All right. Good morning, everybody. Thank you for joining us here on a beautiful morning session here at the Jefferies Global Healthcare Conference here in London. I am Michael Yee, one of the senior biotechnology analysts here at Jefferies, and I'm really excited to have Stuart Arbuckle, Executive Vice President and Chief Operating Officer of Vertex Pharmaceuticals. You know, I started before we jumped on the stage here, and I said the amazing thing here about having Vertex is we have a biotech at an all-time high. So that is a great thing here, given how challenging it is in the biotech sector. So it is refreshing to have Vertex up here with us, and part of that is because there's so many things going on, so hopefully we can hit on some of the key topics in just 25 minutes. Stu, maybe if I turn it over to you, the first thing I would just ask you is to give us a very brief snapshot of some of the things that you're excited about for 2024. Obviously, with CF, with... I know people will want to talk, you know, briefly about pain, and also, you have a launch coming up for hopefully an approval for sickle cell. So a lot going on. Maybe just give us a few brief comments about what you guys are focused on for 2024, and then we'll get into some of the- Sure Some of the details. Well, thanks, Mike, for having us. Good morning, everybody. Yeah, no, it's a super exciting time to be at Vertex. We do have a lot going on. Clearly, we are continuing to execute in cystic fibrosis, getting to more and more patients around the world, as we've been doing since 2012. We were just talking about when KALYDECO was first approved- Yeah B ack in 2012, and we've continued to execute on that plan to develop medicines for all patients with CF, and we can certainly talk about that. But in addition to CF, we've also got a number of near-term commercial launches, upcoming, fingers crossed, regulators willing and data willing, with exa-cel in both sickle cell disease and transfusion-dependent beta thalassemia. We're eagerly anticipating our pain data, our phase III data in acute pain, phase II data in neuropathic pain. We also have our next-generation triple combination in phase III, the vanzacaftor-based triple combination, where we'll see data on that in the- Yeah B eginning of 2024, so a number of near-term commercial launches. And then in addition to that, we've got a great pipeline as well, which is continuing to advance in things like type 1 diabetes, APOL1-mediated kidney disease, and a number of other diseases as well, where we're already well advanced and in the clinic. Yeah. All of that success has given us a great financial position. We have great financial strength, which gives us enormous flexibility to invest in both internal innovation, which obviously we have a lot going on, but also to look at external innovations. Sure. And, so that's a focus for us. So advance the ball in CF, get ready for those near-term commercial launches, continue to advance the pipeline, and build and use our financial strength. That's what we're focused on. Absolutely. Absolutely. So a ton going on there. Maybe just starting with CF first. Obviously continuing to execute around the world with TRIKAFTA, as well as new countries and new populations. One of the interesting things is that you have an improved version of that drug with phase III data- Yeah T hat comes in early 2024, vanzacaftor. It's once a day, not twice a day- Mm-hmm A nd there's some other potential benefits. Can you just talk a little bit about how investors should look at the result that is coming in a few months, and tell us how important it is to be non-inferior, which is the primary endpoint, versus superior, which some people would like to see, and what are the commercial or ramifications of- Sure E ach of those results? Sure. Yeah, so we just announced our Q3 results, where we had another great quarter of growth in cystic fibrosis. As you said, that's built on getting to more patients around the world, expanding our label down to younger and younger age groups. We're now approved for TRIKAFTA down to two- to five-year-olds in the U.S., and we have applications pending around the world for that. That's a big part of what we're trying to do, is to get to patients younger and younger in life. Then you have to get reimbursement agreements, and then you have to launch, and the team's been doing a fantastic job around the world doing that. We updated our guidance to approximately $9.85 billion for this year, up from the previous range of $9.7 billion-$9.8 billion. If we achieve that, that'll be another year of double-digit growth for the company. It'll be our ninth