Thanks for your patience. Good evening, everyone. My name is Susie Lisa, and I'm the Senior Vice President of Investor Relations for Vertex Pharmaceuticals. Thank you so very much for those of you joining us here in the room in Chicago at the American Diabetes Association 85th Scientific Sessions for our zimislecel update. It's an exciting day for Vertex with the update today at ADA, with the NEJM article, and the summer solstice. Big day. Thank you for all of you joining us online as well. We will be making forward-looking statements on this call. They're subject to the risks and uncertainties discussed in detail in our filings with the Securities and Exchange Commission. These statements include, without limitation, those regarding expectations for Vertex's T1D programs and actual outcomes and events could differ materially. Here's the agenda. We will begin our event with our very own Felicia Pagliuca, who is the Senior Vice President of Cell and Genetic Therapy Research. She earned her PhD in Biology from Cambridge University, where she was a Marshall Scholar, and did her postdoc fellowship at Harvard in the Stem Cell Institute as a member of Doug Melton's lab. She went on to become a scientific co-founder of Semma Therapeutics and their VP of Cell Biology R&D before joining Vertex via acquisition of Semma back in 2019. After Felicia gives us an overview of our Type 1 diabetes approach and portfolio, we are extremely pleased to have two physicians here for you tonight to share their views on the zimislecel data, the Type 1 diabetes landscape, and the potential for zimislecel in the real world. Our first speaker is Dr. Michael Rickels. He's a professor in diabetes and metabolic disease at the Perelman School of Medicine at the University of Pennsylvania and has extensive clinical research and experience in islet cell transplantation in patients with Type 1 diabetes. Dr. Rickels serves as the co-chair of the External Steering Committee for the Vertex T1D portfolio, which includes zimislecel. We're also very pleased to have us to be joined by Dr. James Markmann, a professor of surgery and vice president of transplant services at University of Pennsylvania. Dr. Markmann has been directly involved in pancreas and islet transplant programs and caring for patients during and after procedures. He is the principal investigator at the University of Pennsylvania clinical trial site for the forward trial of zimislecel. For the Q&A session, we'll have all of our speakers here to answer your questions. Because we're also webcasting this live, we ask during the Q&A that you wait for a microphone with my colleagues Manisha Pai and Kristin Hodes. Thanks for all their help for making this happen tonight. For those on the webcast, we recommend that you access the webcast slides as you listen to the call. The call is being recorded, and a replay will be available on our website. Now it's my pleasure to hand it over to Felicia. All right. Thank you, Susie, and welcome, everyone. My name is Felicia Pagliuca, and I'm very pleased to be here with you this evening, especially on such a special day for all of us working on the Type 1 diabetes program at Vertex. You're here tonight to hear about zimislecel, our most advanced program for T1D, which, as you know, is a serious disease caused by the immune destruction of one particular cell type in the body, the insulin-producing beta cells that reside within the pancreas. In this cartoon, you can see on the left-hand side a picture of a pancreas, and the pancreas is dotted with these clusters of cells called the pancreatic islets. The purple cell depicted here is the very special cell, the insulin-producing beta cell. In Type 1 diabetes, the immune system goes awry and destroys all of those essential insulin-producing beta cells. You can see what that looks like on the right-hand side here. In people with Type 1 diabetes, they do not make any of their own insulin as a result of this immune destruction of the beta cell. They end up in a situation where they no longer produce any of their own insulin and rely for the rest of their lives on insulin treatment, which requires very careful glucose monitoring. Although that insulin therapy is life-saving, it is essentially the same way that we have treated Type 1 diabetes since 1921, when insulin was first discovered more than 100 years ago. This is entirely inadequate to meet the needs of patients and their families, both in terms of acute health complications, serious secondary complications that occur over time, as well as the tremendous burden on quality of life. If we look here on this slide, I'll highlight just a few of the difficulties faced by people living with Type 1 diabetes. As I mentioned, Type 1 requires intensive lifelong management. Despite advances in technology, the unmet need is very high. Almost 4 million people have been diagnosed with Type 1 diabetes in North America and Europe. We expect the initial zimislecel indication could serve about 60,000 of those patients. These 60,000 patients have the highest unmet medical need. These are patients who experience severe hypoglycemic events, a serious and potentially life-threatening complication of insulin therapy. Serious hypoglycemic events are events where one's blood sugar drops so low, so quickly, that it requires the assistance of a third party, spouse, paramedic, or other in order to recover. As you can see on the right-hand side, those severe hypoglycemic events can result in seizures, cardiac arrhythmia, coma, and even death. Importantly, those individuals who experience recurrent severe hypoglycemic events can have an increased mortality rate up to fivefold those who do not experience SHEs. Despite available therapies today, including pumps and continuous glucose monitors, nearly 10% of individuals living with Type 1 diabetes experience these dangerous recurrent severe