Good evening. Welcome to the Vertex first quarter 2021 financial results conference call. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex. Making prepared remarks on the call tonight, we have Dr. Reshma Kewalramani, Vertex's CEO and President, Stuart Arbuckle, Chief Commercial and Operations Officer, and Charles Wagner, Chief Financial Officer. We recommend that you access the webcast live on our website as you listen to this call. This conference call is being recorded, and a replay will be available on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including without limitation, those regarding Vertex's marketed CF medicines, our pipeline, expectations regarding the closing of the CRISPR transaction which is subject to antitrust clearance, and Vertex's future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that we will review select non-GAAP financial results and guidance this evening. I will now turn the call over to Dr. Reshma Kewalramani. Thank you, Michael. Our goal is to continue to transform cystic fibrosis and other serious diseases, and in so doing, reach more patients and drive future growth. One quarter into 2021, I'm very pleased with the progress we're making across the board in support of this goal. We are treating more patients with our CFTR modulators than ever before, and our clinical pipeline, spanning seven disease areas and three modalities, has advanced significantly. In addition, we continue to execute on our strategy to use external innovation to complement our internal innovation efforts, including two new deals announced already this year. I'll start with CF. Vertex has built an exceptionally strong and durable franchise and earned a leadership position in cystic fibrosis. Our CF medicines have transformed the treatment of this disease, and we continue to significantly increase the number of patients we're treating. Our first quarter revenues totaled more than $1.7 billion, which represents a 14% year-over-year growth and reflects the high level of treatment penetration of TRIKAFTA in the U.S. and strong Kaftrio launch in international markets. We're poised for continued significant growth in the coming years as we achieve additional approvals and reimbursement agreements for our medicines globally, and as we bring our medicines to younger patients. The clinical benefit that the triple combination delivers is remarkable, and with this medicine, we believe we can treat 90% of all people with CF. We are not stopping there. We're investing to bring new and potentially better regimens such as the VX-121-561 tezacaftor combination to patients. This new combination is a once-a-day regimen with potential for enhanced patient benefit as well as enhanced economics with a reduced royalty obligation. Finally, we remain committed to, and are making progress in, developing genetic therapies for the remaining 10% of CF patients. In summary, consistent with our strategy to bring transformative medicines to all patients with CF, the combination of label expansion, additional approvals and reimbursement agreements, and the next generation of products will continue to provide significant top and bottom-line growth in the coming years. Let me turn to our clinical pipeline, which includes programs in seven disease areas and spans small molecules, cell, and genetic therapies. We have made substantial progress across the breadth of the pipeline and are poised for multiple data readouts in the next six to 12 months. First, CTX001. CTX001 is our most advanced program beyond CF. In the last year, we've generated remarkable clinical data that demonstrates the potential of this therapy to be a one-time functional cure for patients suffering from sickle cell disease and beta thalassemia. CTX001 has been granted RMAT, Fast Track, and Rare Pediatric Disease designations from the FDA for both sickle cell disease and beta thalassemia, as well as PRIME designation from the EMA for both diseases. With the compelling clinical profile and rapid progress of CTX001 towards registration and commercialization, now is the ideal time for Vertex to take the lead for this program and bring the full breadth of our development, regulatory, manufacturing, and commercialization expertise so that we can reach all eligible patients who may benefit from CTX001 as quickly as possible. As Stuart will discuss in a moment, there are nearly 170,000 patients with sickle cell disease and beta thalassemia in the U.S. and Europe, of whom 32,000 patients have severe disease, and we believe will be eligible for CTX001 therapy with the current conditioning regimen. This number could extend significantly once gentler conditioning regimens are available. To date, more than 30 patients have been dosed with CTX001, and we anticipate sharing updated data from the ongoing sickle cell and transfusion-dependent thalassemia studies with more patients and longer duration of follow-up at upcoming medical meetings this year. We also expect to complete enrollment in both of these studies this year. Lastly, we have not yet completed our discussions with regulators regarding filing expectations. Based on conversations to date, we believe regulatory submissions for approval of CTX001 may be possible in the next 18-24 months. We'll provide further details as we conclude our discussions. Moving on to the AATD program. Our approach targets the underlying cause of this disease by using a small molecule corrector to appropriately fold the misfolded Z-AAT protein. We believe this is the optimal approach for treating AATD, and it is the only approach that addresses both the lung and liver manifestations of the disease. VX-864 is our most advanced molecule in