successive year of double-digit growth in cystic fibrosis, which is a tribute to the way the team's executing. But as you've said, we have an improved version. Our goal in CF is always to be to get to everybody with cystic fibrosis, develop medicines for everybody with cystic fibrosis, and deliver increasing levels of clinical benefit, and that's what we believe the vanzacaftor triple combination offers us. It essentially, we are trying to get all patients to carrier levels of chloride transport, which is essentially the level of chloride transport or CFTR function that the parents of kids with CF have. The parents of kids with CF don't have the symptoms of cystic fibrosis as we know it. So if we can get children with CF down to carrier levels of chloride transport, our hope is we'll essentially be able to prevent them developing CF as we know it today. The vanzacaftor triple combination, based on our in vitro data, but also our clinical data, we believe has the prospects of delivering greater levels of CFTR function, as measured by sweat chloride. Okay. That's what we're focused on. The trial, as you said, is a head-to-head study. The regulatory endpoint is non-inferiority versus TRIKAFTA on FEV1. Obviously, that's a very high bar. TRIKAFTA delivers- Yeah I ncredible clinical benefit, but we'll also be looking at other markers of disease, such as sweat chloride. Sweat chloride is the pharmacodynamic marker of sweat chloride of CFTR function in people. And we believe if we can show equivalent levels of FEV1, but greater levels of CFTR function as measured by sweat chloride, and the fact that the combination is once a day, that will be a compelling profile to patients and physicians, and we've certainly done sufficient market research to validate that hypothesis. The fact that improved CFTR function leads to superior outcomes is not something that's not difficult. That's not hard for people to imagine. I like to imagine, but do the payers in the U.S., and do payers or governments abroad, view with confidence and agree with you that that is a profile that is reimbursable and viable over TRIKAFTA for just sweat chloride? It- Superiority versus FEV, if it happens? It's hard, it's hard to talk about payers in the hypothetical, because they're gonna want to see the data, which obviously makes sense. Right. But let me remind you, in a number of countries, we have our portfolio agreements- Sure W hich essentially envisage a world where we've already told people: "This is our strategy. This is what we're gonna deliver. We're looking to continue to increase the level of clinical benefit." So for a number of countries, we already have agreements in place- Right Which imagine our future product launches and future developments. So, and then we'll have to see what the data, the data shows. But as I said, again, the link that patients with more severe CF have worse CFTR function- Yeah A nd higher levels of sweat chloride is well known. Indeed, that's how CF is diagnosed, and so it's not a great leap of faith to imagine the reverse. If you're improving CFTR function, as shown by lower levels of CFTR, so sweat chloride, that will lead over time to improved clinical outcome. I think, because of the contracts that are, I guess, packaged, I'm not sure- Portfolio agreements. Portfolio- Yep A greements, and in the U.S., where it's more straightforward, that there should be no issue with that. One of the things that Wall Street, I think we're working to get clarity on, is trying to explain to Wall Street why sweat chloride should be a very, very relevant and acceptable surrogate for clinical outcomes, because the Street doesn't know anything kind of beyond FEV. Right. So that is something- Yeah T hat the message is that you're-- you guys are- Indeed P ushing forward. Hopefully, people understand that, but they're still trying to get comfortable with that. Yep. FEV1, just a couple of other points on that. I I mean, FEV1 is obviously a very important short-term outcome. Yes. But as you have seen from the real-world data, data we've generated with TRIKAFTA, some of those longer-term outcomes, the results are even more impressive. So if you look at reductions in hospital exacerbations- Yeah T hese very severe infections- Yeah T hat lead them to being hospitalized- Yeah D ramatic reductions. Yeah. If you look at increases in survival, dramatic increases. Yeah. If you look at reductions in lung transplants, in some countries, there hasn't been a lung transplant in a CF patient for over a year. Hmm. Because of the drug? That's because of CFTR- Yeah M odulators. Okay. The short-term impacts are important, but the long-term