hypoglycemic events. As you can see, despite optimal medical care, Type 1 diabetes is associated with substantial morbidity, including microvascular and macrovascular complications, reduced life expectancy, and the incredible burden of living with this disease day in and day out and treating it with a medicine like insulin with such a tight, narrow therapeutic range that results in these potential severe hypoglycemic events at one end of the spectrum and the consequences of living with hyperglycemia or too high blood sugar, which has negative impacts on many organ systems leading to those secondary complications. Imagine there was a better way. Imagine there was a way to replace those cells that have been destroyed by the immune system. Let me tell you about zimislecel. Zimislecel is our investigational islet cell therapy. This is a cell therapy that we manufacture starting from stem cells, which we fully differentiate into those glucose-responsive, insulin-producing stem cell-derived islets. These are off-the-shelf allogeneic cells that have the potential to replace those islet cells that are destroyed in people living with Type 1 diabetes. Zimislecel itself, as a cell therapy, is delivered via an infusion into the hepatic portal vein in a simple procedure, and it's protected from immune destruction with a standard steroid-free induction and maintenance immunosuppressive regimen. This protects the cells from the immune system. Both the cell infusion procedure and the immunosuppression regimen are well established and well understood. While we'll talk about zimislecel today, which we see as an incredible advance for this patient population, as is the case for all of our work at Vertex, our research continues, and we continue to serially innovate. We're working on projects to invent alternate immunosuppression agents and regimens. We're working on gene-edited hypoimmune approaches, as well as other technologies which are advancing through research. Before I hand it over to Dr. Rickels, I want to summarize where we are with zimislecel. Most importantly, our pivotal trial, our Phase I, II, III study, is progressing rapidly. As we disclosed earlier this year and late last year, we have converted our study into a Phase I, II, III pivotal study, which is expected to enroll approximately 50 subjects, and it's expected to complete enrollment and dosing this summer. Importantly, we have had very positive engagements with regulatory agencies and believe our regulatory designations underscore the recognized high unmet need and transformative potential for zimislecel. Those designations include the Regenerative Medicine Advanced Therapy designation, or RMAT, as well as Fast Track designation here in the U.S., PRIME designation in Europe, and the Innovation Passport under the Innovative Licensing and Access Pathway in the United Kingdom. Lastly, we expect now to submit regulatory submissions next year in 2026. As a result, we are actively preparing for the launch and commercialization of zimislecel. We see this as a highly concentrated market that can be served with a specialty commercial model consistent with our overall approach and strategy at Vertex. With that, I'm going to hand it over to Dr. Rickels to talk you through some of the data that has us so excited about bringing this potential therapy to patients with Type 1. Thank you, Felicia. Thank you, Susie, and colleagues at Vertex for the opportunity to present on the data from the Forward 101 study that we presented just earlier here at the American Diabetes Association meeting. Are the slides? Oh, I get them here. Yep. Okay. There you go. All right. This is the presentation given just in the hour preceding this meeting of durable glycemic control and elimination of exogenous insulin use with VX-880 in patients with Type 1 diabetes. I had the privilege of presenting this here at ADA on behalf of my colleague, co-investigators, steering committee members, and Vertex Pharmaceuticals. These are my disclosures, which include, as Felicia mentioned, serving as co-chair of the steering committee, as well as a site co-investigator for the Forward study. As you have heard, zimislecel is an islet cell therapy in clinical development for those individuals with Type 1 diabetes experiencing severe hypoglycemia. This cell product is investigational, allogeneic, stem cell-derived, and a fully differentiated insulin-producing islet cell therapy. Zimislecel is administered by portal vein infusion for intrahepatic engraftment under a steroid-free induction and maintenance immunosuppression regimen, as has been established both as the site and for the immunosuppression with deceased donor islet transplantation. The Forward Study has been a Phase I, II study that's completed enrollment. As Felicia mentioned, it has now been converted to a Phase III pivotal study. For the Phase I, II portion, it was completed under three sequential parts as an open-label design. Part A, with two individuals receiving half the target dose. In Part B, five individuals receiving sequentially the full target dose. In Part C, individuals concurrently treated with the full target dose of zimislecel. These individuals have been adults with Type 1 diabetes complicated by impaired awareness of hypoglycemia and having experienced at least two severe hypoglycemic events in the year prior to screening. The primary efficacy endpoint for the Phase I, II portion was freedom from severe hypoglycemia from day 90 to 365 and the achievement of a hemoglobin A1c less than 7% or at least a 1 percentage point reduction in hemoglobin A1c during the first year of follow-up. The data being presented are cut as of October 2024, when the Phase I, II portion of this trial was completed and prior to its conversion to the Phase III pivotal Phase. The efficacy data will be those for the 12 individuals receiving a full target dose of zimislecel