would just add to that. The caller was wondering, why wouldn't the patient just go in? Well, really, we don't want to wait for the vision to deteriorate before the patient comes back for therapy. We want to stay ahead of it, and we can often see changes and things prior. So if a patient takes the attitude that we're just going to wait until the vision goes and then go back and see the doctor, I think it will be a losing venture. So having the patients come in -- and most of our patients need treatment every month or every 2 months and so it is a burden. And we've really seen that -- how the COVID can affect this with many of the patients missing their follow-ups and their vision deteriorating and losing vision.

Yes. I would say, thanks for the question. We take one from the call. So we have Wimal, maybe allow you to talk now. The operator in full control.

Can you hear me?

Yes, we can hear you.

Okay. Wimal Kapadia from Bernstein. So just 2 questions, please. How do you think about the market potential across the 2 key indications for the PDS? Which population do you think the PDS is more suited? Is it DME where we know you are dealing with a more heterogeneous population? Or is it wet AMD, which is a better controlled population? Then my second question is for the 4 patients who required supplemental treatment. Were they correlated with the worst BCVA dip post-surgery? And did they drop below the threshold that does require retreatment? Or is that not the case? And then finally, just a very quick one. Do you have any thoughts on the lifespan for the PDS? How many refills before you need to take out the device and put a new one in?

So Karl, I'll take the first question. And Chris, you can take the following question.

Yes, yes.

So Wimal, thanks for the questions. So we see potential in both disease areas and for different reasons. With AMD, as Dr. Pieramici said, if you miss a few visits -- and we saw this in the COVID situation. You miss a few visits and patients start losing vision very rapidly. So it's a different dynamic. We see that more than 50% of the patients cannot be extended beyond 3 months on the therapies that are on the market. So you can think of that 50% as a potential pool of patients who would benefit from PDS. And then, of course, the surgeons have to sort of look at the benefit risk for that individual patient. So in AMD, in neovascular AMD, there's a clear need for something like Port Delivery where you have outcome certainty. Now when it comes to diabetic macular edema, there are 2 aspects. One is these patients are much younger. These are working age patients for the most part. There are lots of comorbidities. So you can imagine the polypharmacy that goes on for a typical DME patient. And providing the ability to sort of come in every 6 months in diabetic macular edema patients is going to be important, so they can get on with the rest of their life. The other piece is diabetic retinopathy. And this is a progressive condition, right? So DME is a manifestation of edema, you have diabetic retinopathy. And again, for these patients, having a solution like Port Delivery System, where you have, again, certainty that you're delivering anti-VEGF on a regular basis, on a continuous basis is going to help us and potentially have a reduction of the diabetic retinopathy severity score. So we see both these indications being important from patient as well as from a patient care perspective. Chris?

Thank you. So in terms of the question regarding the 4 refills, the 4 supplemental injections. So these cases were -- in fact 3 of those were actually an error made by the -- a mistake made by the reading center. So actually, they did not in reality, require the refills -- sorry, the supplemental IVT injections. So that left with one patient who actually did meet the criteria for a supplemental IVT injection. And that patient did well after that IVT injection has continued to do well. With regards to the durability of the device, each, as part of medical device testing, we have validated and robustly quality assured the device in terms of ex vivo manufacturing, and these devices have been refilled hundreds of times, which is much, much longer than the expected lifespan of patients in terms of 6 monthly refills. And the second important point there is that we've had these devices in eyes since the very beginning of [indiscernible], which initiated in 2015. So by the time that we bring this to market, we will have between 5 and 6 years of refills and most important in life data. So I'm happy to take any more questions from…

Hey, Chris, how long have the Phase I patients gone now? Is this about 7, 8 years now?

So the Phase I patients were first implanted in 2010. So they've had -- they've been implanted since 2010, so up to 10 years for them.

Thank you. Thank you very much. Maybe take the next question also from the call. Tim Anderson would be the next one. Tim, please.

Tim here. Can you hear me? Yes, hopefully, you can hear me.

It's a bit difficult, but we'll try. Yes.

Can you talk about where do you think the biggest challenges are likely to be in trying to commercialize PDS system? It seems like there's a variety of ocular adverse events that could be worrisome like endophthalmitis relative to monthly dosing, especially in a post-beta view world.