impacts are one of the really important clinical outcomes. Got it. Last thing I'll say is about vanzacaftor. People get very focused on the transition- Mm O n transition patients. Mm-hmm. Are people gonna switch from TRIKAFTA to vanzacaftor if it comes along, if it's the same on FEV1? What I think a lot of people are forgetting is, there are about 6,000+ patients around the world who've tried our current CFTR modulators and have had to discontinue. What% is that? It's about 10%- Okay Ish of patients who've been- Yeah. Because remember, you already have- Initiated L ike the highest compliance rates. We have the highest persistence- Ninety something C ompliance I've ever seen. Yeah, I mean, persistence is about 90% or so, so only about 10% or so of people over time ever discontinue. Okay. Then our compliance rates are in the mid-80s- Okay W hich is as high as I've ever seen in any disease area. You believe people, those- So those people have already demonstrated that they want to be on a CFTR modulator, but they've had to discontinue for a variety of different reasons. So I do believe that is a population who will be very interested in a new treatment option being available. So I know people get very focused on the switch. How many people are gonna switch from TRIKAFTA to vanzacaftor? I personally am not as focused on that, as I am on how many new patients might be interested in a new treatment option if vanzacaftor gets approved. Yeah. Beyond just the people who, Well- O ne of the convenience- Once a day. B etter efficacy, not a huge risk to switch over to the new one. That is a very, common and well accepted pharmaceutical approach to get them on the better drug. Right. As well as patients who are not on a drug, so that is additive to revenue- Correct I f those new patients get on. Okay, so the next huge opportunity that people are rightfully focused on, because of an opioid epidemic and other huge problems in the pain space- Mm-hmm I s, the opportunity for new oral pain therapy. Yep. You have Phase II chronic DPN, diabetic peripheral neuropathy, data coming up by the end of the year. So- Correct. Last I checked, we had a month and a half left, as well as phase III acute data. Talk to the audience about the chronic diabetic peripheral neuropathy opportunity versus the acute opportunity. Sure. One is a short-term duration, but a lot of people. The other is a chronic indication, a lot of people as well. But people are thinking about this as chronic is really the big one, and acute, smaller- Sure B ut still important. So let's just go back to why are we doing this? There hasn't been a new class of pain med in decades. We're still using the same things we've used for 30, 40, 50 years, reformulated version, but there hasn't been a new class of pain med in absolutely decades. And the approach we're taking is to try and attack the underlying human biology of pain, which is the way pain is signaled to the brain. So there are specific pain receptors. There are specific pain neurons in the body. That's all they do, is transmit the pain signal. And essentially, there are two sodium channels. One initiates the pain signal, that's NaV1.7. The other one propagates the pain signal, that's NaV1.8. So we and many, many others for decades have been working in the pain space. In fact, we've been working on pain longer than we've been working on cystic fibrosis, so over 25 years. So what we have with VX-548 is a very potent and selective NaV1.8 inhibitor, which we've developed and demonstrated in phase 2 studies in acute pain. Has a great profile. As you said, we have 2 different studies ongoing. So let's talk about the pain market. We segment the pain market essentially into 3 areas: acute pain, neuropathic pain, which is obviously chronic pain, and then there is kind of chronic nociceptive pain, which is everything else you might think of. It could be osteoarthritic knee pain. Back pain. It could be lots of back pain, apart from lumbosacral radiculopathy, which we'll come back to. Okay. All right. So but there's a whole host of other inflammatory conditions, nociceptive pain, huge, huge opportunity, but very primary care. The areas we're focused on are acute and chronic neuropathic pain. So acute pain, let's just talk about the U.S., where we've got the best data on the number of patients. Acute pain, there's approximately 80 million patients in the U.S. each year will have acute pain episodes that require a prescription medication, 80 million a year. There are billions of prescriptions written. The vast majority of them are generic. As I said, there's not been a new class of pain med in absolute decades. Despite