and having at least 12 months of follow-up. The safety data will also include the two individuals receiving a half target dose in part A. These 14 individuals have been, you can see, adults, non-obese, with longstanding Type 1 diabetes. Hemoglobin A1c by design had to be greater than 7% and less than 10%, with undetectable C-peptide and typical insulin requirements for individuals with Type 1 diabetes, all using real-time continuous glucose monitoring and the majority insulin delivery via infusion pump, with the majority of those on hybrid closed-loop systems. These individuals had all experienced between two and four severe hypoglycemic events in the year prior to screening. All 12 participants have restored clinically meaningful and sustained glucose-responsive endogenous insulin production and improved glucose tolerance, as demonstrated through standardized mixed meal tolerance testing. You can see on the left the C-peptide levels, which is our measure of endogenous insulin secretion, is undetectable both fasting and with meal stimulation at baseline, and that both fasting and meal-stimulated C-peptide is restored by 90 days following zimislecel infusion. This degree of endogenous insulin production is further improved by six months, where you see increases in fasting and stimulated C-peptide that are then well maintained throughout the 12 months of follow-up. On the right, you can see the glucose response, and with at baseline marked hyperglycemia developing after ingestion of the standardized meal. Already at 90 days, substantial reduction in both fasting as well, most importantly in the meal-stimulated C-peptide. Again, we see that further improvement with the increasing insulin production at six months. It is then again very well maintained throughout the year of follow-up. These 12 participants all had reduction in hemoglobin A1C to targets under 7%, as you can see on the left, with all starting above 7%. All came well under that recommended threshold and maintained excellent glycemic control throughout follow-up. Insulin requirements, you can see, becoming substantially reduced in 10 of 12 individuals eliminating insulin requirements. It seems to occur most often by about six months following zimislecel infusion and in 10 of 12 off insulin at 12 months, with two individuals remaining on a reduced dose of insulin who had both received some steroids during the peritransplant period that was not part of the protocol. All 12 participants demonstrated substantial improvements in time spent in the target glucose range of 70-180 milligrams per deciliter. For high-risk individuals such as these experiencing severe hypoglycemia, the ADA recommends considering a lower target of 50%, which was even this cohort unable to achieve prior to transplant. The recommended target of being more than 70%, which we know is important for preventing long-term diabetes-related complications, was already achieved by this cohort at day 90 and became further improved, as you saw with the physiologic meal tolerance test data, that by six months, almost 90% time spent in that normal glucose range of 70-180, and that really being maintained throughout the year of follow-up. Substantial improvement in time in range that we do not really see with any other current treatment for Type 1 diabetes. This, you can see together with the substantial reduction of insulin requirements occurring over time coinciding with the improvement in glucose control and overall a more than one and a half percentage point reduction in hemoglobin A1c. All 12 individuals in the Phase I, II portion met the primary endpoint of absence of severe hypoglycemia through the evaluation period and meeting those recommended targets for glycemic control. The majority of adverse events were mild or moderate in severity. Those with a causal relationship to any study drug were mostly attributed to immunosuppressive therapy. Those attributed to zimislecel were mostly transient elevations in liver transaminase levels that we see with any portal vein administration of an islet cell therapy. There were no severe adverse events considered related to zimislecel. There have been two deaths that were previously reported and not considered related to zimislecel. The most common adverse events were diarrhea, headache, nausea. These together with, I mentioned already, the transient increases in liver function tests, but the decreased white blood cells, decreased renal function. These also all expected and common with the immunosuppression regimen that's used and generally manageable with dose modification and close monitoring of drug levels and the patient's status. This is all consistent with what we know from these medications and the infusion procedure from our experience with deceased donor islet transplantation. To summarize, all 12 participants who received a full dose of zimislecel in a single infusion demonstrated engraftment of the islet cells with restored glucose-responsive endogenous insulin production as measured by C-peptide that was associated with elimination of severe hypoglycemic events and improvement in glycemic control to meet and really exceed current ADA target levels of an A1C under 7% and time in range above 70%. This with 10 of the 12 individuals eliminating use of insulin and all meeting the Phase I/II primary endpoint of the elimination of severe hypoglycemic event together with meeting those ADA glycemic control targets. The safety profile that we've seen is consistent with the immunosuppression regimen and infusion procedure that's well established. The now Phase III portion of this study is well underway and anticipated to complete enrollment and dosing later this summer. With that, I'd just like to thank all of the study participants, their families, the investigators, their teams, and steering committee members, colleagues at Vertex Pharmaceuticals, who've