Yes. Thank you, Tim. That goes, Atul, to you and to Chris. It's mix of both.

Yes. So I'll address the commercial challenges. So Tim, there are a couple of things to work through. Number one, we want to make sure that this is a very purposeful launch of the device because we don't see this as a launch of a product. We see this as a launch of a platform. So we are looking at not the next 3 years, we're looking at the next 15, 20 years in terms of setting up the Port Delivery System as a viable platform. So the PDS team uses the term purposeful launch where we want to sort of work very closely with the surgical community in making sure that their first experience, their first few experiences with the product is positive. And this was a learning from the Phase II and Phase III. The surgical training that was done, the collaboration with the surgical community was really important. So that's one aspect for us to make sure that we are being very thoughtful, very purposeful and very strategic in the launch process because, for us, we believe that the segment we create, the market we create will own this in Port Delivery. So it's important that we do that right. Number two is going to be working through the reimbursement. So we are balancing the reimbursement strategy, making sure that the surgeons are adequately compensated. They're not losing money on this. And at the same time, the payers have a value, additional value that they can see from the Port Delivery System. And again, the dynamics are a bit different in the U.S. versus ex U.S. and as you can imagine, we are also interested in working closely with the HTA markets where the societal benefit of something like PDS, where you have outcome certainty would be attractive to many, sort of, payers. And I think the third piece, we are working in ensuring that we, as a company, are ready for a device launch. We know how to launch biologics, but we are launching a medical device here, and we are bringing on talent that is sort of very familiar with the device commercialization and also our people out there. Chris mentioned the Surgical Device Liaisons. Now these are all trained nurses for the most part. And they have done a phenomenal job in the U.S., and we are sort of building out that team outside the U.S. as well. Chris, you want to talk about AEs?

Yes. So a couple of points here. First of all, starting with the vitreous hemorrhage. As you see -- as you recall from the Phase II LADDER study, at the beginning of that study, we had up to 50% rate of vitreous hemorrhage. We then improved the surgical technique, and that went down to approximately just under 5%. And despite almost doubling the number of clinical trial sites between the Phase II and the Phase III, going from about just under 50 to just under 90 sites, we remain able to not only maintain that success with the vitreous hemorrhage control, but really, we saw great results. Despite the vitreous hemorrhage rate being under 5%, there were no requirements for surgical intervention. So no vitrectomies were required for those hemorrhages and they resolved of their own due course. The second piece there is the endophthalmitis. Now out of the 4 cases, 3 were related to the conjunctival erosion issues. We believe that there are -- that these conjunctival erosion issues are addressable through continuous surgical training, and we are working very, very closely with our surgeons to see what we can do and to continue to improve and reduce the rates of conjunctival erosion. And we believe that we will be able to do that over time. I think the second piece of the endophthalmitis is that of those 4 patients, 3 returned to the either baseline or better visual acuity. I mean I think just in terms of the Surgical Device Liaison training, I mean, and how that's going, Dr. Pieramici, would you like to just kind of summarize to the audience how that's been going from your side?

Yes. I think there's a real commitment with this to make sure that the procedure is done properly. And the Surgical Device Liaisons are really people who are skilled in the operating room. They're -- a lot of them are -- used to be scrub techs and such. And so they come and they walk step-by-step through the procedure. And I think it's made a big impact. And they're planning on doing that going forward as well. Chris, I would agree with you that I think that this conjunctival retraction endophthalmitis association does give us a target of something that we can try to monitor better for and then intervene early before an infection happens. So I think just as we did with vitreous hemorrhages in the LADDER trial, I think some mitigation, better technique with closing of the conjunctiva being taught and then monitoring carefully for any signs of early retraction will really reduce endophthalmitis case, which is really the main concern. I think these other adverse events are more mild and not so concerning to most physicians.

And just to add to what Dr. Pieramici was saying, just to provide some context, 15 years ago, when we had the ANCHOR, MARINA studies, when you go back to that literature, the endophthalmitis rates were 1.3%, 1.4% in those pivotal studies. And over a period of time, the retina community has worked incredibly hard to bring those rates down. So I think science takes us forward. I think the more we work, the more we sort of focus on these issues. We can bring those rates down, and we are fairly confident of doing that.