the program. We have completed enrollment, and recently, we also completed dosing in the phase II proof of concept study of VX-864. Patients are now in the process of completing the 28-day safety follow-up period. We are on track for a data readout later this quarter. Turning to APOL1-mediated kidney disease. APOL1-mediated kidney disease is a particularly aggressive form of renal disease, characterized by proteinuria, declining renal function, and progression to ESRD. Our lead molecule in this program, VX-147, is being studied in a phase II proof of concept study in APOL1-mediated FSGS, evaluating safety, pharmacokinetics, and reduction of proteinuria in patients over the course of 13 weeks. We expect to have the results from this study in the second half of 2021. Turning to our pain program. Earlier this week, we announced that we plan to advance VX-548, the next lead molecule in our pain program, into phase II development. With VX-150, we were the first to validate the NaV1.8 target with three positive phase II proof of concept trials in three different pain indications. The recent decision to move VX-548 to phase II was based on supportive phase I data in healthy volunteers, including safety, tolerability, and pharmacokinetics. In these studies, the molecule exhibited a favorable profile at doses considerably lower than those required with our previous NaV1.8 inhibitors. The phase II studies will evaluate the safety and efficacy of VX-548 in the treatment of acute pain following bunionectomy and also in abdominoplasty. These are well-characterized settings for the evaluation of two broad categories of acute pain, visceral and non-visceral. We expect the studies to start in the second half of this year. Finally, in our type 1 diabetes program, we received FDA Fast Track designation for the cells-alone study. We initiated the phase I, II study in patients with difficult-to-treat type 1 diabetes in Q1. Screening is now open. We look forward to providing updates on our progress this year. With those comments, I'll hand it off to Stuart. Thank you, Reshma. Today, I am pleased to review with you our Q1 commercial performance and our excitement about the prospects for CTX001. One year into the pandemic, our CF revenues continue to grow. Our Q1 global revenues were $1.7 billion, driven by continued strong execution in both the U.S. and the EU. Our performance in the U.S. continues to be impressive. To date, nearly all eligible CF patients in the U.S. have initiated treatment with TRIKAFTA based on the original approval in patients 12 years and older with at least one F508del mutation, and persistence and compliance remain high among these patients. In December 2020, TRIKAFTA's approval was expanded in the U.S. to include patients 12 years and older with rare mutations. Many of these patients have now initiated treatment as well, and we are pleased by the uptake we have seen in this newly eligible group. Outside of the U.S., in markets where patients have access, the adoption of Kaftrio is just as impressive as in the U.S. We have seen rapid uptake, particularly in the U.K. and Germany, and persistence and compliance are similarly strong, reflecting the very favorable risk-benefit profile of Kaftrio. Our ex-U.S. revenues in Q1 were $470 million, 43% higher than the same period last year, primarily due to the successful launch of Kaftrio. Earlier this year, we shared our updated estimate that there are approximately 83,000 people living with CF in the U.S., Europe, Canada, and Australia. Today, we are treating about half of all patients, leaving an additional 30,000 patients who could benefit from our medicines but who are not yet treated. Going forward, we are very confident that we will be able to reach these patients. Approximately two-thirds of the untreated patients are 12 and older, and we expect we will be able to treat these patients through the ongoing launch, uptake, and reimbursement of Kaftrio outside the U.S. In countries where we have regulatory approval and reimbursement, our teams are working hard to reach all eligible patients who could benefit from Kaftrio. In countries such as France, Spain, and Australia, where we have regulatory approval but have not yet secured reimbursement, our teams continue to make progress to ensure access, and we are confident that we will be able to secure reimbursement in the remaining large markets. For example, TRIKAFTA was recently approved in Australia, and we are committed to continuing to work collaboratively with the Pharmaceutical Benefits Advisory Committee there to ensure all 2,200 patients who can benefit from treatment have government-funded access to TRIKAFTA as quickly as possible. Lastly, in Canada, we are still awaiting regulatory approval, and we expect approval there in the second half of this year. The majority of the remaining approximately 10,000 patients are younger than 12. Our work to secure approvals for these younger patient populations is ongoing, and we are making good progress here. We anticipate approval of TRIKAFTA in 6- 11 year-olds in the U.S. in mid-2021, and have filed the regulatory submission for this population in Europe as well. In summary, our continued progress in achieving label expansion, new approvals and reimbursements, and development of new products will drive continued growth in the years to come. In all of this, we are grateful for the tireless work and continued support of the global CF community. Let's now turn to CTX001, which is our next medicine that is rapidly advancing toward regulatory submissions and commercialization. Given the tremendous progress of CTX001 that we and our partners at CRISPR have made, as well as