all put a tremendous amount of energy into making this study possible. This is the QR code for the New England Journal of Medicine article where this study is now appearing for the first time online, coinciding with the presentation here at ADA. Thank you for your attention. I am going to now turn it over to my friend and colleague, James Markmann. Thank you, Mike. Good evening, everyone. As you heard, my name is James Markmann. I'm a multi-organ transplant surgeon at Penn. Previously, I was the Chief of Transplant at Massachusetts General and Co-Director of the Center for Transplant Sciences at Massachusetts General Hospital. I specialize in pancreas, islet, liver, and kidney transplantation. I completed my MD, PhD, and training and residency at Penn and my transplant surgery fellowship at UCLA. I've had continuous NIH funding for more than 25 years and published more than 400 papers, most related to immune tolerance and pancreas and islet transplantation. My disclosure is listed at the bottom of the slide. I wanted to tell you a bit about my practice and the patients I care for and why we're so excited about the potential to have a therapy like zimislecel. I was fortunate to become involved in islet transplantation just out of college when I joined a lab at Penn and rapidly understood the reasons why everybody on the team was so excited about developing islets as an allotherapy for patients with labile Type 1 diabetes. The Edmonton trial and the studies that followed proved that transplanted islet cells from deceased donors could be effective at reversing diabetes. However, this was clearly an imperfect approach. There was an inadequate supply of pancreata. Processing was very inefficient. Islet quality and number was variable. On average, it required processing four pancreases to get enough islets to achieve insulin independence in the recipient. The key point is that islet quality and supply quantity are major barriers to helping more patients. Zimislecel is anticipated to directly address these shortcomings. To try and address diabetic patients' needs while at Penn, I developed one of the first successful pancreatic islet programs in the country and later went on to do the same at Mass General. I conducted many successful islet transplantations with deceased donor cells and yet recognized, as I just noted, that there are significant shortcomings with that approach, principally the supply, quantity, and quality of the islets. When a Type 1 diabetic patient who qualifies for islet transplant based on issues of severe hypoglycemia and hypoglycemic unawareness and then first decides they'd like to consider an islet cell therapy, we spend a lot of time with the patient talking about the procedure, educating them about post-transplant care, including immunosuppression to protect the cells, and then post-transplant, making sure that they have the support they need. Generally, Dr. Rickels and I do this together when we see a diabetic patient. These discussions also often reveal the depth of the burdens these patients carry with them that are caused by the disease that go beyond the challenges of meeting glycemic targets to avoid the well-known complications that affect eyes, kidneys, nerves, and cardiovascular system. I thought it would be worth mentioning a couple of patients that really stand out to me to illustrate these points. One patient was an individual with a long history of Type 1 diabetes and a history of multiple severe hypoglycemic episodes and one that caused a terrible motorcycle accident, among many other debilitating episodes. When we discussed the specifics of undergoing an islet transplant, including the potential risks and unknowns, their response was quite striking. Paraphrasing the comments, they were adamant that they understood and accepted the potential risks and indicated that if undergoing the procedure could give them even a chance of avoiding severe hypoglycemic events, each one carrying with them the risk of death, it would all be worth it. They were especially interested that if their case was not a success, if we learned by it, they would be very satisfied with the outcome. The other patient was middle-aged and had been managing their diabetes for 30 to 40 years and was interested in learning about islet cell therapy. At one point in the conversation, they said, "Do you mean there's a chance I might not need to continue using my pump and sensor?" After a moment or two, they burst out into tears with the thought that their burden could be alleviated. It was really a very powerful interaction. The burden that our diabetic patients experience is difficult to appreciate until we speak with them in depth about the possibility that they might be able to recover a more normal existence. To recap, the patients come for consideration for islet transplants, struggle with problematic hypoglycemia that can lead to unpredictable and potentially fatal side effects. This is compounded by the overall burden of managing Type 1 diabetes as well as struggling to manage their disease effectively to minimize the devastating longer-term effects of Type 1 diabetes when glucose levels are not well controlled. This slide shows the general approach to the transplant of zimislecel. This is an approach that, Mike, can you turn yours off? This is an approach that had been used for many years with prior islet protocols. The patient generally comes in a couple of days before transplant to initiate immunosuppression. The infusion occurs on day zero. Generally, the patients are discharged on day two and continue on immunosuppression thereafter. Overall, about a five-day hospital length of stay, beginning with induction immunosuppression and then maintenance immunosuppression. Zimislecel is delivered by an intravenous infusion into the liver through the hepatic portal vein where the islets lodge in the liver and function