Tim, I hope we could address all your questions. So we have now in the meantime, a more logistical challenge, I have to say, because I wasn't expecting so many questions. So we have 9 people who raised their hand. We have 12 people in the Q&A. So I would say let's continue with one question from the phone. I don't have a question here, but it's from the U.K. and it ends with 839-767, I allowed to talk. I don't know who it is exactly. And then we will take some questions via the Q&A, yes.

This is Elizabeth Walton. I'm from Crédit Suisse. I'm wondering if I can ask a question to Dr. Pieramici. In terms of thinking about making decisions between the Port Delivery System or faricimab for your patients? What do you think about between the 2? And what factors would come into play in making such a decision?

Well, I guess I'm going to have to wait to see what the results of the faricimab trial are before I really make any final decisions. But I think the Port Delivery System is going to be something that's not for everybody, but the patients who are needing injections every month or every 2 months or maybe every 3 months, this is the kind of thing that they really may go for. And so I think there'll be a fairly large number of patients at the end of the day who may potentially opt for this. The faricimab trial, if it has the durability that we saw in the Phase II trials in the Phase III trial, you're talking 3 or 4 months of a drug, yes. And it has been mentioned that I would think that the next thought in my mind would be to put this in the Port Delivery System and make it even longer. So the simpler we can make the treatment regimen for people, the better it's going to be, particularly in this elderly population, they have trouble coming back. Because you'll see, if you look at real-world data or post clinical trial data, everything sort of seems to regress towards the mean, and that's because of undertreatment in large part. So yes, I don't exactly know. I'm sort of anxiously awaiting the results of the faricimab trials to see how this drug really does work and fit in, if it's more efficacious. I mean if it turns out to be more efficacious and more durable, then I'd say, great, I'd use that, and then let's figure a way to put it in the Port Delivery System.

And if I can just squeeze in a quick follow-up. You previously said you couldn't fit faricimab into the Port Delivery System because the molecule is too big that you were working on some antibody fragments. Any update on potential timing to move forward with those?

Sure. I can take that, Elizabeth. So faricimab is not going to be in the Port Delivery System. So what we have done is we have a VEGF, Ang-2 DutaFab. And this is the right size, as Chris said in his presentation, and we will start Phase I this year. And we now have a very clear pathway with our LADDER and ARCHWAY experience. So now we have our early-stage colleagues from pRED working with our late-stage colleagues, and we are looking at an accelerated pathway of bringing this to market in the coming years. The idea, again, for us, Elizabeth, is to think of port delivery as our hardware, and then we keep coming up with software upgrades, and we keep pushing the durability 6 months, 9 months, 12 months until the community asks us to stop. But I think we are looking at the DutaFab platforms, and we have a couple of other MOAs as well. So we want to make sure that there are enough options for patients to -- and physicians to use inside the Port Delivery System.

Thank you, Elizabeth. So there is a question from Richard Parkes from Exane. He says, I have a question for Dr. Pieramici. Can you help us understand how physicians are likely to perceive the surgical complications seen in the trial? So how do they charge on this thing? And whether the patients -- maybe this is going more to you, Atul, whether the patients experiencing complications were included in the patient preference questionnaire. So in other words, is the patient preference questionnaire really a full and fair reflection of what you have seen in the trial, so seeing the same issue from both sides?

Well, I'll talk about how the community views this. I think -- I mean I talked from my vantage point, having talked to other people. Yes, I think the endophthalmitis to me is the biggest concern that I think people will have. The other complications are more mild -- and things like vitreous hemorrhages, they cleared and they really weren't a visual problem. Retinal detachments can occur in patients getting intravitreal injections as well. I think that you have to look at this as there's an endophthalmitis rate, but there's also a risk of endophthalmitis with intravitreal injections, and each one, the risk is very low. But if a patient -- and I have patients who've had 150 intravitreal injections in 1 eye, if you put that risk in perspective with the potential risk of this Port Delivery System, I think that you'll find that things sort of balance. And as I mentioned before, I think that we really can look at this potential problem. There's a real association between the retractions and erosions in endophthalmitis, so we have an avenue to prevent this. I mean when we do an intravitreal injection, we do things to try to prevent it as well, but there's always some low rate. I think going back with meticulous teaching and also monitoring for retraction over time, we can really reduce these rates. So I'm hopeful that, yes, the community is going to embrace this, and they're going to try to find ways to reduce it, as Atul mentioned, as we have done with endophthalmitis following intravitreal injections to the rate that it's 1 out of every 2,000 or something like that now, where it was a percentage or a near percentage in the original trials.