Vertex's established expertise in development, manufacturing, regulatory, and commercialization in serious diseases, both companies believe that having Vertex lead all aspects of the CTX001 program going forward would provide for the most efficient and expeditious path to bring this medicine to patients. By doing this, we aim to ensure a coordinated global launch, which will maximize the potential of this program for both patients and our shareholders. CTX001 is a groundbreaking therapy that has demonstrated great momentum, with the potential to be the first approved genetic therapy for patients with sickle cell disease. Sickle cell disease and beta thalassemia represent a multibillion-dollar commercial opportunity. Today, there are approximately 32,000 patients in the U.S. and Europe who would likely be eligible for gene-editing therapy based on the severity of their disease and the current busulfan-based conditioning regimen. Vertex, CRISPR, and a number of other companies are actively pursuing gentler conditioning regimens. Such regimens would potentially expand the eligible patient population to approximately 170,000 total patients in the U.S. and Europe. The commercial opportunity in sickle cell disease and beta thalassemia fits well within Vertex's strategic focus on specialty markets. Patients are primarily cared for by hematologists, and the treatment will be focused at transplant centers in the U.S. and Europe, which can be covered by a specialist infrastructure. By taking the leadership role on CTX001, we will be able to leverage our proven expertise in product launches, reimbursement, and access to bring the curative potential of this treatment to more patients more quickly around the world. Given we believe that regulatory submissions could happen in the next 18-24 months, our pre-commercial work is underway. CTX001 is breaking new grounds in many respects, I'm very much looking forward to providing more details on this exciting work on future calls. Now I'll hand it over to Charles. Thanks, Stuart. In the first quarter of 2021, Vertex continued its record of exceptional financial performance. First quarter total product revenues were $1.7 billion, a 14% increase compared to the first quarter of 2020. These results included $1.25 billion of revenue in the U.S., and $470 million from outside the U.S. The ex-U.S. results represent growth of 43% over the prior year, driven largely by the rapid uptake of Kaftrio in countries where we have secured reimbursement, particularly England and Germany. Our first quarter non-GAAP combined R&D and SG&A expenses were $530 million, compared to $477 million for the first quarter of 2020. Expenses in Q1 were primarily driven by investment in innovation, and we expect our R&D investments will continue to be substantial as we drive toward proof of concept data and further clinical and regulatory progress across our broad pipeline. Our continued growth in revenues, combined with carefully managed growth in spending, translates to a first quarter non-GAAP operating margin of 58%. With our strong revenue and profitability, we ended the first quarter with $6.9 billion in cash. Consistent with our corporate and R&D strategy, we're investing more in innovation than ever before, including external innovation. This was most recently exemplified by both our amended collaboration agreement with CRISPR and our new discovery collaboration with Obsidian Therapeutics. On to guidance. We are maintaining our previously issued 2021 guidance for total product revenues in the range of $6.7 billion-$6.9 billion. Our Q1 revenues were very strong, but they also include an approximately $50 million benefit from channel inventory fluctuations that are not directly reflective of underlying patient demand. As a reminder, our 2021 guidance reflects our expectations for currently approved products in regions where we are reimbursed, plus an expectation of TRIKAFTA approval for the 6-1 1 year-old population in the U.S. in mid-2021. It does not include any additional reimbursements that we might obtain this year. For non-GAAP OpEx, we are reiterating our guidance range of $2.25 billion-$2.3 billion. We expect to continue allocating greater than 70% of OpEx to R&D as we further advance our pipeline programs. We are poised to generate important clinical data from a number of programs over the course of the year, these datasets will drive decisions on further investment. For our non-GAAP tax rate, we are guiding to a range of 21%-22% this year. In summary, I'm very pleased with our performance in the first quarter of 2021 and look forward to updating you on our continued progress over the course of this year. Now back to Reshma for closing remarks. Thanks, Charlie. In sum, we've made significant progress across the business. We have confidence in and continue to execute on our innovation-based growth strategy. Our strategy is working, and our investments, both internal and external, are driving discovery and development of game-changing new medicines. Vertex is delivering exceptional financial performance. Our CF business is poised to continue to grow, and our broad pipeline continues to advance. Thanks, and we'll now open the call to questions. Thank you. As a reminder, to ask a question, you'll need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Michael Yee from Jefferies. Your line is now open. Michael, your line is now open. If your phone's on mute, could you please unmute it? Operator, we can move to the next question in queue. Thank you. Our next question comes from Phil Nadeau from Cowen and Company. Your line is now open. Good afternoon. Thanks for taking my question. I think the most common