there. The procedure is done by either a transplant surgeon or an interventional radiologist. Overall, the portal vein is considered a minimally invasive procedure compared to other transplant surgeries, such as pancreas or liver. Any transplant cells need to be protected from the immune system. The current practice is to give patients immunosuppressive therapy. The regimen we use is a well-established steroid-free immunosuppressive regimen that has been developed specifically for islet transplantation. The regimen is designed to optimally protect the islet cells from the immune system with an induction Phase at the time of the procedure that includes anti-thymocyte globulin and a maintenance regimen of tacrolimus and sirolimus. I think it's worth talking about some of the considerations of immunosuppressive therapy, as this is an area where sometimes details are misunderstood. While immunosuppressive therapy does carry some risks, these are all very well characterized from decades of experience with multiple transplant types. These are generally manageable for most patients. In fact, there's a large prior experience with a similar immunosuppressive regimen with deceased donor islet genetic islets. This was very well managed and received. We use multiple tactics to ensure the best outcomes for patients, including dose monitoring and dose adjustments, as well as counseling on expected side effects and mitigation strategies, such as hygiene techniques and use of antimicrobials. As I've already mentioned, for many patients taking immunosuppression with a predictable well-known risk profile that can be mitigated is a welcome trade-off that enables them to receive transformative, potentially curative therapy that could greatly reduce their burden of care. I believe many patients will view zimislecel as having a very favorable risk-benefit profile and leading to tangible improvements in their quality of life. In contrast to deceased donor islets, with zimislecel, we know the islets are high quality, expected to work, and there is a sufficient supply and quality of cells for transplant. For our T1D patients with significant challenges in management and achieving clinical goals, we believe this has the potential to be a great addition to our treatment armamentarium that could shift the paradigm for severe Type 1 diabetes patients. I am very optimistic about the potential role in the real world for zimislecel. I will stop there and turn it over to Felicia. Thank you so much. Is the back on? Yep. Thank you so much, Mike and Jim, for your presentations. I'll just leave you with one slide to wrap up what we've discussed today. I think our top conclusion is that zimislecel has clearly shown transformative benefit for people living with Type 1 diabetes. Type 1 diabetes, as you know, is a large patient population with a high unmet need. That is acutely the case for the patients that we're talking about today and the patients that Mike and Jim care for. Those are the individuals with recurrent severe hypoglycemic events. Those are the approximately 60,000 individuals that could potentially be eligible for zimislecel if it's approved. The updated zimislecel data you've seen today demonstrated durable therapy with curative potential for people living with Type 1 diabetes. With potential global regulatory filings in 2026, we're expanding our manufacturing and commercial capabilities to ensure launch readiness so that we can be ready to reach those patients. Serial innovation is underway with additional T1D programs in preclinical stage. We could not be more excited about the potential of cell therapy for people living with Type 1 diabetes. With that, I'll hand it back to Susie. I think we'll open it up for questions. Great. Thanks. Yes, please ask for the I think there's Mohit right there behind you, Manisha, if you want to go ahead. Please state your name, firm, and then ask the question. Thank you very much. Thank you very much. My name is Mohit Bansal. I'm from Wells Fargo. My question is for doctors. Great presentation and great data so far. In your practice, how do you think about the patient population which could benefit from these patients? I mean, how many patients would you say that could be? In the context of CGMs as well lately, what we have seen with the continuous glucose monitoring, the episodes of severe hypoglycemic events have been coming down significantly. How do you think about the opportunity here? Thank you. Thank you. That's a great question. Clearly, what we've seen with real-world data in the management of Type 1 diabetes in the U.S., probably with continuous glucose monitoring, has had the greatest impact on reducing the incidence of severe hypoglycemic events. Within that, there's a more modest effect of whether you take injections or pump or a hybrid closed-loop delivery for insulin. Even with hybrid closed-loop therapy in the U.S., we still have about 15% of individuals reporting the experience of severe hypoglycemic events. Beyond that, 40% of that population is unable to achieve the current American Diabetes Association recommended targets for time in the glucose range, 71-80 being 70%. In addition to the group that is continuing to experience severe hypoglycemic events, we know that even with continuous glucose monitoring, impaired awareness of hypoglycemia is not addressed by those technologies. There remains a physiologic impairment to defend against low glucose, regardless of the improvements in technology. That group, we really feel, has been a tremendous unmet need for novel therapies in Type 1 diabetes. Do you want to comment as well? No. Okay. Great. Next question. Terrence? Thanks so much. Terrence Flynn, Morgan Stanley. I had a two-part question. The first is just on the primary endpoint for Phase three. This is for the company. Have you guys commented what the minimum% response needed for