So perhaps I could comment first, Atul, then over to you. So just in terms of the question regarding the complications in the patient preference questionnaire. I just want to just take you back to the vision. I think despite all of these complications, the vision was equivalent and pretty much exactly the same between the monthly ranibizumab arm and the Port Delivery System arm. And just to highlight again the retention. So only 2 patients in the Port Delivery System arm did not have data at the 36- and 40-week data. So all of the patients with complications were included in the BCVA change. And the same is the case for the patient preference questionnaire. So despite all the complications, 90 -- as you can see here, 93% preferred the Port Delivery System despite those complications. So I think that's kind of really important. So I think, hopefully, that's answered your question. Atul, any other comments?

Yes, no further comments.

So it was included, of course, and everything. They are, yes. Thought so. Good. I'll take another one here from the web here with the questions, from Gena Wang. She asked, "for the PDS, the retreatment criteria seems very loose, I guess for both, for the control arm and for the active arm. Is that in line with current real-world practices? What retreatment criteria are signed off by the FDA in general terms?"

Okay. I'll take that and then maybe Dante, I can pass you over to real-world clinical practice. I think, again, going back to the basics, for the Port Delivery System, what we're looking for is confidence and quality patient outcomes. So that's why we selected, based on the LADDER study, the fixed 6 monthly retreatment interval. The retreatment criteria were not so much retreatment, but they were supplemental intravitreal ranibizumab treatments given when there was a perceived need based on the supplemental criteria. These were fairly -- you had to have a significant -- a clinically meaningfully significant increase in your retinal thickness or up to a 15-letter reduction in visual acuity. As you've seen with the fact that over 98% of patients went to the full 6 months without requiring these supplemental injections and the fact that the best corrected visual acuity was equivalent to only a 0.3-letter difference at the week 36, week 40. I think the reality is that those retreatment criteria are probably appropriate because what we wanted to avoid is unnecessary interventions when, in fact, the Port Delivery System does provide a continuous treatment of ranibizumab throughout that time. In terms of the FDA, the FDA is, as we know, they are not particularly interested in retinal thickness because there's been very poor correlation or absence of correlation of retinal thickness with visual acuity outcomes, and we're really interested in what this means for patients. So they're interested in kind of a 15-letter change but less interested in thickness on the retina. Dr. Pieramici, any comments in terms of real-world practice?

Yes. I mean I'd just emphasize what you said. I mean this is the same supplemental therapy or rescue therapy that was used in the LADDER trial. And at the end of the day, the visual results and anatomical results were the same using this criteria. So the proof's in the results, you sort of take a guess when you set up the trial, but it worked out well. I think it's a little bit of a moving target. I think initially, when we first started with anti-VEGF agents, we're always trying to dry everything up, and we've learned that certain things like a residual subretinal fluid, pigment epithelial detachments really don't need to be dried up completely. And actually, there may be some utility in having a little bit of leakage in these cases. So it's a bit of a moving target right now. I think we're more comfortable with the Port Delivery System because we know that there's a continuous stream of the anti-VEGF agent coming out and the pharmacokinetic data from the LADDER trial would support this that you can measure out to past 12 months at some level in the serum. So we're more confident that there's something there as opposed to an intravitreal injection, where 6 or 8 weeks later, there may not be anything there anymore. So we're worried that those patients if they miss a follow-up or something, it's going to be more of a catastrophe. So that's how I think we view it. It's a little bit -- there's a little bit of variety in the community out there, and I think we're loosening up our criteria more. So -- and I think these criteria are not necessarily atypical for other trials that have used rescue therapy as well.

Thank you. Let's take the next question from the phone. Steve Scala, please, from Cowen. Steve? I did unmute Steve, but maybe the operator can help me, Henrik.