question we've been getting from investors recently is on the AAT program, and it's what would serve as proof of concept in the upcoming data that you're seeing. Can you maybe give us your most recent thoughts on what levels are necessary, what proportion of patients need to be responders and whatnot? A second part related to that question. In the past, you've been guiding to moving another AAT molecule into the clinic this year. Didn't seem like from your prepared remarks that's still the case. Can you confirm whether there has actually been a change there and maybe give us a reason why if the guidance has changed? Thanks. Yeah. Hey, Phil. This is Reshma. Let me take that for you. I think that the questions really are, where are we with the A64 program, what are we expecting, what would be success, and a little bit about the portfolio approach and other molecules. Let me take that in pieces. You know this, but to review for others on the call, we are taking small molecule correctors to refold the misfolded Z-AAT protein. That's our approach to this disease. The reason it's important to understand that is that fundamentally, this is the only approach that holds the potential to treat both liver and lungs, hence our enthusiasm for this approach. VX-864 is in the clinic. You heard me in the prepared remarks talk about the fact that we've hit some really important milestones. We are done with enrollment. Our patients have completed the dosing period, and they are now in the 28-day safety follow-up period. Here's what I'm looking for from the study and what I would consider success. Really three things. The first, safety. This is the first time we've had VX-864 in patients with AATD, so that's obviously front and center. Second, a dose exposure or a dose response relationship, and third, elevations in functional AAT levels. That's really what I'm looking for and what I would be very excited to see. In terms of the portfolio and molecules beyond VX-864, as with all of the programs in the pipeline, Phil, we have a whole portfolio of molecules, and that continues to be true for AATD as well. That's very helpful. Thank you. Thank you. Our next question comes from Geoff Meacham from Bank of America. Your line is now open. Hey, everyone. Thanks for the question. I just have two quick ones. On the updated economics with CRISPR on CTX001, was the decision based on ongoing data, or was there some regulatory feedback or maybe commercial analysis? I know it's always better to lead a program when you can, wasn't sure what the ultimate catalyst was for the deal. Just to follow up on AAT, just assuming that there is a clean safety profile, Reshma, do you view the corrector approach as kind of the only approach for Vertex? Is there a thought that you're committed to AAT and may have other mechanisms of action even more beyond what you have in the pipeline today? Thanks. Yeah, sure. Let me start with the question around the amended agreement with CRISPR. Geoff, it's a number of catalysts that happened over the course of the last, let's say, six to eight months that led us to amending the agreement. If you go back to last year, between last year and now, we have delivered proof of concept results from both sickle cell and beta thalassemia. Not only that, but we have data that we've shown from 10 patients, and the data are really nothing short of remarkable. We're also at a point now where we've dosed more than 30 people in this program, and we are looking to complete enrollment in both beta thal and sickle cell disease this year. The program has a lot of momentum behind it, and it is progressing overall even faster than we expected. You put that all together, this is really just the perfect time for Vertex to take the leadership role and bring the full weight of our experience and infrastructure and expertise to get to as many patients as possible, as quickly as possible. With regard to your question on AATD, the answer to your question around how committed are we, how do we think about this disease, this disease fits our strategy like a glove, and we are exceptionally committed to AATD. With regard to the approach, there is no better approach to AATD than small molecule correction of the misfolded protein. The Z-AAT protein that is misfolded in the disease, that is the underlying cause of the disease. With the small molecule approach, you have the opportunity to target that underlying cause of disease, and in so doing, treat both the liver and lung manifestations. We are absolutely committed to AATD and to the small molecule correctors. Got you. Okay. Thank you. Thank you. Our next question comes from Michael Yee from Jefferies. Your line is now open. Can you hear me now? Yeah, Mike. Thanks. Okay, great. I actually have a question about diabetes. I know Reshma has to talk about this, but actually there's data later this year. Can you maybe just comment about what proof of concept is? Would it be surprising to see changes in HbA1c, et cetera? Maybe just talk about the value of what we'd see there realizing it's the naked cells. Thank you so much. Yeah. Hey, Michael, I think you're asking about the type 1 diabetes program, and just to understand a little bit about the background and maybe a little bit about where we are, and I certainly heard your question about when we can expect to see some data. Okay, the type 1 diabetes program is a cell-based program that comes really in two flavors. One, let's call the naked cell approach. That's the one that had the IND cleared earlier in the year. That's the one that's in patients. The study in patients is ongoing right now, the phase I, II study. That program is in the phase I, II stage. The second