approval is? What's the minimum bar the FDA wants to see? The second part is the FDA announced this new national priority review program. Just wondering if 880 would meet the criteria that they've laid out and if you've had any discussions there with the FDA. The second or third part, I guess, the ability to redose. I know that's a question that we've talked about in the past, but any update in terms of how you're thinking about the ability to redose? Sorry. The question was on redosing. I think we lost it there. Felicia? Yeah. I can start with the first part of the question was around the primary endpoint. The primary endpoint in the Phase one, two, three study was upgraded to insulin independence based on the really powerful efficacy data that we've seen so far. You saw in the Phase one, two study, the primary endpoint was around elimination of severe hypoglycemic events while maintaining or improving their glycemic control. Everybody hit the mark there. What we also saw is profound benefit with the vast majority of patients achieving insulin independence. I think the data that we've seen, the data that we've shared with the FDA, makes us confident that this is the type of data that is going to be supportive of potential approval for the zimislecel. I think the second question was around. Felicia, sorry. I think can we just check the mic there? Is that better or worse? Go ahead. Can you hear me? That's better. Yeah. All right. Did you hear the first response, or do I need to start over? Hopefully, everyone got the primary endpoint component of this. The second question was around new news coming out of the FDA on priority reviews. Obviously, when we think about transformative therapies that could really have a tremendous impact on patients here in the U.S., this is absolutely one of those therapies. I can say that we've certainly been very encouraged by the conversations that we've had over the past months with FDA, including our end of Phase two meeting, and really look forward to continuing to collaborate to bring therapies with this kind of benefit-risk profile as quickly as we possibly can to people across this country. I think the last question was on redosing. As Mike and Jim alluded to, with a therapy like zimislecel, you do have the potential for redosing if needed because this is an off-the-shelf therapy that we can supply on demand. Certainly, that is something that has precedent in the donor islet field. Certainly a possibility as needed. Felicia, maybe just in case, do you want to repeat the answer about the primary endpoint from Phase two to Phase three? Sure. Sorry about the microphone difficulties. The first question was around the primary endpoint. As you saw in the slides, the primary endpoint for the Phase one, two portion of the study was elimination of severe hypoglycemic events with maintenance or improvement in glycemic control. We upgraded that primary endpoint to insulin independence as we converted the study to a Phase three after collaboration with regulators across the globe. We are very excited that the data is strongly supportive of our ability to deliver that kind of benefit to the majority of patients in the study. Do you have a question, Dina? Hi. This is Dina Ahn for Mikey from Jefferies. Just quick two questions about, I guess, just moving on or digging more into the point about the FDA. What have the conversations been like given the new administration? Specifically, talked with CBER about what they want to see and more so actual regulatory sign-off on the Phase three. Okay. I think it's again now working. I guess just a question about the next-gen programs. I know you guys mentioned that you're working on a couple more in preclinical. I know that you've had a recent update about the device program. Just kind of wondering what is the innovation that's going on there. I guess capacity-wise, how many patients would you be able to treat within the first year if this was to get approved? Thank you. Felicia. Yeah. Back on the FDA question. As I said, I think the conversations that we've had with the FDA have been very collaborative, very encouraging. I think all of the leaders that we see at FDA really care about bringing truly transformative medicines to patients. I think when you look at the kind of data and the kind of impact of getting to insulin independence for patients with Type 1 diabetes, of getting to insulin independence with vastly improved glycemic control, of getting to insulin independence with no more severe hypoglycemic events, I think when we look at that, that's a perfect case study for the kind of medicines that we want to invent, that we want to develop, that we want to get approved here in the U.S. We are really encouraged by that. As I said, looking forward to working collaboratively with the FDA here and with regulators globally to bring this to patients. The second question you had was the next generation. As you can imagine, zimislecel is a major breakthrough for these patients. It's a major breakthrough we see for Type 1 diabetes. It is also the pioneer medicine and the foundation for serial innovation in Type 1 diabetes. You can imagine that we have a very deep and broad portfolio of research happening at Vertex on using these cells in different ways to get to more and more patients. We have work ongoing on novel immunotherapies. We have work ongoing on various kinds of gene editing that we think has the potential to render these cells hypoimmune. We have work ongoing on next-generation technologies, including understanding the potential for devices and what we can learn from the early clinical study that we recently completed. I think in summary, we're very optimistic that this is a very important starting point that we will build on over years to come for people living with Type 1 diabetes. I think your last question was around capacity. I am very excited