that, this is a multi-billion-dollar market in the U.S. alone. Our belief is, if we can bring a product forward, which has great efficacy on pain and doesn't have the adverse effects, including addictive potential of things like opioids, that will be a huge opportunity in acute pain in the U.S. And by the way, when we say acute pain, talking about severe acute pain, we're talking about first, there's one in bunionectomy, one in abdominoplasty, and one in other. Correct. We're not talking about pain where they're prescribing kind of low-level pain. Yeah. So we are- Severe pain- Yes A fter, like, a procedure. Yeah. Well, we are seeking a label for moderate to severe acute pain. Okay. That's the label we're seeking from the FDA, irrespective of the cause of that pain. Okay. So we are doing studies, as you rightly said, in phase 3, one in abdominoplasty, one in bunionectomy, and then we have an all-comers study. Okay. We're doing those 'cause those are well-established pain models for regulatory approval, but the label we're seeking is for broad, moderate to severe acute pain, irrespective of the cause. So it could be surgery, but it could be trauma, it could be a fall, it could be a burn. Acute pain is essentially defined by time. Okay. So it's the length of the prescription that you would receive. It's the treatment of pain for less than 90 days. Okay. So that's the acute pain market. The, as you said, we have three studies ongoing. We will be unblinding all of that data, looking at it, and reporting out on it all at the same time because they are essentially a package of studies, and we need to know exactly what's happening in all of them to know exactly what our path forward will be. Okay. That will be in the beginning of 2024, when we will have all that data, have looked at it, analyzed it, and be in a position to be able to decide what we're gonna do and share that data. That's acute pain- Okay P hase 3 program. Okay. Neuropathic pain, we're in phase 2. Neuropathic pain is an umbrella term that describes a whole category of different diseases but are all characterized by damage to the nerves. Diabetic peripheral neuropathy is one type of it, small fiber neuropathy, trigeminal neuralgia. There's a variety of different causes of pain, but they're all in this bucket of neuropathic pain. We have a phase 2 study ongoing in diabetic peripheral neuropathy. We will have the results. We'll unblind that study. We'll look at those results and report out on those by the end of this year. Neuropathic pain in total, there's about 10 million people in the U.S.- Right W ho receive a prescription for neuropathic pain every year. As I said, it's a collection of areas. We've just said on our Q3 call that we are starting another phase two study in a different type of neuropathic pain called lumbosacral radiculopathy. Right. Between those two pain states, of the total number, the 10 million patients who have neuropathic pain, about 20% of them have diabetic peripheral neuropathy, and about 40% of them have LSR, lumbosacral radiculopathy. So that's where that program is. Okay. We'll have the DPN data by the end of this year. We're just beginning the study in LSR. Again, what we're looking for is a package of data that will enable us to get a broad label for neuropathic pain. Right. That is our intent. As you said, neuropathic pain, fewer patients at 10 million, but those patients are being treated chronically. Yes. These are chronic- Yes P ain conditions. I would remind folks that, Lyrica, I guess, Neurontin. Yep These are the big- Correct B randed drugs that were approved. There's others, but those were- Yep T wo of the biggest ones. Lyrica was doing around $5 billion-$7 billion peak. Correct. That's the opportunity. That was, like, a decade ago. Our estimate is about $3 billion of that was in neuropathic pain. Okay Because it had a range of different indications. Okay. Not surprisingly, I mean, these are- Okay R epurposed CNS medicines. Right. I mean, that's the thing to remember about these things. They work in the CNS. They're not actually. They're changing the perception of pain. Right. They're not actually tackling the underlying cause of pain. A bit like opioids, they work centrally. These are repurposed- Yeah A nxiolytics, antiepileptics, et cetera. So, two questions. One is, coming away from the third quarter earnings call, one of the big announcements was that Vertex was starting the second pain- Yes P hase two. So naturally, people said, "Well, how can you invest..." And you're Chief Operating Officer: "How can you guys invest X amount?" Throw out a number. $50 million, you can tell me if that's