one is the cells plus device program. Let me just step back and explain two more things here. There is very little biological risk in terms of the approach that we're taking to type 1 diabetes. Because we understand very clearly what the cause of disease is. It's autoimmune destruction of pancreatic islet cells. Maybe more importantly, we have known for many years that islet cell transplants lead to great outcomes in patients with type 1 diabetes. That is already known. Islet cell transplants have been done for years. The issue has been the quality and quantity of cells, and that's exactly the solution that Semma and now Vertex are bringing forward. With the naked cell program, this would be about, let's say, 60,000 patients. These are patients with severe diabetes that I think could benefit from this program, which would include chronic immunosuppression. If we go to the cell and device program, there are over 1 million people just in the U.S. and an equivalent number in the E.U. with type 1 diabetes that could benefit from the cell and device program. That, of course, would not require any immunosuppression. With regard to timing, the naked program is cleared as IND. It's in the phase I-II now. You recall that we're starting at a lower dose, then just like with CTX001, we would then get to the target dose. I would say that just like the CTX001 program, you should think of it as an efficient program, a reasonable number of patients will give us a good sense of the profile. I would say that you should have a mindset towards 2022 for a data readout from that program. Thank you. Thank you. Our next question comes from Cory Kasimov from JP Morgan. Your line is now open. Good afternoon, guys. Thanks for taking my question. On the strategic front, on the heels of the expanded deal with CRISPR as well as the smaller Obsidian collaboration, just curious if we should be thinking about business development or M&A any differently going forward. There's some recent expectation of larger deals to come. Is that still the plan, or are we kind of looking at the smaller, earlier stage ones where you can add more of your expertise? Thank you. Yeah. Hey, this is Reshma again. Let me take that one for you. Our business development or external innovation strategy is exactly the same as it has been over the last several years. What I mean by that is we're looking for assets in CF that complement our internal pipeline. We're looking for tools to expand our toolkit, and we're looking for assets that fit our disease areas of interest. When I say that, I mean assets that we, Vertex, could add value, research, development, regulatory, et cetera. I've been really pleased with the deals that we've done. You could look at Semma Therapeutics or Exonics Therapeutics as examples, but you could also just look back in the last couple of weeks with the amended agreement with CRISPR Therapeutics and the collaboration agreement with Obsidian Therapeutics. That's what you should think about when you think about our external innovation approach, and you should expect to see more of the same. Okay, helpful. Thank you. Thank you. Our next question comes from Salveen Richter from Goldman Sachs. Your line is now open. Thanks. On the 11 micromolar threshold for AAT serum levels, how are you thinking about that in context of dose response and what you're trying to ascertain with the upcoming phase II data? Just a second question, if you could just remind us where you stand on the in vivo CRISPR-Cas9 work on Duchenne and DM1. Sure, Salveen. This is Reshma. I could answer those questions for you. Let me tackle DMD and DM1 first, then I'll come back to AATD. We're making good progress on the DMD and DM1 programs that are both in late preclinical development. Obviously, you've seen what's been going on in the field with regard to real setbacks that others have experienced. What we're doing is being very deliberate and very careful about process development, analytical development, dosing, and we are making progress in those regards. I'm eager to share with you when those programs will come into the clinic, that's for another day. With regard to the AATD question, there's no magic number here. What we're looking for from this proof of concept study is the totality of the evidence. As I mentioned, that is safety, that's dose responsiveness, dose exposure. What I mean specifically by that is that there is an association with higher dose to greater exposure or greater response, and certainly elevations in functional AAT levels. I'm eager to talk to you about the data and the next steps. We're very close now. I fully expect that the data readout will be later this quarter. Thank you. Thank you. Our next question comes from Mohit Bansal from Citigroup. Your line is now open. Great. Thanks for taking my question and congrats on all the progress. A question, again, another question on AAT. Our checks suggest that AAT levels do fluctuate naturally in human body, depending on if you are in acute phase or not. To that end, let's just say if you see some elevation in functional AAT levels from VX-864, is there any reason to believe it could be just due to a chance alone specific to these patients rather than being an effect of the drug? Yeah. Mohit, this is Reshma. I really do understand your question. Mohit, what we're talking about when I say I want to see elevations in functional AAT level is real elevations. When I say we're looking for dose responsiveness, that's part of what we're looking for, right. We are looking to see that exposure increases with dose and that responsiveness, the actual functional AAT levels, vary with dose. Those are all elements of what we're