about the investment that we have made in manufacturing at Vertex. We have an incredibly talented manufacturing team that lives side by side with our research teams in Boston and are actively preparing for the commercial launch of zimislecel. You've also heard that we've invested externally in partnerships that are going to be enabling to meet the demand that we expect for this product, including a partnership with Lonza, where we're building out manufacturing capacity in New Hampshire, partnership with TreeFrog, where we're really inventing new technologies to scale this production. Very encouraging work ongoing on the manufacturing side for zimislecel. Thanks. Go ahead. Hi. Good evening. This is Jarway Ahn for Geoff Meacham from CITI. Maybe a question first for the docs. What would you describe would be the ideal candidate for this type of treatment? Given the immunosuppressive regimen, is there perhaps an age group that would be ideal to undergo this type of procedure? The second part would be more of a commercial angle. What do you think is the patient awareness of 880 with this type of stem cell transplant procedure? What type of patient uptake could you envision at launch? Could there be a bolus of initial patients, or could there be limiting factors based on chair availability? Thanks. Thanks. I'll be happy to start with the first one. The patient population, considering the need currently for immunosuppression, is adults with Type 1 diabetes. Those who've developed impaired awareness of hypoglycemia typically have had at least 5-10 years of diabetes, with Type 1 diabetes having a peak incidence in childhood. With adulthood being quite a long period of time, there are a very large number of adults who have had what we consider to be established or longstanding Type 1 diabetes, where they have, as you've seen from the cohort demonstrated here, no residual capacity for insulin secretion on their own. That renders these individuals also unable to defend against hypoglycemia physiologically because of the absence of a glucagon counter-regulatory response from their native islets. With that, the exposure to hypoglycemia increases with the disease duration. That is what drives the then adaptation to no longer recognize and be able to either respond physiologically or through symptom generation to the fact that their glucose is getting low. This impaired awareness of hypoglycemia, even with modern technologies, is present in about 30% of adults with Type 1 diabetes. There is a very large portion of the population who is at about currently still six-fold increased risk for severe hypoglycemia when you have impaired awareness of hypoglycemia. While current immunosuppression does also mean being cautious about kidney function, current protocols in immunotherapy for other forms of solid organ transplantation are becoming much safer in terms of reducing possible risk for kidney function. We are really hopeful that we will be able to extend the disease eligible population in the not-too-distant future. Dr. Merker, you want to talk about patient awareness? I think that's better. Yeah. Just to follow on Mike's comment, there may be other indications or populations that would benefit from zimislecel. We think of the patients who have had a kidney transplant that are already immunosuppressed. There, we do not need to have the condition of severe hypoglycemic unawareness and ongoing hypoglycemia. They are already obligated to immunosuppression. It is sort of a no-brainer. Perhaps other patients, such as patients who have had a total pancreatectomy, that have really debilitating labile disease because they do not have counter-regulatory hormones to go and keep their sugars up. There may be other populations besides the traditional one we have thought about so far that would be excellent candidates as well. Hi there. Lisa Bako from Evercore ISI. Just a couple of questions for me. First of all, I know maybe a little early, but if you could give us any pricing benchmarks or way to think about that. I was curious about this new class of liver selective glucokinase activators and how those may or may not kind of also treat severe hypoglycemia, if that's what you're trying to solve for here, and what the role would be for zimislecel in the context of those therapies as well. Thanks. Felicia, do you want to start on benchmarks? Yeah. I think. I think. Can you hear me? Yeah. I think it's too early really to comment on pricing. As you can tell, we are nearing the end of enrolling the study but haven't yet completed the study. Too early to say on that. Perhaps I'll hand it over to Mike or Jim on the second question around the GKAs. Yeah. The liver selective glucokinase activator, the VTV, has one that's in Phase three clinical trials. We're all hopeful for some continuation of the effect that's been shown in their Phase two program for reducing exposure to hypoglycemia. I think it's addressing one part of the problem in Type 1 diabetes. The bigger problem that we're really hoping to move towards in the future is really normalizing glucose control and regulation. I believe that what the future will bear out is having a cell therapy that not only can address the low end of the range, but also, more importantly, the high end of the range, and really help people maintain normal glucose levels that we know are important for preventing the long-term diabetes-related complications that affect the eyes, kidneys, nerves, cardiovascular system, in addition to helping them to mitigate the day-to-day challenges of avoidance of hypoglycemia. No. We're going to try this one. How about now. There we go. Hi. Malcolm Hoffman here for Evan from BMO Capital Markets. Question for Dr. Rickels. It was noted in the Q&A of the oral presentation prior to this event that some were concerned about the possibility of spontaneous hypoglycemia early and longer after