kind of a phase two result. $50 million to co-start a study. You start $50 million, but the first pain study, chronic neuropathic pain, is literally reading out a month. Yeah. So he goes, "Stu, how are you gonna spend $50 million? Why don't you just wait a month to see the results? Or maybe Vertex already knows that the results are good. Yeah, so let me address that last point. We do not know the results. The results have not been unblinded. Nobody in the company has seen the results of the ongoing DPN study. That's not why we began the study in LSR. The reason why we've been looking at LSR is the underlying biology is exactly the same. It's caused by nerve impairment. That's what's causing LSR. The reason why we were able to start the DPN study previously is DPN is a tried and tested type of neuropathic pain. Mm. Multiple products have been approved for diabetic peripheral neuropathy, including Lyrica. So there's an established regulatory path. There's an established market for it. So that's why we were looking at DPN first. Nothing has ever been approved in the United States for LSR. So we had to work with the regulators to work through a path of what would the studies look like that would give them and us confidence that we're working in that disease area. We just concluded those discussions with the regulators. That's what's allowed. Okay U s to start the study. It's a very important population. As I said, 40% of patients—40% of the 10 million patients treated for neuropathic pain in the U.S. are treated because they have a diagnosis of LSR. Okay. It's a very important disease in its own right. It's almost half of the y ou said 40%. It's 40, it's just over 40%. It's an important indication. It's very important. So, uh- Nothing approved. One of the data points that are coming up when this result reads out, which is in a month and a half or so, within the next- Within a month and a half, yeah. Is that, you're trying to beat a placebo in diabetic peripheral neuropathy, that is the primary analysis, and there's also an active control arm of Lyrica. Right. Can you explain to investors how important it is to compare to that result? What is the relevance of that? Some people are like, "Do you expect that your drug is as good as Lyrica? You want it to be billions of dollars. If it's numerically lower, how do we-- how does, how does... How important is that? How relevant is that? Yep. Is it possibly better than Lyrica? Yep. Can you talk about those different? Sure S cenarios, and how to interpret- Yep T he active control arm? So I think the first important thing is to understand the design of the study. The design of the study is there to show proof of concept that VX-548 works in diabetic peripheral- To beat a placebo, yes. So we are comparing patients being treated with their own baseline. We have a reference arm, which is Lyrica. Yeah. It is there for context. The study is not gonna be big enough to be able to statistically compare between any of the doses in phase 2 for 548 and the Lyrica arm. It is there for context because we know it's gonna be an important thing for us to consider as we go into phase 3. But you will not be able to do statistical comparisons between whatever we see with the doses of 548- Okay A nd what we see with the Lyrica arm. Okay. I would encourage people to look back. We did the same thing in phase two- Yes I n acute pain. Yes. In our acute pain studies, we compared 548 with placebo. We also had a reference arm, which had an opioid in it, but again, it was there for context. Yes F or us to look at- Yes T o provide some reference. It's not there for statistical comparisons. If we were trying to power a phase 2 study for that, it would be huge. Well, just- That's not what we want to do. So is the idea, and I've actually never asked David Altschuler this. Is the idea that the efficacy level of this drug similar to a Lyrica? If you go back to the acute studies, it was similar to Vicodin. I'll use the word similar. And is that the idea that this is about as good as those drugs, or is it better or? We are looking- What's the best- O verall for it to have a better benefit-risk profile than anything else that's out there. So let's think about opioids. Opioids have great efficacy- Okay I n general- Okay But a terrible tolerability profile, not just the addictive potential, and they have addictive potential. Okay. Overall, we're looking for a package of data which has a better benefit-risk profile. Same thing with the gabapentinoids and things like that. They have variable efficacy. They don't work in everybody, and they also have a significant tolerability profile, largely by