looking for. When I say functional AAT levels go up, that's what we're looking for. I mean real elevations in functional AAT levels. Got it. Helpful. Thank you. Thank you. Our next question comes from Liisa Bayko from Evercore ISI. Your line is now open. Hi. Thanks for taking my question. I wanted to ask a little bit about the pain program. You started to talk about it a little bit more, VX-548. Can you maybe talk about how it's different from VX-150, which actually made it quite far into the clinic? In terms of your intentions clinically, I know you're studying some acute indications. Are you going to be eventually studying chronic as well, or is this more suited for chronic? Those are my questions. Thanks. Yeah. Sure, Liisa. Let me break this up into two parts, and I am going to take the first, and I am going to ask Stuart to comment on the second. I am going to tackle the things that you need to know from an R&D perspective, and I am going to ask Stuart to comment on the commercial prospects here. Three things, Liisa, to know from the R&D perspective. First, the target. The target here is NaV1.8, and that is important to know because NaV1.8 is a genetically validated target, but it is also a pharmacologically validated target in exactly right, it was VX-150 that had positive phase II proof of concept readouts across three different pain indications, acute, neuropathic, and let us call it musculoskeletal pain. The second thing to know is our approach with VX-548. VX-548, as it's emerged from its phase I trial, it really has all of the properties that we're looking for, not only in terms of safety and tolerability, but also PK and exposure, and at doses that are considerably lower than what we saw with our previous NaV1.8 inhibitors, including 150. That obviously has significant benefits in a multitude of ways, but including in formulation and manufacturability. The last thing I'll say on the R&D side is we're starting with acute pain. Bunionectomy will be first and then abdominoplasty. We're doing that because the pathway to registration is a visceral and non-visceral indication. Acute pain, as the name implies, it's a very short duration of treatment. It's a couple of days. We've done bunionectomy studies before. We know how to do it. That's kind of how I'm viewing that. I'm going to turn it over to Stuart to tell you a little bit more about the market size and the opportunity there. Yeah. Hey, Liisa. In the acute and neuropathic segments of the pain market, they're both currently multi-billion dollar segments of the market, both largely dominated by generics currently, and both in need of significant innovation. We're looking to bring forward an agent which is both superior in terms of efficacy and tolerability. As a result of that, we believe it'll be used in a great deal of patients in both of those segments. Because we're targeting that superior profile, we think we'll be able to compete in a really strong way with generic opioids and also generic pregabalins in the neuropathic segment of the market. Both of those as well are markets which are served by a relatively concentrated group of prescribers. We feel that those segments in particular play into our overall corporate strategy of focusing on specialty markets. Okay. Thank you. Thank you. Our next question comes from Gena Wang from Barclays. Your line is now open. Thank you. I will also ask one question on AAT. Reshma, you mentioned that those responses are also one very important criteria. Can you share with us, how did you choose doses in the phase II study? Do you also anticipate further dose escalation if phase II data showing still have some room or either not reaching optimal or the safety looks good, will you planning to dose further up? Sure. Gena, the way we choose our doses for AATD are really the same as we do for all of our programs. You know our programs in CF very well. Maybe that's a good example to talk through. What we're really looking at is our in vitro data and translating what we see in our models into the clinic and into patients. Obviously, we have a track record of doing that quite well in CF. That is exactly the same methodology that we use here in AATD. If I just elevate a little bit, Gena, what I think your question behind your question might be is, gosh, how confident are you that you're going to be able to bring forward a medicine for this disease? How confident are you in this mechanism? In general, how do we view this? Let me be very clear about that. We are committed to this disease. This disease fits our strategy like a glove. We've been working on this mechanism for many years, and we feel high confidence that we have the right approach. I'm looking forward to sharing with you the data. As I said, that's going to be coming out very soon, in this quarter. Thank you. Thank you. Our next question comes from Robyn Karnauskas from Truist. Your line is now open. Hi. Very good. Well done. Two really quick questions. Let's start with the triple. The triple combo VX-121. I know you haven't talked a lot about it, but what sort of control arm would you need? What is the angle with advancing that program? What kind of expectations would you have for that program on pain? I think my direct question would be, you've always said if you get a good phase II, you'd want to partner first to go into phase III. Is that still the case? Do you think a partner would want to partner in? That'd be a big deal for you to go into chronic pain, and that would be a catalyst for you as well. Is that still the plan for pain? Then going back to VX-121, educate us on what your plan is for that. Thank you. Sure. Hey, Robyn. It's Reshma. Let me do pain first. We