transplantation. You had provided some context as to where this could happen in some other therapies. Could you explain again why you may or may not be concerned about this for VX-880? Thanks. I guess I'm not concerned about this for VX-880 because it hasn't been our experience to date with the forward study. As I try to explain, the early is in the context of deceased donor islet transplantation. Some of those isolation preps, the quality is not always great. You may be infusing a lot of dead cells with released insulin in the media. That could lead to some experience of hypoglycemia shortly after the infusion. That's not something that we're seeing in this program. The long-term hypoglycemia is not present in deceased donor islet transplantation, but in autologous islet transplantation, which is for individuals who require a total pancreatectomy for benign disease. That's typically in the United States for current acute or chronic pancreatitis. As Dr. Markmann explained, when you remove the entire pancreas, you're not only dependent on insulin, but also you've removed any glucagon counter-regulatory cells as well. These individuals can have very challenging times with glucose control. To mitigate that, the islets can be isolated from the diseased pancreas and infused into the portal vein for intrahepatic engraftment, as we do for allogeneic islets. Some of those individuals do have spontaneous hypoglycemia long-term. That is even in individuals who are not requiring insulin. In that situation, it's a very apples-to-oranges kind of comparison because those islets are in an individual who now has a, when you remove the pancreas, you remove the duodenum, a part of the stomach, and reconstruct the biliary and gastrointestinal system. It's basically like Roux-en-Y gastric bypass without restricting the size of the stomach. We know that those individuals have elementary hypoglycemia that occurs spontaneously. There are other reasons for those people. It is not something that we are concerned about with this population. Thank you. This is Adam on for Jess, JP Morgan. Following up on Mohit's and Jess' question earlier, what portion of Type 1 patients you take care of would you expect to pursue 880 in early launch Phase and maybe looking out longer, say, five years post-launch? Maybe as a follow-up, if Vertex can develop a next-generation version that avoids the need for immunosuppression or significantly reduces it, what proportion of patients would you expect to pursue it then? Is that for me again? Sure. I mean, that's a really hard question to answer. We have a substantial number of patients who, and also, I would say my practice is a bit biased because patients seek me out because they want a cell therapy solution for their diabetes. I think there's a very large portion that want islet cell therapy and would line up for this. Currently, in Phase one, two, and now Phase three, our clinical trial parameters limit the eligible population. It's a little hard for me to go give you exact percentage numbers. There's a substantial portion of adults with diabetes who would really do anything for the chance to be alleviated from the burden of daily self-management and hour-to-hour concerns about where their glucose is, what they're doing with their insulin, their activity, what they're eating, how they're going to sleep, what if they're traveling, what do they do with these time zones, how do I, my partner's traveling. They usually are the one that catch me when I'm getting low. There's a substantial proportion of, and again, my practice is biased, but I would say of the adult population with Type 1 diabetes who would be very interested in an available cell therapy. Dr. Markmann, anything? No? Okay. Next question. Go ahead, Brian. Yeah. Thanks. Brian Dollinger on behalf of Dave Reisinger, Leering Partners. My question was related to the portal vein is often considered a pretty suboptimal transplantation site. One of the questions that I had was, is Vertex making any effort for extrahepatic engraftment? If so, when might we see this develop? Thank you. Sorry, Mike. Can you hear me? She's coming up. Go ahead now. Is that better? Here we go. There have been lots of sites tried that are extrahepatic in experimental models. They do work. You do have hyperinsulinism and probably not as quite a perfect regulation. As you noted, the liver site is not perfect. There is an inflammatory response where we lose a lot of the islets. I think there is a lot of opportunity to explore other sites potentially. I'm not commenting on whether Vertex is interested in doing that right now. As you know, there has been work from the Chinese putting it in the sub-rectus below the rectus sheath and some other examples of extrahepatic cells that are functional. We do not have any idea about the potency or the comparison between. I think it is early to really comment on that, except to say that at least in theory, there is quite a number of extra portal sites that could carry islets. They would each have different safety profiles in terms of what's required to get the cells there. I will just add, as I said, we have a very deep and broad research effort ongoing on all things Type 1 diabetes cell therapy. I have to say, the data really speak for themselves. The portal vein works. The efficacy is profound for patients who have received zimislecel via portal vein infusion. As you heard from Jim, it is a relatively simple, minimally invasive procedure that we see the potential for many physicians, whether it is interventional radiology or surgeons, to perform across the country. We really see great potential for zimislecel delivered through the portal vein for these patients. One final question, or we can wrap it there. Great. Thank you very much, everyone. Felicia, Mike, Jim. Thank you very much. We really appreciate it. And thanks to all of you for coming.