the fact that they work in the CNS. Okay. Again, overall, we're looking for a better benefit-risk profile. That could be better efficacy, that could be equivalent efficacy and better side effects. Uh-huh. Overall, we're looking for a better benefit-risk profile in both acute pain and in neuropathic pain against the relevant standards of care, and the relevant standards of care in acute pain is typically opioids. Yeah. In neuropathic pain, it's typically considered to be the gabapentinoids. I think, and I'll say this, too, with the acute studies that are reading out, if you guys have a clinically meaningful, and I'd say Wall Street views clinically meaningful as, in kind of any disease, at least a 15% or 20% reduction or improvement in the result, that is a win. You guys will file that in acute. In chronic, a win against placebo of 20% is solid. I'm sure you're gonna advance forward. Wall Street's like, "Is it as good as the control arm?" You know, they wanna use it as a reference point, and so people are trying to look at that. Understood. Okay. Lastly, in just two minutes, I would be remiss to not say that obviously you have a PDUFA date in the U.S. for sickle cell and transfusion-dependent beta thalassemia. I'll start with just sickle cell, because that is a majority of the U.S. market- Yep C ommercial opportunity. Your confidence on approval and the launch, can you just tell us in a minute or so how to think about and understand the launch? Because people have watched gene therapy not be so great. Sure. $2 million. So yeah, we have a PDUFA date- Yeah In the U.S. for Sickle Cell Disease- Yep I s December the eighth. December eighth. Our PDUFA date for transfusion-dependent thalassemia is March thirtieth. Ah. So the approval is just in sickle cell disease. As you say, sickle cell disease is the bigger patient population in the U.S. Overall, we think there's about 32,000 patients worldwide who are in, sorry, in the U.S. and the E.U., who are likely to be good candidates for exa-cel, given the current busulfan-based conditioning regimen. So these are patients at the more severe end of the scale, who are experiencing multiple pain crises or having transfusions every three or four weeks. Of that 32,000, about 25,000 are sickle cell disease. Of those, the majority, about 18,000 or so, are in the United States. Awesome, okay. So it is the bigger opportunity between the U.S. and Europe. It's the bigger opportunity in the U.S. Our confidence in the approval, the data looks great. As you probably know, we had an advisory committee with the FDA just, was it last week or the week before? It was very recently. Yep. which was focused specifically not on the benefit risk profile, which they seemed to accept- Yeah B ut on the question of off-target editing. Yeah. Yeah. Yeah. And so we are feeling good about the data. Obviously, it's in the gift of the FDA, so we await their judgment. But what I will tell you is we're launch-ready. We're excited about the opportunity to bring this to market. What we have said is, yeah, this is not this is a complex and long procedure for a patient to go through. This is a multi-month procedure- Many months to get the -that somebody has to go through. So if you're a sickle cell disease patient, once you and your physician have identified that you want to have a gene therapy like, our CRISPR-Cas9 based gene editing therapy, they have to have transfusions for eight weeks to prepare them for the mobilization and apheresis phase. Then they have to come in, often for two rounds of apheresis, to collect their stem cells. Then those cells are sent to our manufacturing facilities to be edited. Mm. Then they have to be tested and quality controlled before they're released. Then they have to be shipped back to the transplant center. Then the patient has to schedule that- Yep I nto their lives- Yep because they will probably be in hospital for some 4-6 weeks as part of the procedure, because you have to have your bone marrow- Yep Ablated to receive the therapy. So this is a multi-month journey that the patient is embarking on. Yep. I just think that's an important consideration- Yep F or people to think about. This is not like they're all going to get initiated on day one. Let's put it that way. Once we get approved, there will be some time to, as we get to 2024, for actually- Yep getting the drug. Correct. We have some time to prepare for that, educate, and Wall Street will be focused on that, as well as the pain results coming out. Yep. A lot to look forward to. Appreciate it, and we all eagerly look forward to the results. Thank you, Mike. Appreciate it. Thanks, sir. Appreciate it.