are focused on acute pain and neuropathic pain. Those are both pain conditions, as you heard Stuart say, that we believe to be Vertex-ian and to be managed in the specialty markets manner in which we feel very comfortable. That's what we are focused on. Acute pain first and then neuropathic is what we're looking at. What you've heard us say in the past is when we get to considerations in musculoskeletal pain, for example, that is not something that we would commercialize. What we're talking about here is acute pain and neuropathic pain. Going to CF, the next wave of combination of potentiators and correctors is indeed the combination of VX-121, VX-561, and tezacaftor. Really what we're looking at here is a combination that has the potential to have superior efficacy for patients, once-a-day dosing. Also improved economics. What I mean by that is going from royalties that are in the low double digits to low single digits. We are wrapping up our conversations with regulators on that program, and we are readying that program to go to phase III, which I expect will happen later this year. Reshma, how do you get there? That'd be a great enticing opportunity for your Vertex shareholders. How do you convert people to that drug? Do you have a sense of how you would go that direction? Robyn, when we bring molecules forward into late-stage development like the 121 tezacaftor-561 combination, we are doing so because we have full expectation that we are going to be able to do something that is better for patients. We are all about first in class and best in class, we aim to out-innovate ourselves. Bringing this forward to patients is about having better efficacy, once-a-day dosing for them. There is, of course, going to be a control arm, and I fully expect the control arm to be the triple combination. Triple combination is a fantastic medicine. It has the potential to treat up to 90% of patients, and what we see in the real world in terms of efficacy has been what we saw in the clinical trials. Yes, indeed, this is a very high bar, but that is what we're aiming for. Thank you. Thank you. Our next question comes from Matthew Harrison from Morgan Stanley. Your line is now open. Great. Good afternoon. Thanks for taking the question. Stuart, I was wondering if I could just get you to comment in a little bit more detail on uptake across the European countries where you do have reimbursement, and then maybe give us some sense for the timeline of what you're thinking about in terms of the countries where you don't yet. Thanks very much. Yeah. Hey, Matt. Thanks for the question. Yeah, the uptake in the countries outside the U.S. where we do have reimbursement has been very strong. Indeed, almost superimposable on what we saw here in the U.S., both in terms of uptake, but also in terms of the levels of persistence and compliance that we've seen. That's what's really driven the strong growth of our ex-U.S. revenues in Q1 versus the same period last year. We've seen 43% growth over the same quarter last year. That's very impressive, as I say, driven by uptake in those markets where we already have reimbursement. We're continuing to make good progress in getting reimbursement in new countries. Indeed, during the first few months of this year, we have added new reimbursement agreements in places like Finland and Israel and Switzerland. We're continuing to work with countries where we have regulatory approvals but don't yet have reimbursement. In Europe, that would be countries like France and Italy and Spain. Obviously, we recently received regulatory approval in Australia. We're working with the PBAC there. Obviously, we're still waiting for regulatory approval in Canada. What I can tell you is that we continue to feel very confident that we are going to get both regulatory approvals and reimbursement agreements in those countries. That's why we continue to believe that we have very strong growth in our CF franchise in the years to come. Thank you. Our next question comes from Brian Abrahams from RBC Capital. Your line is now open. Hey there. Thanks so much for taking my questions. Just a couple of quick ones on AAT. From your ongoing work, do you have a sense for how long it might take to reach steady-state levels of functional AAT in the serum? I guess I'm just wondering if we should look at the 28-day data as a snapshot in time or reflecting the full potential of the agent. How functional would the corrected AAT detected by your assay be relative to wild type? Thanks. Yeah. Hey, this is Reshma. I can take both of those for you. From all of the work that we've done pre-clinically and in our modeling work, 28 days is going to be sufficient for us to reach steady state. I think that that data that we get from this phase II proof of concept study is going to be very helpful. With regard to whether or not the AAT, the corrected AAT is functional or not, we are indeed going to be measuring antigenic AAT levels, but we're also going to be measuring functional AAT levels, and those assays are reasonably straightforward. I don't think that that's going to pose any challenge. Thanks. Just to complete the thought, Brian, in all of the experiments that we've done, the corrected protein that we produce with the small molecule approach is the same as wild type. Got it. Thank you. Thank you. Our next question comes from Alethia Young from Cantor Fitzgerald. Your line is now open. Hey, guys. Thanks for taking my question. Congrats on the quarter. I guess I just wanted to talk a little bit about when you think we might start to see some novel conditioning regimens for CTX001. Do you think that's something that possibly could happen relatively soon after potential commercial launch or is it you think more couple of years from getting to a more tolerable conditioning regimen? Thanks. Yeah. Alethia, this is Reshma. Let me address that one for you. You know the conditioning regimen, as we talked about earlier, is really important in opening up this opportunity for the patients beyond that original 32,000 that we discussed that I think are severe enough that they would be amenable to the busulfan-based therapy, right? I do think that the initial launch will be with current conditioning regimens. That being said, I do also believe it's a matter of when, not if, gentler conditioning regimens will be here. The reason I say that is we, at Vertex, are working on gentler regimens. CRISPR Therapeutics is working on gentler regimens, as are a number of other companies. There are targets that we already know about. There are cell surface markers on hematopoietic stem cells that are the specific cells that we want to target. Those are already known, CD117, for example, and the payloads are already known as well. Remember, this gentler conditioning regimen has potential use for both oncology indications as well as what we would be looking at in terms of sickle cell and beta thalassemia. Net sum, there's a lot of work in this area. I do think it's a matter of when and not if. I think that this is something that is in the near future. Great. Thank you. Thank you. Operator, we're ready for the next question. Thank you. Our next question comes from Paul Matteis from Stifel. Your line is now open. Hey, thanks so much. I wanted to ask one more question on business development. Might be my mistake, but I've kind of gotten the sense over a couple prior quarters that you've been more open to doing larger transactions. When we look at the balance sheet this year, you made close to $10 billion in cash. What's your thought here on deal size? I guess you had said, Reshma, more of the same. Does that mean we shouldn't really expect a deal that's, say, bigger than $1 billion or so, and maybe more likely a number of kind of smaller strategic transactions? Thanks. Hey, Paul. It's all about our strategy. I laid out our business development strategy a few minutes ago. It's not about deal size, and I'm not going to add to the speculation, but you should feel high confidence that the strategy is exactly the same. Okay. Thank you. Alright, thank you. Our next question comes from Brian Skorney from Baird. Your line is now open. Hey, thanks for taking the question. I wanted to kind of get some of your insights on the gene editing approach for DMD and how to kind of think about the various mutations that occur in dystrophin and how do you correct it. We're all sort of used to the various mutations based on the exon skipping amenable groups. Even within those areas, there seem to be many unique mutations. I guess, when you think of gene editing, would you have to tackle each one of these mutations in a separate product, or is there something out of the box in terms of an edit that can be done to sort of tackle the whole disease landscape with one product? Yeah. When you talk about DMD, there are two fundamentally different approaches to this. One is with micro-dystrophins, which many others are doing, not us. Our approach, which is based in CRISPR gene editing to reframe the reading of the codon so that we can produce full-length or near full-length protein. Right? When you think about the advantages and disadvantages of each, and there are, the potential advantage to a micro-dystrophin approach is that it's a singular approach for multiple exons. The great disadvantage, of course, is that it's not anywhere close to a full-length protein. Our approach is the full-length protein, which has the great benefit of being what is exactly the protein that is what we are trying to target. Having full-length protein is critically important. What we see as the approach here is to come forward with the first exon and then to have an approach and an agreement with regulators that once we have that first exon, that the second, third, fourth would be far more efficient. Obviously, our intent is to bring those forward on shorter timelines because the bulk of the work will have been done with the first exon. Got it. Just to clarify, would the approach to the edit be to effectively edit out the entire exon 51 in the case of an exon 51 amenable mutation? Maybe I could explain it this way. What we're really talking about to get to all of the mutations in DMD is we would need a few vectors, just a few different guides, then we could get to all of the amenable mutations. Remember, the big picture item here really is a bigger difference than whether we need to have one vector or not. It will take a few vectors and a few guides, but the more important issue is the micro-dystrophins are a very short form of the protein that are not expected to provide the benefit of the full-length protein. You know that in January of this year, there was the first readout of a randomized control trial using micro-dystrophin, and it was not a positive trial. That's why the bigger picture item to keep in mind here is that our approach is a near full-length or full-length dystrophin. Great. Thank you. Aaron, thank you. Now I would now like to turn the call back over to Michael Partridge for closing remarks. Thanks, operator. Thank you all for tuning in to our first quarter conference call. The investor relations team is available tonight if you have additional questions. Have a good night, and you can now disconnect. This concludes today's conference call. Thank you for participating, and you may now disconnect. Thank you and have a great day.